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Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander women. Participants in this study included 1734 Asian (n = 785 case and 949 control participants), 266 Native Hawaiian/Pacific Islander (n = 99 case and 167 control participants), 1149 Hispanic (n = 505 case and 644 control participants), and 24 189 White (n = 9981 case and 14 208 control participants) from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% CIs for risk associations by race and ethnicity. Heterogeneity in EOC risk associations by race and ethnicity (P ≤ .02) was observed for oral contraceptive (OC) use, parity, tubal ligation, and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in Native Hawaiian/Pacific Islander and Asian women. The inverse association for tubal ligation with risk was most pronounced for Native Hawaiian/Pacific Islander participants (odds ratio (OR) = 0.25; 95% CI, 0.13-0.48) compared with Asian and White participants (OR = 0.68 [95% CI, 0.51-0.90] and OR = 0.78 [95% CI, 0.73-0.85], respectively). Differences in EOC risk factor associations were observed across racial and ethnic groups, which could be due, in part, to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies. This article is part of a Special Collection on Gynecological Cancers., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Purpose: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC)., Experimental Design: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss., Results: RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1., Conclusions: Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation., (©2024 The Authors; Published by the American Association for Cancer Research.)

Aims: Mucinous ovarian carcinoma (MOC) is a rare ovarian cancer histotype with generally good prognosis when diagnosed at an early stage. However, MOC with the infiltrative pattern of invasion has a worse prognosis, although to date studies have not been large enough to control for covariables. Data on reproducibility of classifying the invasion pattern are limited, as are molecular correlates for infiltrative invasion. We hypothesized that the invasion pattern would be associated with an aberrant tumour microenvironment., Methods and Results: Four subspecialty pathologists assessed interobserver reproducibility of the pattern of invasion in 134 MOC. Immunohistochemistry on fibroblast activation protein (FAP) and THBS2 was performed on 98 cases. Association with survival was tested using Cox regression. The average interobserver agreement for the infiltrative pattern was moderate (kappa 0.60, agreement 86.3%). After reproducibility review, 24/134 MOC (18%) were determined to have the infiltrative pattern and this was associated with a higher risk of death, independent of FIGO stage, grade, and patient age in a time-dependent manner (hazard ratio [HR] = 10.2, 95% confidence interval [CI] 3.0-34.5). High stromal expression of FAP and THBS2 was more common in infiltrative MOC (FAP: 60%, THBS2: 58%, both P < 0.001) and associated with survival (multivariate HR for FAP: 1.5 [95% CI 1.1-2.1] and THBS2: 1.91 [95% CI 1.1-3.2])., Conclusions: The pattern of invasion should be included in reporting for MOC due to the strong prognostic implications. We highlight the histological features that should be considered to improve reproducibility. FAP and THBS2 are associated with infiltrative invasion in MOC., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Background: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system., Methods: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong)., Results: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis., Conclusions: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management., (© 2023. The Author(s).)

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC., (© 2023 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

Background: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC., Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated., Results: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss., Conclusion: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Objective: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients., Methods: We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration., Results: Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates., Conclusion: In summary, MOCs are mostly immunogenically 'cold', suggesting they may have limited response to current immunotherapies., Competing Interests: Declaration of Competing Interest NSM has received a travel grant from NanoString technologies, unrelated to this work. DDLB has received research support grants from Roche-Genentech, AstraZeneca, and BeiGene (paid to institution); and personal consulting fees from Exo Therapeutics, that are outside the submitted work. MF has participated in Advisory Boards/Consulting from Astra Zeneca, Novartis, GSK, Takeda, Lilly, MSD Eisei and received honoraria/speakers' fees from AstraZeneca, GSK, ACT-Genomics; Research funding to institution: from AstraZeneca, Novartis, Beigene, all unrelated to this work. ADeF has received funding from AstraZeneca, unrelated this work. NS has received honoraria for invited participation in advisory boards hosted by Astra-Zeneca-MSD and Glaxo SmithKline, unrelated to this work. UM had stock ownership in Abcodia until October 2021, and UCL had a license agreement (2011–2021) with Abcodia not related to this work. BHN is a co-founder of Innovakine Therapeutics Inc., unrelated to this work., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Recently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC., Methods: Two prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis., Results: Consistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p < 0.0001). GMNN protein expression was not significantly associated with overall HSGC patient survival. However, HGSCs with >35% GMNN expression showed a trend for better outcomes, though this was not significant., Conclusion: We provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry., (© 2022. The Author(s).)

Purpose: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features., Experimental Design: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55)., Results: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%)., Conclusions: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies., (©2022 The Authors; Published by the American Association for Cancer Research.)

ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis-associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas, through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8 + tumour-infiltrating lymphocytes (CD8 + TILs), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOCs and 25% of ENOCs. We found no associations between ARID1A loss and outcomes, stage, age, or CD8 + TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p = 0.012) and was associated with MMRd (p < 0.001) and the presence of CD8 + TILs (p = 0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOCs we also observed an association with ARID1A loss-of-function mutation as a result of small indels (p = 0.035, versus single nucleotide variants). In ENOC, the association with ARID1A loss, CD8 + TILs, and age appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8 + TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss-of-function mutations in endometriosis-associated ovarian cancers and brings clarity to the prognostic significance. © 2021 The Pathological Society of Great Britain and Ireland., (© 2021 The Pathological Society of Great Britain and Ireland.)

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36-0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Anti-microtubule agents are widely used to treat ovarian cancers, but the efficacy is often compromised by drug resistance. We investigated co-targeting the actin/tropomyosin cytoskeleton and microtubules to increase treatment efficacy in ovarian cancers and potentially overcome resistance., Methods: The presence of tropomyosin-3.1 (Tpm3.1) was examined in clinical specimens from ovarian cancer patients using immunohistochemistry. Combinatorial effects of an anti-Tpm3.1 compound, ATM-3507, with vinorelbine and paclitaxel were evaluated in ovarian cancer cells via MTS and apoptosis assays. The mechanisms of action were established using live- and fixed-cell imaging and protein analysis., Results: Tpm3.1 is overexpressed in 97% of tumour tissues (558 of 577) representing all histotypes of epithelial ovarian cancer. ATM-3507 displayed synergy with both anti-microtubule agents to reduce cell viability. Only vinorelbine synergised with ATM-3507 in causing apoptosis. ATM-3507 significantly prolonged vinorelbine-induced mitotic arrest with elevated activity of the spindle assembly checkpoint and mitotic cell death; however, ATM-3507 showed minor impact on paclitaxel-induced mitotic defects. Both combinations substantially increased post-mitotic G1 arrest with cyclin D1 and E1 downregulation and an increase of p21 Cip and p27 Kip ., Conclusion: Combined targeting of Tpm3.1/actin and microtubules is a promising treatment strategy for ovarian cancer that should be further tested in clinical settings., (© 2021. The Author(s), under exclusive licence to Cancer Research UK.)

Human biobanks are recognised as vital components of translational research infrastructure. With the growth in personalised and precision medicine, and the associated expansion of biomarkers and novel therapeutics under development, it is critical that researchers can access a strong collection of patient biospecimens, annotated with clinical data. Biobanks globally are undertaking transformation of their operating models in response to changing research needs; transition from a 'classic' model representing a largely retrospective collection of pre-defined specimens to a more targeted, prospective collection model, although there remains a research need for both models to co-exist. Here we introduce the Health Science Alliance (HSA) Biobank, established in 2012 as a classic biobank, now transitioning to a hybrid operational model. Some of the past and current challenges encountered are discussed including clinical annotation, specimen utilisation and biobank sustainability, along with the measures the HSA Biobank is taking to address these challenges. We describe new directions being explored, going beyond traditional specimen collection into areas involving bioimages, microbiota and live cell culture. The HSA Biobank is working in collaboration with clinicians, pathologists and researchers, piloting a sustainable, robust platform with the potential to integrate future needs., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.

Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7 - /CK20 + /CDX2 + /PAX8 - . This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.

Objective: Advanced stage mucinous ovarian cancers are diagnostically and therapeutically challenging. Histotype specific trials have failed due to low recruitment after excluding non-ovarian primaries. Mucinous ovarian cancers are commonly metastatic from other sites however lack definitive diagnostic markers. We suggest a classification of mucinous ovarian cancers of uncertain primary origin 'MO-CUPs' in clinical trials. This study aims to identify drug targets to guide treatment and future trials., Methods: We analyzed a large de-identified, multi-platform tumor profiling dataset of MO-CUPs enriched for advanced stage and recurrent cases submitted to Caris Life Sciences. Available data included a 45-gene next-generation sequencing (NGS) panel, gene amplification of HER2 and cMET and 18 immunohistochemical (IHC) markers of drug sensitivity/resistance., Results: Mucinous tumors from 333 patients were analyzed, including 38 borderline tumors and 295 invasive cancers. The most common mutations in a subset (n = 128) of invasive cancers were KRAS (60%), TP53 (38%), PIK3CA (13%) and PTEN (9%). Borderline tumors had higher rates of BRAF mutations, and PGP and TOP2A overexpression than invasive cases. KRAS mutant invasive cancers had lower expression of thymidylate synthase (p = 0.01) and higher expression of TUBB3 (p = 0.01) than KRAS wildtype tumors., Conclusions: To our knowledge, this is the largest series profiling mucinous ovarian cancers and almost certainly includes cases of ovarian and non-ovarian origin. Given the difficulty recruiting patients to histotype-specific trials in rare subsets of ovarian cancer, it may be more important to focus on identifying potential treatment targets and to personalise treatment and design clinical trials in MO-CUPS agnostic of primary site to overcome these issues., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Iatrogenic immunosuppression is a strong risk factor for non-Hodgkin lymphoma (NHL) but the dose-related association between individual immunosuppressive agents and NHL risk is unknown. We conducted a population-based cohort study of 4131 adult Australian liver, heart and lung transplant recipients (1984-2006). We ascertained NHL incidence by probabilistic record linkage between transplant registries and the Australian Cancer Database, and abstracted risk factor data at transplantation and at regular intervals thereafter from medical records. We estimated adjusted hazard ratios (HR) for early (<1 year after transplantation; n = 29) and late (≥1 year; n = 61) NHL using the Fine and Gray proportional subdistribution hazards model that accounted for death as a competing risk. After adjustment for immunosuppression, the risk of both early and late NHL did not significantly differ by organ type. In final models, higher mean daily doses of azathioprine were associated with increased risk of both early [HR 2·20, 95% confidence interval (CI): 1·21-4·01] and late NHL (HR 1·78, 95% CI: 1·12-2·84). There was no association between any other maintenance immunosuppressive agent and NHL risk. This study provides evidence that differences in immunosuppression may explain variation in NHL incidence by organ type, and high doses of azathioprine may independently predict NHL risk., (© 2016 John Wiley & Sons Ltd.)

Background: Iatrogenic immunosuppression is a risk factor for lip cancer but the determinants are unknown., Objective: We sought to quantify the association between the type, dose, and duration of iatrogenic immunosuppression and lip cancer risk in solid organ transplant recipients., Methods: We conducted a population-based cohort study of all adult Australian liver, heart, and lung transplant recipients from 1984 to 2006 (n = 4141). We abstracted longitudinal data from medical records and ascertained incident lip cancer (n = 58) and deaths (n = 1434) by linkage with national registries. We estimated multivariable hazard ratios (HR) for lip cancer using the Fine and Gray proportional subdistribution hazards model, accounting for death as a competing risk., Results: Lip cancer risk (n = 58) increased with high mean daily dose of azathioprine (HR 2.28, 95% confidence interval [CI] 1.18-4.38), longer duration of immunosuppression (HR 9.86, 95% CI 2.10-46.3), increasing year of age at transplantation (HR 1.14, 95% CI 1.04-1.25), earlier transplantation era (HR 8.73, 95% CI 1.11-68.7), and history of smoking (HR 2.71, 95% CI 1.09-6.70)., Limitations: Data on potential confounders such as personal solar ultraviolet radiation exposure were not available., Conclusion: Higher doses of azathioprine increase lip cancer risk, with implications for managing immunosuppressed populations and our understanding of the relationship between solar ultraviolet radiation and lip cancer., (Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Cancer is the number one cause of death in Australia with colorectal cancer being the second most common cancer type. The translation of cancer research into clinical practice is hindered by the lack of integration of heterogeneous and autonomous data from various data sources. Integration of heterogeneous data can offer researchers a comprehensive source for biospecimen identification, hypothesis formulation, hypothesis validation, cohort discovery and biomarker discovery. Alongside the increasing prominence of big data, various translational research tools such as tranSMART have emerged that can converge and analyse different types of data. In this study, we show the integration of different data types from a significant Australian colorectal cancer cohort. Additionally, colorectal cancer datasets from The Cancer Genome Atlas were also integrated for comparison. These integrated data are accessible via http://www.tcrn.unsw.edu.au/transmart. The use of translational research tools for data integration can provide a cost-effective and rapid approach to translational cancer research.

Unconfounded comparative data on the type and dose of immunosuppressive agents among solid organ transplant recipients are sparse, as are data on longitudinal immunosuppressive therapy since transplantation. We addressed this issue in a population-based cohort of Australian liver (n = 1895), heart (n = 1220), and lung (n = 1059) transplant recipients, 1984-2006. Data on immunosuppressive therapy were retrospectively collected at discharge, three months, and one, five, 10, and 15 yr after first transplant. We computed unadjusted and adjusted estimates for the association between the type and dose of immunosuppressive therapy and organ type. After adjustment for confounders, use of induction antibody and maintenance corticosteroids was more common in heart and lung compared to liver recipients (p < 0.001), and antibody therapy for rejection more common in liver recipients (p < 0.001). Liver recipients were more likely to receive calcineurin inhibitor monotherapy, with or without corticosteroids, compared to heart and lung recipients (p < 0.001). Liver recipients consistently received lower doses of azathioprine than heart and lung recipients (p < 0.001). These differences in immunosuppression may partly explain variations in immunosuppression-related morbidity by transplanted organ, for example, malignancy risk. Longitudinal changes in the type and the dose of immunosuppressive therapy over time since transplantation also demonstrate the need for time-dependent data in observational research., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To examine the validity and impact of record linkage using name code compared to full name records., Methods: A registry of 45,419 opioid substitution clients (1985-2007) was linked with national population-based death and cancer registries using registrant's name, date of birth, sex, state, postcode and date of death. Records were linked using full name and then using the first two letters of the given and surname (2×2 name code). Sensitivity and specificity were computed and regression analysis used to identify factors related to linkage accuracy. Standardised mortality ratios (SMR) and standardised cancer incidence ratios (SIR) were estimated., Results: The sensitivity and specificity of name code compared to full name linkage were 65.31% and 99.91% for death records and 76.81% and 99.89% for cancer records. Registrants' age and sex and accuracy of the registries were associated with risk of false linkages. Death and cancer risks (SMR 6.98, 95%CI 6.77-7.19; SIR 1.16, 95%CI 1.08-1.24) were significantly under-estimated using name code linkage (SMR 4.39, 95%CI 4.23-4.56; SIR 0.92, 95%CI 0.85-0.99)., Conclusion: Record linkage using 2×2 name code has low sensitivity but high specificity, resulting in conservative estimates of death and cancer risk. This may translate to meaningful differences in outcomes., (© 2014 Public Health Association of Australia.)

There are limited data characterizing the subtype-specific incidence of lymphoid neoplasms in the World Health Organization (WHO) Classification era. Data were obtained on all incident lymphoid neoplasms registered in Australia during 1982-2006. Subtypes were grouped using the InterLymph nested hierarchical classification, based on the 2008 WHO Classification. Temporal trends were examined using Joinpoint regression; average annual percentage change in incidence was computed. Multiple Poisson regression was used to compare incidence by sex and age. The incidence of all non-Hodgkin lymphoma (NHL) increased by 2.5%/year during 1982-1996 and was stable thereafter. During 1997-2006, several mature B- and natural killer (NK)-/T-cell NHL subtypes increased in incidence, including diffuse large B-cell (1.3%/year), follicular (2.5%/year), Burkitt (6.8%/year), marginal zone (13.2%/year), mantle cell (4.2%/year), peripheral T-cell lymphoma (4.7%/year) and plasmacytoma (7.1%/year). While chronic lymphocytic leukemia incidence was stable, small lymphocytic lymphoma incidence declined (8.1%/year). Hodgkin lymphoma (HL) incidence increased during 1997-2006 (2.2%/year), both classical (4.3%/year) and nodular lymphocyte predominant (12.1%/year) HL. Diagnostic artifact, evidenced by a sustained decline in the incidence of NHL not otherwise specified (NOS; 5.8%/year) and lymphoid neoplasms NOS (5.6%/year), limits the interpretation of temporal trends for some subtypes. A marked male predominance was observed for almost all subtypes. Incidence of mature B- and NK-/T-cell NHL subtypes increased sharply with age, except for Burkitt lymphoma/leukemia. For HL subtypes, a bimodal age distribution was only evident for nodular sclerosis HL. Variation in incidence patterns over time and by sex and age supports etiological differences between lymphoid neoplasm subtypes., (© 2014 UICC.)

Background: Cancer of unknown primary (CUP) is a common cancer yet little is known about the reliability of incidence data., Methods: We audited 574 CUP (C80.9) diagnoses (median age 81 years) registered by the New South Wales (NSW) Central Cancer Registry (2004-2007) in a cohort of Australian Government Department of Veterans' Affairs clients. The registry did not clarify diagnoses with notifiers during this period due to interpretation of privacy legislation. For the audit, current registry practice was applied by seeking additional information from CUP notifiers and reclassifying diagnoses as necessary. In addition, clinicopathological characteristics were extracted from notifications. Fisher's exact test and Student's t-test were used to compare the demographic and clinicopathological characteristics of the CUP subgroups. Age/sex-standardised CUP incidence rates and 95% confidence intervals were calculated, standardised to the 2001 Australian population., Results: 172 (30.0%) cases were reclassified to a known primary site, mostly cutaneous, and nine (1.6%) were found to be non-malignant diagnoses. After the audit the age/sex-standardised CUP incidence rates decreased from 26.0 (95% CI 21.2-30.8) to 15.9 (95% CI 12.5-19.3) per 100,000 person-years. Of the 393 remaining CUP cases, 202 (51%) were registered on the basis of a clinical diagnosis (46 by death certificate only) and 191 (49%) by pathological diagnosis (79 by cytology alone). Compared to cases with a pathological diagnosis, cases with a clinical diagnosis were older (85.6 vs. 82.0 years, p<0.001), and the reported number and location of metastases differed (p<0.001); metastatic sites were more likely to be unspecified for clinical diagnoses (36.1% vs. 4.2%)., Conclusions: Cancer registry processes can markedly influence CUP incidence. Future population-based CUP research should take this into account, and consider stratification by basis of diagnosis due to differences in patient and tumour characteristics., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Transplant recipients are at elevated risk of melanoma and may have poorer outcomes than nontransplant recipients. We conducted a national, population-based, matched cohort study of Australian kidney transplant recipients and randomly selected members of the general population matched for age, sex, state and year of diagnosis with invasive cutaneous melanoma (1982-2003). Melanoma histopathological characteristics were extracted from cancer registry notifications and death data were obtained from the National Death Index (1982-2011). Histopathology was compared using conditional logistic regression and overall survival analyzed using Cox proportional hazard models. Compared to melanomas in nontransplant recipients (n = 202), melanomas in transplant recipients (n = 75) had a higher Clark's level (p = 0.007) and higher American Joint Committee on Cancer pathologic stage (p = 0.002), but not Breslow thickness (p = 0.11). Posttransplant melanoma conferred higher risk of death (adjusted hazard ratio 4.26, 95% CI 2.71-6.72, p < 0.001) after adjustment for the matching variables, pathologic stage, histological type and anatomic site. This was not explained by transplantation alone. Melanomas in transplant recipients are more invasive than those in nonrecipients. More aggressive tumor behavior is also supported by a markedly poorer outcome. Treatment algorithms developed for the general population with melanoma may not apply to transplant recipients. A review of patient education and skin cancer screening guidelines is warranted., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Given the uncertainty surrounding solar ultraviolet radiation (UVR) exposure and risk of lymphoid neoplasms, we performed an ecological analysis of national Australian data for incident cases diagnosed between 2002 and 2006. Subtype-specific incidence was examined by latitude band (<29°S, 29-36°S, ≥37°S), a proxy for ambient UVR exposure, using multiple Poisson regression, adjusted for sex, age-group and calendar year. Incidence increased with distance from the equator for several mature B-cell non-Hodgkin lymphomas, including diffuse large B-cell [incidence rate ratio (IRR) = 1.37; 95% confidence interval (CI): 1.16-1.61 for latitude ≥37°S relative to <29°S], lymphoplasmacytic (IRR = 1.34; 95% CI: 1.12-1.61), mucosa-associated lymphoid tissue (IRR = 1.32; 95% CI: 0.97-1.80) and mantle cell lymphoma (IRR = 1.29; 95% CI: 1.05-1.58), as well as plasmacytoma (IRR = 1.52; 95% CI: 1.09-2.11) and plasma cell myeloma (IRR = 1.15; 95% CI: 1.03-1.27). A similar pattern was observed for several mature cutaneous T-cell neoplasms, including primary cutaneous anaplastic large cell lymphoma (IRR = 4.26; 95% CI: 1.85-9.84), mycosis fungoides/Sézary syndrome (IRR = 1.72; 95% CI: 1.20-2.46), and peripheral T-cell lymphoma not otherwise specified (NOS) (IRR = 1.53; 95% CI: 1.17-2.00). Incidence of mixed cellularity/lymphocyte-depleted (IRR = 1.60; 95% CI: 1.16-2.20) and nodular sclerosis Hodgkin lymphoma (IRR = 1.57; 95% CI: 1.33-1.85) also increased with distance from the equator. Many of these subtypes have a known association with infection or immune dysregulation. Our findings support a possible protective effect of UVR exposure on the risk of several lymphoid neoplasms, possibly through vitamin D-related immune modulation critical in lymphomagenesis., (Copyright © 2013 UICC.)

Evidence is sparse on the relative mortality risk posed by de novo cancers in liver and cardiothoracic transplant recipients. A retrospective cohort study was conducted in Australia using population-based liver (n = 1926) and cardiothoracic (n = 2718) registries (1984-2006). Standardized mortality ratios (SMRs) were computed by cancer type, transplanted organ, recipient age and sex. During a median 5-year follow-up, de novo cancer-related mortality risk in liver and cardiothoracic recipients was significantly elevated compared to the matched general population (n = 171; SMR = 2.83; 95% confidence interval [95%CI], 2.43-3.27). Excess risk was observed regardless of transplanted organ, recipient age group or sex. Non-Hodgkin lymphoma was the most common cancer-related death (n = 38; SMR = 16.6; 95%CI, 11.87-22.8). The highest relative risk was for nonmelanocytic skin cancer (n = 23; SMR = 49.6, 95%CI, 31.5-74.5), predominantly in males and in recipients of heart and lung transplants. Risk of death from de novo cancer was high in pediatric recipients (n = 5; SMR = 41.3; 95%CI, 13.4-96.5), four of the five deaths were non-Hodgkin lymphoma. De novo cancer was a leading cause of late death, particularly in heart and liver transplantation. These findings support tailored cancer prevention strategies, surveillance to promote early detection, and guidelines for managing immunosuppression once cancer occurs., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Population-based evidence on the relative risk of de novo cancer in liver and cardiothoracic transplant recipients is limited. A cohort study was conducted in Australia using population-based liver (n = 1926) and cardiothoracic (n = 2718) registries (1984-2006). Standardized incidence ratios (SIRs) were computed by cancer type, transplanted organ and recipient age. Cox regression models were used to compare cancer incidence by transplanted organ. During a median 5-year follow-up, the risk of any cancer in liver and cardiothoracic recipients was significantly elevated compared to the general population (n = 499; SIR = 2.62, 95%CI 2.40-2.86). An excess risk was observed for 16 cancer types, predominantly cancers with a viral etiology. The pattern of risk by cancer type was broadly similar for heart, lung and liver recipients, except for Merkel cell carcinoma (cardiothoracic only). Seventeen cancers (10 non-Hodgkin lymphomas), were observed in 415 pediatric recipients (SIR = 23.8, 95%CI 13.8-38.0). The adjusted hazard ratio for any cancer in all recipients was higher in heart compared to liver (1.29, 95%CI 1.03-1.63) and lung compared to liver (1.65, 95%CI 1.26-2.16). Understanding the factors responsible for the higher cancer incidence in cardiothoracic compared to liver recipients has the potential to lead to targeted cancer prevention strategies in this high-risk population., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Introduction: Medulloblastoma is the most common central nervous system tumour in children aged 0-4 years, with 75% of cases occurring in patients <16 years, and rare in adults. The intent of this audit is to review a single centre's experience and to compare outcomes with other centres' outcomes., Methods: This Ethics approved retrospective audit evaluates the paediatric population aged <16 years who received radiotherapy as their initial or salvage treatment at the Prince of Wales Hospital Cancer Centre between 1972 and 2007. The primary and secondary end-points were progression-free survival (PFS) and cancer-specific survival (CSS), with comparisons made between patients treated before and after 1990, and the impact of high- and low-risk disease., Results: There were 80 eligible patients, 78 who had radiotherapy at initial presentation, and 2 at the time of recurrence. Median age was 6.5 years, 52 were boys and 28 were girls. Seventy-eight patients had a surgical procedure and ultimately received craniospinal radiotherapy. Of these 78 patients, 32 (40%) had a macroscopically complete resection. The 5-year PFS was 69.7%. The 5-year PFS for patients treated pre and post 1990 was 66.1% and 71.8%, respectively. The 5-year CSS for high- and low-risk patients was 61.1% and 78.4%, respectively. Ultimately, 33% of patients were dead due to disease., Conclusion: This audit demonstrates those children referred to this facility for treatment have comparable survival to that of other major centres., (© 2012 The Authors. Journal of Medical Imaging and Radiation Oncology © 2012 The Royal Australian and New Zealand College of Radiologists.)

Background: In 2007, New South Wales Health mandated the separation of ethical and scientific review from research governance at all New South Wales public health sites based on their distinction in the National Health and Medical Research Council National Statement. This separation allowed for single-site ethical review of multicentre studies., Aims: To investigate the time taken for governance approval of multicentre studies through the site-specific approval (SSA) process., Methods: A retrospective audit of the SSA process for five non-interventional studies proposed by a university cancer research unit., Results: The median total governance approval time for all submissions (n= 28) was 12 weeks (range 2.5-64); median time from starting the SSA to submission was 8 weeks (range 1-48) and median time for governance approval was 5 weeks (range 0.3-40). Approval times were shorter for public compared to private institutions. Reasons for delays in finalising submissions for approval were the absence of institutional governance officers, lack of clarity regarding signatories, the need to identify a principal investigator employed by the institution, and lack of recognition of ethical approval by private institutions. The need to develop legal agreements between the university and hospital was the main reason for lengthy delays in obtaining approval., Conclusions: The advantages of a harmonised single ethical review process were undermined by the coexistence of a fragmented, complex and lengthy governance approval process. This experience has implications for the success of the national Harmonisation of Multi-Centre Ethical Review (HoMER) model. A harmonised and fully supported national approach to research governance should be developed contemporaneously with HoMER., (© 2011 The Authors. Internal Medicine Journal © 2011 Royal Australasian College of Physicians.)

Background: Olfactory neuroblastoma is a rare paranasal sinus malignancy. The traditional approach was craniofacial resection (CFR) and then postoperative radiotherapy until 1998. This review will chart development of a new protocol., Methods: This ethics-approved audit evaluated the number of new patients diagnosed with olfactory neuroblastoma, with information relating to patient, disease, and treatment factors noted., Results: There were 24 eligible patients, 16 men, 8 women, 7 Kadish stage B, 17 stage C. The planned treatment was: chemotherapy (cisplatin/etoposide) and determine treatment dependent on response in 6 patients, surgery and radiotherapy in 16 patients, and single-modality treatment only (surgery, radiotherapy 1) in 2 patients. Surgery to radiotherapy occurred in 17 patients. With salvage treatment ultimate local control was 79%., Conclusions: There was a higher local control in those patients who had surgery; abandoning this may carry a higher risk of local failure. The use of response to chemotherapy to determine local treatment remains experimental., (Copyright © 2010 Wiley Periodicals, Inc.)

Objectives: Providing the primary recurrence is localized, salvage treatment is possible for nasopharyngeal carcinoma (NPC). This is a review of the experience of retreatment of this malignancy highlighting the roles of surgery and repeat radiotherapy., Methods: The Tumor Registry of the Prince of Wales Cancer Centre was audited for patients with an initial diagnosis of squamous/nonsquamous cell NPC who had primary treatment with radiotherapy, and now presented for retreatment. Features relating to patient, disease and treatment factors were evaluated. The primary end point was subsequent local control, and secondary endpoints were overall and cancer-specific survival., Results: Over a 30-year period 39 patients were eligible, with 25 receiving both primary and retreatment at Prince of Wales Hospital. There were 25 males and 14 females with a median age of 50 years. Thirty-six patients had radiotherapy, 4 had stereotactic radiosurgery, 5 had brachytherapy, and the remainder had external treatment. Surgery was performed in 10 patients, of whom 3 had this as the only retreatment modality. Radiotherapy doses for retreatment ranged from 15 Gy (stereotactic radiosurgery) to 71.28 Gy (mean fractionated dose). Local control was achieved in 16 patients giving an overall rate of 41.0%, and the 5-year overall survival rate was 33.3%. Treatment modality was a significant prognostic factor for local control (P < 0.001) and cancer-specific survival (P < 0.05)., Conclusion: The presence of local recurrence after definitive treatment of NPC may still be salvageable. The best outcomes with reirradiation occur in the context of limited volume recurrence and a disease-free interval greater than 18 months.

Background: Early glottic carcinoma has a high local control prospect with radiotherapy. This review evaluates a single center's experience., Methods: All patients from 1967 to 2006 diagnosed with Tis/T1/T2/N0 early glottic carcinoma treated definitively with radiotherapy at Prince of Wales Hospital were reviewed. Local control and cancer-specific survival (CSS) rates were primary endpoints, and the impact of various factors on these outcomes was statistically analyzed., Results: This review of 522 patients includes 24 with Tis, 356 with T1, and 142 with T2. Ultimate local control rates were as follows: Tis 87.5%, T1 94.7%, and T2 84.5%. Multivariate analysis found fitness for surgery, no involvement of anterior commissure, normal cord movement, and radiotherapy dose >60 Gy significant for local control. Fitness for surgery, no involvement of the anterior commissure, normal cord movement, and no ventricular involvement were significant prognostic factors for CSS., Conclusion: Definitive radiotherapy for early glottic carcinoma provides high local control rates, with the option of surgical salvage to achieve ultimate local control., ((c) 2009 Wiley Periodicals, Inc.)