Comprehensive Target Engagement by the EZH2 Inhibitor Tulmimetostat Allows for Targeting of ARID1A Mutant Cancers.

Recurrent somatic mutations in the BAF chromatin remodeling complex subunit ARID1A occur frequently in advanced urothelial carcinoma, endometrial cancers, and ovarian clear cell carcinoma, creating an alternative chromatin state that may be exploited therapeutically. The histone methyltransferase EZH2 has previously been identified as targetable vulnerability in the context of ARID1A mutations. Here, we describe the discovery of tulmimetostat, an orally available, clinical stage EZH2 inhibitor and elucidate its therapeutic potential for treating ARID1A mutant tumors. Tulmimetostat administration achieved efficacy in multiple ARID1A mutant bladder, ovarian, and endometrial tumor models and improved cisplatin response in chemotherapy-resistant models. Consistent with its comprehensive and durable level of target coverage, tulmimetostat demonstrated greater efficacy than other PRC2-targeted inhibitors at comparable or lower exposures in a bladder cancer xenograft mouse model. Tulmimetostat mediated extensive changes in gene expression in addition to a profound reduction in global H3K27me3 levels in tumors. Phase I clinical pharmacokinetic and pharmacodynamic data indicated that tulmimetostat exhibits durable exposure and profound target engagement. Importantly, a tulmimetostat controlled gene expression signature identified in whole blood from a cohort of 32 cancer patients correlated with tulmimetostat exposure, representing a pharmacodynamic marker for the assessment of target coverage for PRC2-targeted agents in the clinic. Collectively, this data suggests that tulmimetostat has the potential to achieve clinical benefit in solid tumors as a monotherapy but also in combination with chemotherapeutic agents and may be beneficial in various indications with recurrent ARID1A mutations.

Implementing cone-beam computed tomography-guided online adaptive radiotherapy in cervical cancer.

Background and purpose: Adaptive radiotherapy (ART) in locally advanced cervical cancer (LACC) has shown promising outcomes. This study investigated the feasibility of cone-beam computed tomography (CBCT)-guided online ART (oART) for the treatment of LACC. Material and methods: The quality of the automated radiotherapy treatment plans and artificial intelligence (AI)-driven contour delineation for LACC on a novel CBCT-guided oART system were assessed. Dosimetric analysis of 200 simulated oART sessions were compared with standard treatment. Feasibility of oART was assessed from the delivery of 132 oART fractions for the first five clinical LACC patients. The simulated and live oART sessions compared a fixed planning target volume (PTV) margin of 1.5 cm around the uterus-cervix clinical target volume (CTV) with an internal target volume-based approach. Workflow timing measurements were recorded. Results: The automatically-generated 12-field intensity-modulated radiotherapy plans were comparable to manually generated plans. The AI-driven organ-at-risk (OAR) contouring was acceptable requiring, on average, 12.3 min to edit, with the bowel performing least well and rated as unacceptable in 16 % of cases. The treated patients demonstrated a mean PTV D98% (+/-SD) of 96.7 (+/- 0.2)% for the adapted plans and 94.9 (+/- 3.7)% for the non-adapted scheduled plans (p<10-5). The D2cc (+/-SD) for the bowel, bladder and rectum were reduced by 0.07 (+/- 0.03)Gy, 0.04 (+/-0.05)Gy and 0.04 (+/-0.03)Gy per fraction respectively with the adapted plan (p <10-5). In the live.setting, the mean oART session (+/-SD) from CBCT acquisition to beam-on was 29 +/- 5 (range 21-44) minutes. Conclusion: CBCT-guided oART was shown to be feasible with dosimetric benefits for patients with LACC. Further work to analyse potential reductions in PTV margins is ongoing.

Statewide Examination of Access to Cancer Surgery During the COVID-19 Pandemic.

INTRODUCTION: The COVID-19 pandemic caused interruptions in the delivery of medical care across a wide range of conditions including cancer. Trends in surgical treatment for cancer during the pandemic have not been well described. We sought to characterize associations between the pandemic and access to surgical treatment for breast, colorectal, and lung cancer in Illinois. METHODS: We performed a retrospective cohort study evaluating inpatient admissions at Illinois hospitals providing surgical care for lung cancer (n = 1913 cases, n = 64 hospitals), breast cancer (n = 910 cases, n = 108 hospitals), and colorectal cancer (n = 5339 cases, n = 144 hospitals). Using discharge data from the Illinois Health and Hospital Association's Comparative Health Care and Hospital Data Reporting Services database, average monthly surgical case volumes were compared from 2019 to 2020. We also compared rates of cancer surgery for each cancer type, by patient characteristics, and hospital type across the three time periods using Pearson chi-squared and ANOVA testing as appropriate. Three discrete time periods were considered: prepandemic (7-12/2019), primary pandemic (4-6/2020), and pandemic recovery (7-12/2020). Hospital characteristics evaluated included hospital type (academic, community, safety net), COVID-19 burden, and baseline cancer surgery volume. RESULTS: There were 2096 fewer operations performed for breast, colorectal, and lung cancer in 2020 than 2019 in Illinois, with the greatest reductions in cancer surgery volume occurring at the onset of the pandemic in April (colorectal, -48.3%; lung, -13.1%) and May (breast, -45.2%) of 2020. During the pandemic, breast (-14.6%) and colorectal (-13.8%) cancer surgery experienced reductions in volume whereas lung cancer operations were more common (+26.4%) compared to 2019. There were no significant differences noted in gender, race, ethnicity, or insurance status among patients receiving oncologic surgery during the primary pandemic or pandemic recovery periods. Academic hospitals, hospitals with larger numbers of COVID-19 admissions, and those with greater baseline cancer surgery volumes were associated with the greatest reduction in cancer surgery during the primary pandemic period (all cancer types, P < 0.01). During the recovery period, hospitals with greater baseline breast and lung cancer surgery volumes remained at reduced surgery volumes compared to their counterparts (P < 0.01). CONCLUSIONS: The COVID-19 pandemic was associated with significant reductions in breast and colorectal cancer operations in Illinois, while lung cancer operations remained relatively consistent. Overall, there was a net reduction in cancer surgery that was not made up during the recovery period. Academic hospitals, those caring for more COVID-19 patients, and those with greater baseline surgery volumes were most vulnerable to reduced surgery rates during peaks of the pandemic and to delays in addressing the backlog of cases.

Gender Disparities and Differences Among Urologists Included in Top Doctor Lists.

OBJECTIVE: To understand gender trends among urologists included in "Top Doctor" lists as more women practice urology, we (1) Evaluated whether Top Doctor lists reflect a contemporary distribution of urologists by gender; (2) Describe regional differences in gender composition of lists; (3) Report similarities and differences among men and women Top Doctors. METHODS: All urologists in regional Top Doctor Castle Connolly lists published in magazines between January 1, 2020 and June 22, 2021 were included. Physician attributes were abstracted. American Urological Association (AUA) census data was used to compare the number of men and women Top Doctor urologists to the number of practicing men and women urologists within each list's zip codes. Log odds ratios (OR) and (95% confidence intervals) were used to compare likelihood of list inclusion by gender overall and by region. RESULTS: Four hundred and ninety-four Top Doctor urologists from 25 lists were analyzed, of which 42 (8.50%) were women. Women urologists comprised 0%-27.8% of each list, with 7 lists (28.0%) including zero women urologists. Using AUA census data, OR for list inclusion of men urologists compared to women was 1.31 (1.01, 1.70) overall, with OR = 0.78 (0.36, 1.72) in the West, OR = 1.39 (1.03, 1.89) South, OR = 1.46 (0.8, 2.67) Northeast, OR = 1.90 (0.50, 7.18) Midwest. Women top urologists completed fellowship more often than men (66.7%, 55.1%) and were significantly more likely to complete female pelvic medicine and reconstructive surgery (FPMRS) fellowship (P <.001). CONCLUSION: Men urologists were significantly more likely to be included in Top Doctor lists than women urologists. Top women urologists were significantly more likely to complete FPMRS fellowship.

Patient Understanding of Tumor Genomic Testing: A Quality Improvement Effort.

PURPOSE: Tumor genomic testing (TGT) has become increasingly adopted as part of standard cancer care for many cancers. Despite national guidelines around patient education before TGT, available evidence suggests that most patients' understanding of genomics remains limited, particularly lower-income and minority patients, and most patients are not informed regarding potential incidental germline findings. METHODS: To investigate and address limitations in patient understanding of TGT results, a Plan-Do-Study-Act (PDSA) approach is being used to assess needs, identify opportunities for improvement, and implement approaches to optimize patient education. We reviewed published guidelines related to pre-TGT provider-patient education and to identify key points (Plan). A provider quality improvement survey was completed (Do), which highlighted inconsistency in pre-TGT discussion practice across providers and minimal discussion with patients regarding the possibility of incidental germline findings. RESULTS: Patient focus groups and interviews (N = 12 patients) were completed with coding of each transcript (Study), which revealed themes including trouble differentiating TGT from other forms of testing, yet understanding that results could tailor therapy. The integration of data across this initial PDSA cycle identified consistent themes and opportunities, which were incorporated into a patient-directed, concise animated video for pre-TGT education (Act), which will form the foundation of a subsequent PDSA cycle. The video addresses how TGT may/may not inform treatment, the process for TGT using existing tissue or liquid biopsy, insurance coverage, and the potential need for germline genetics follow-up because of incidental findings. CONCLUSION: This PDSA cycle reveals key gaps and opportunities for improvement in patient education before TGT.

Association of body mass index and inflammatory dietary pattern with breast cancer pathologic and genomic immunophenotype in the nurses' health study.

BACKGROUND: Breast tumor immune infiltration is clearly associated with improved treatment response and outcomes in breast cancer. However, modifiable patient factors associated with breast cancer immune infiltrates are poorly understood. The Nurses' Health Study (NHS) offers a unique cohort to study immune gene expression in tumor and adjacent normal breast tissue, immune cell-specific immunohistochemistry (IHC), and patient exposures. We evaluated the association of body mass index (BMI) change since age 18, physical activity, and the empirical dietary inflammatory pattern (EDIP) score, all implicated in systemic inflammation, with immune cell-specific expression scores. METHODS: This population-based, prospective observational study evaluated 882 NHS and NHSII participants diagnosed with invasive breast cancer with detailed exposure and gene expression data. Of these, 262 women (training cohort) had breast tumor IHC for four classic immune cell markers (CD8, CD4, CD20, and CD163). Four immune cell-specific scores were derived via lasso regression using 105 published immune expression signatures' association with IHC. In the remaining 620 patient evaluation cohort, we evaluated association of each immune cell-specific score as outcomes, with BMI change since age 18, physical activity, and EDIP score as predictors, using multivariable-adjusted linear regression. RESULTS: Among women with paired expression/IHC data from breast tumor tissue, we identified robust correlation between novel immune cell-specific expression scores and IHC. BMI change since age 18 was positively associated with CD4+ (ß = 0.16; p = 0.009), and CD163 novel immune scores (ß = 0.14; p = 0.04) in multivariable analyses. In other words, for each 10 unit (kg/m2) increase in BMI, the percentage of cells positive for CD4 and CD163 increased 1.6% and 1.4%, respectively. Neither physical activity nor EDIP was significantly associated with any immune cell-specific expression score in multivariable analyses. CONCLUSIONS: BMI change since age 18 was positively associated with novel CD4+ and CD163+ cell scores in breast cancer, supporting further study of the effect of modifiable factors like weight gain on the immune microenvironment.

Psychosocial Needs of Gynecological Cancer Survivors: Mixed Methods Study.

BACKGROUND: Internet and social media platforms offer insights into the lived experiences of survivors of cancer and their caregivers; however, the volume of narrative data available is often cumbersome for thorough analysis. Survivors of gynecological cancer have unique needs, such as those related to a genetic predisposition to future cancers, impact of cancer on sexual health, the advanced stage at which many are diagnosed, and the influx of new therapeutic approaches. OBJECTIVE: This study aimed to present a unique methodology to leverage large amounts of data from internet-based platforms for mixed methods analysis. We analyzed discussion board posts made by survivors of gynecological cancer on the American Cancer Society website with a particular interest in evaluating the psychosocial aspects of survivorship. METHODS: All posts from the ovarian, uterine, and gynecological cancers (other than ovarian and uterine) discussion boards on the American Cancer Society Cancer Survivors Network were included. Posts were web scraped using Python and organized by psychosocial themes described in the Quality of Cancer Survivorship Care Framework. Keywords related to each theme were generated and verified. Keywords identified posts related to the predetermined psychosocial themes. Quantitative analysis was completed using Python and R Foundation for Statistical Computing packages. Qualitative analysis was completed on a subset of posts as a proof of concept. Themes discovered through latent Dirichlet allocation (LDA), an unsupervised topic modeling technique, were assessed and compared with the predetermined themes of interest. RESULTS: A total of 125,498 posts made by 6436 survivors of gynecological cancer and caregivers between July 2000 and February 2020 were evaluated. Of the 125,489 posts, 23,458 (18.69%) were related to the psychosocial experience of cancer and were included in the mixed methods psychosocial analysis. Quantitative analysis (23,458 posts) revealed that survivors across all gynecological cancer discussion boards most frequently discussed the role of friends and family in care, as well as fatigue, the effect of cancer on interpersonal relationships, and health insurance status. Words related to psychosocial aspects of survivorship most often used in posts included "family," "hope," and "help." Qualitative analysis (20 of the 23,458 posts) similarly demonstrated that survivors frequently discussed coping strategies, distress and worry, the role of family and caregivers in their cancer care, and the toll of managing financial and insurance concerns. Using LDA, we discovered 8 themes, none of which were directly related to psychosocial aspects of survivorship. Of the 56 keywords identified by LDA, 2 (4%), "sleep" and "work," were included in the keyword list that we independently devised. CONCLUSIONS: Web-based discussion platforms offer a great opportunity to learn about patient experiences of survivorship. Our novel methodology expedites the quantitative and qualitative analyses of such robust data, which may be used for additional patient populations.

Genomic features of rapid versus late relapse in triple negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogeneous disease and we have previously shown that rapid relapse of TNBC is associated with distinct sociodemographic features. We hypothesized that rapid versus late relapse in TNBC is also defined by distinct clinical and genomic features of primary tumors. METHODS: Using three publicly-available datasets, we identified 453 patients diagnosed with primary TNBC with adequate follow-up to be characterized as 'rapid relapse' (rrTNBC; distant relapse or death ≤2 years of diagnosis), 'late relapse' (lrTNBC; > 2 years) or 'no relapse' (nrTNBC: > 5 years no relapse/death). We explored basic clinical and primary tumor multi-omic data, including whole transcriptome (n = 453), and whole genome copy number and mutation data for 171 cancer-related genes (n = 317). Association of rapid relapse with clinical and genomic features were assessed using Pearson chi-squared tests, t-tests, ANOVA, and Fisher exact tests. We evaluated logistic regression models of clinical features with subtype versus two models that integrated significant genomic features. RESULTS: Relative to nrTNBC, both rrTNBC and lrTNBC had significantly lower immune signatures and immune signatures were highly correlated to anti-tumor CD8 T-cell, M1 macrophage, and gamma-delta T-cell CIBERSORT inferred immune subsets. Intriguingly, lrTNBCs were enriched for luminal signatures. There was no difference in tumor mutation burden or percent genome altered across groups. Logistic regression mModels that incorporate genomic features significantly outperformed standard clinical/subtype models in training (n = 63 patients), testing (n = 63) and independent validation (n = 34) cohorts, although performance of all models were overall modest. CONCLUSIONS: We identify clinical and genomic features associated with rapid relapse TNBC for further study of this aggressive TNBC subset.

Author Correction: FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Metastatic breast cancer patient perceptions of somatic tumor genomic testing.

BACKGROUND: To assess metastatic breast cancer (MBC) patient psychological factors, perceptions, and comprehension of tumor genomic testing. METHODS: In a prospective, single institution, single-arm trial, patients with MBC underwent next-generation sequencing at study entry with sequencing results released at progression. Patients who completed surveys before undergoing sequencing were included in the present secondary analysis (n = 58). We administered four validated psychosocial measures: Center for Epidemiologic Studies Depression Scale, Beck Anxiety Inventory, Trust in Physician Scale, and Communication and Attitudinal Self-Efficacy scale for Cancer. Genetic comprehension was assessed using 7-question objective and 6-question subjective measures. Longitudinal data were assessed (n = 40) using paired Wilcoxon signed rank and McNemar's test of agreement. RESULTS: There were no significant differences between the beginning and end of study in depression, anxiety, physician trust, or self-efficacy (median time on study: 7.6 months). Depression and anxiety were positively associated with each other and both negatively associated with self-efficacy. Self-efficacy decreased from pre- to post-genomic testing (p = 0.05). Objective genetics comprehension did not significantly change from pre- to post-genomic testing, but patients expressed increased confidence in their ability to teach others about genetics (p = 0.04). Objective comprehension was significantly lower in non-white patients (p = 0.02) and patients with lower income (p = 0.04). CONCLUSIONS: This is the only study, to our knowledge, to longitudinally evaluate multiple psychological metrics in MBC as patients undergo tumor genomic testing. Overall, psychological dimensions remained stable over the duration of tumor genomic testing. Among patients with MBC, depression and anxiety metrics were negatively correlated with patient self-efficacy. Patients undergoing somatic genomic testing had limited genomic knowledge, which varied by demographic groups and may warrant additional educational intervention. CLINICAL TRIAL INFORMATION: NCT01987726, registered November 13, 2013.

Biological predictors of chemotherapy-induced peripheral neuropathy (CIPN): MASCC neurological complications working group overview.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating condition associated with a number of chemotherapeutic agents. Drugs commonly implicated in the development of CIPN include platinum agents, taxanes, vinca alkaloids, bortezomib, and thalidomide analogues. As a drug response can vary between individuals, it is hypothesized that an individual's specific genetic variants could impact the regulation of genes involved in drug pharmacokinetics, ion channel functioning, neurotoxicity, and DNA repair, which in turn affect CIPN development and severity. Variations of other molecular markers may also affect the incidence and severity of CIPN. Hence, the objective of this review was to summarize the known biological (molecular and genomic) predictors of CIPN and discuss the means to facilitate progress in this field.

FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes.

Mutations in the transcription factor FOXA1 define a unique subset of prostate cancers but the functional consequences of these mutations and whether they confer gain or loss of function is unknown1-9. Here, by annotating the landscape of FOXA1 mutations from 3,086 human prostate cancers, we define two hotspots in the forkhead domain: Wing2 (around 50% of all mutations) and the highly conserved DNA-contact residue R219 (around 5% of all mutations). Wing2 mutations are detected in adenocarcinomas at all stages, whereas R219 mutations are enriched in metastatic tumours with neuroendocrine histology. Interrogation of the biological properties of wild-type FOXA1 and fourteen FOXA1 mutants reveals gain of function in mouse prostate organoid proliferation assays. Twelve of these mutants, as well as wild-type FOXA1, promoted an exaggerated pro-luminal differentiation program, whereas two different R219 mutants blocked luminal differentiation and activated a mesenchymal and neuroendocrine transcriptional program. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) of wild-type FOXA1 and representative Wing2 and R219 mutants revealed marked, mutant-specific changes in open chromatin at thousands of genomic loci and exposed sites of FOXA1 binding and associated increases in gene expression. Of note, ATAC-seq peaks in cells expressing R219 mutants lacked the canonical core FOXA1-binding motifs (GTAAAC/T) but were enriched for a related, non-canonical motif (GTAAAG/A), which was preferentially activated by R219-mutant FOXA1 in reporter assays. Thus, FOXA1 mutations alter its pioneering function and perturb normal luminal epithelial differentiation programs, providing further support for the role of lineage plasticity in cancer progression.

Recent Developments of Novel Pharmacologic Therapeutics for Prevention of Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting toxicity, negatively affecting both quality of life and disease outcomes. To date, there is no proven preventative strategy for CIPN. Although multiple randomized trials have evaluated a variety of pharmacologic interventions for the treatment of CIPN, only duloxetine has shown clear efficacy in a phase III study. The National Cancer Institute's Symptom Management and Health-Related Quality of Life Steering Committee has identified CIPN as a priority for translational research in cancer care. Promising advances in preclinical research have identified several novel preventative and therapeutic targets, which have the potential to transform the care of patients with this debilitating neurotoxicity. Here, we provide an overarching view of emerging strategies and therapeutic targets that are currently being evaluated in CIPN.

Prospective Decision Analysis Study of Clinical Genomic Testing in Metastatic Breast Cancer: Impact on Outcomes and Patient Perceptions.

PURPOSE: To evaluate the impact of targeted DNA sequencing on selection of cancer therapy for patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: In this prospective, single-center, single-arm trial, patients with MBC were enrolled within 10 weeks of starting a new therapy. At enrollment, tumor samples underwent next-generation sequencing for any of 315 cancer-related genes to high depth (> 500×) using FoundationOne CDx. Sequencing results were released to providers at the time of disease progression, and physician treatment recommendations were assessed via questionnaire. We evaluated three prespecified questions to assess patients' perceptions of genomic testing. RESULTS: In all, 100 patients underwent genomic testing, with a median of five mutations (range, 0 to 13 mutations) detected per patient. Genomic testing revealed one or more potential therapies in 98% of patients (98 of 100), and 60% of patients (60 of 100) had one or more recommended treatments with level I/II evidence for actionability. Among the 94 genomic text reports that were released, there was physician questionnaire data for 87 patients (response rate, 92.6%) and 31.0% of patients (27 of 87) had treatment change recommended by their physician. Of these, 37.0% (10 of 27) received the treatment supported by genomic testing. We did not detect a statistically significant difference in time-to-treatment failure (log-rank P = .87) or overall survival (P = .71) among patients who had treatment change supported by genomic testing versus those who had no treatment change. For patients who completed surveys before and after genomic testing, there was a significant decrease in confidence of treatment success, specifically among patients who did not have treatment change supported by genomic testing (McNemar's test of agreement P = .001). CONCLUSION: In this prospective study, genomic profiling of tumors in patients with MBC frequently identified potential treatments and resulted in treatment change in a minority of patients. Patients whose therapy was not changed on the basis of genomic testing seemed to have a decrease in confidence of treatment success.

Functions of the COPII gene paralogs SEC23A and SEC23B are interchangeable in vivo.

Approximately one-third of the mammalian proteome is transported from the endoplasmic reticulum-to-Golgi via COPII-coated vesicles. SEC23, a core component of coat protein-complex II (COPII), is encoded by two paralogous genes in vertebrates (Sec23a and Sec23b). In humans, SEC23B deficiency results in congenital dyserythropoietic anemia type-II (CDAII), while SEC23A deficiency results in a skeletal phenotype (with normal red blood cells). These distinct clinical disorders, together with previous biochemical studies, suggest unique functions for SEC23A and SEC23B. Here we show indistinguishable intracellular protein interactomes for human SEC23A and SEC23B, complementation of yeast Sec23 by both human and murine SEC23A/B, and rescue of the lethality of sec23b deficiency in zebrafish by a sec23a-expressing transgene. We next demonstrate that a Sec23a coding sequence inserted into the murine Sec23b locus completely rescues the lethal SEC23B-deficient pancreatic phenotype. We show that SEC23B is the predominantly expressed paralog in human bone marrow, but not in the mouse, with the reciprocal pattern observed in the pancreas. Taken together, these data demonstrate an equivalent function for SEC23A/B, with evolutionary shifts in the transcription program likely accounting for the distinct phenotypes of SEC23A/B deficiency within and across species, a paradigm potentially applicable to other sets of paralogous genes. These findings also suggest that enhanced erythroid expression of the normal SEC23A gene could offer an effective therapeutic approach for CDAII patients.

SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer.

Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. We use in vitro and in vivo human prostate cancer models to show that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR)-dependent luminal epithelial cells to AR-independent basal-like cells. This lineage plasticity is enabled by the loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2, and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching.

Clinical validation and benchmarking of knowledge-based IMRT and VMAT treatment planning in pelvic anatomy.

PURPOSE: The aim of this work was to determine whether a commercial knowledge-based treatment planning (KBP) module can efficiently produce IMRT and VMAT plans in the pelvic region (prostate & cervical cancer), and to assess sensitivity of plan quality to training data and model parameters. METHODS: Initial benchmarking of KBP was performed using prostate cancer cases. Structures and dose distributions from 40 patients previously treated using a 5-field IMRT technique were used for model training. Two types of model were created: one excluded statistical outliers (as identified by RapidPlan guidelines) and the other had no exclusions. A separate model for cervix uteri cancer cases was subsequently developed using 37 clinical patients treated for cervical cancer using RapidArc™ VMAT, with no exclusions. The resulting models were then used to generate plans for ten patients from each patient group who had not been included in the modelling process. Comparisons of generated RapidPlans with the corresponding clinical plans were carried out to indicate the required modifications to the models. Model parameters were then iteratively adjusted until plan quality converged with that obtained by experienced planners without KBP. RESULTS: Initial automated model generation settings led to poor conformity, coverage and efficiency compared to clinical plans. Therefore a number of changes to the initial KBP models were required. Before model optimisation, it was found that the PTV coverage was slightly reduced in the superior and inferior directions for RapidPlan compared with clinical plans and therefore PTV parameters were adjusted to improve coverage. OAR doses were similar for both RapidPlan and clinical plans (p>0.05). Excluding outliers had little effect on plan quality (p≫0.05). Manually fixing key optimisation objectives enabled production of clinically acceptable treatment plans without further planner intervention for 9 of 10 prostate test patients and all 10 cervix test patients. CONCLUSIONS: The Varian RapidPlan™ system was able to produce IMRT & VMAT treatment plans in the pelvis, in a single optimisation, that had comparable sparing and comparable or better conformity than the original clinically acceptable plans. The system allows for better consistency and efficiency in the treatment planning process and has therefore been adopted clinically within our institute with over 100 patients treated.

A critical evaluation of the PTW 2D-ARRAY seven29 and OCTAVIUS II phantom for IMRT and VMAT verification.

Quality assurance (QA) for intensity- and volumetric-modulated radiotherapy (IMRT and VMAT) has evolved substantially. In recent years, various commercial 2D and 3D ionization chamber or diode detector arrays have become available, allowing for absolute verification with near real time results, allowing for streamlined QA. However, detector arrays are limited by their resolution, giving rise to concerns about their sensitivity to errors. Understanding the limitations of these devices is therefore critical. In this study, the sensitivity and resolution of the PTW 2D-ARRAY seven29 and OCTAVIUS II phantom combination was comprehensively characterized for use in dynamic sliding window IMRT and RapidArc verification. Measurement comparisons were made between single acquisition and a multiple merged acquisition techniques to improve the effective resolution of the 2D-ARRAY, as well as comparisons against GAFCHROMIC EBT2 film and electronic portal imaging dosimetry (EPID). The sensitivity and resolution of the 2D-ARRAY was tested using two gantry angle 0° modulated test fields. Deliberate multileaf collimator (MLC) errors of 1, 2, and 5 mm and collimator rotation errors were inserted into IMRT and RapidArc plans for pelvis and head & neck sites, to test sensitivity to errors. The radiobiological impact of these errors was assessed to determine the gamma index passing criteria to be used with the 2D-ARRAY to detect clinically relevant errors. For gamma index distributions, it was found that the 2D-ARRAY in single acquisition mode was comparable to multiple acquisition modes, as well as film and EPID. It was found that the commonly used gamma index criteria of 3% dose difference or 3 mm distance to agreement may potentially mask clinically relevant errors. Gamma index criteria of 3%/2 mm with a passing threshold of 98%, or 2%/2 mm with a passing threshold of 95%, were found to be more sensitive. We suggest that the gamma index passing thresholds may be used for guidance, but also should be combined with a visual inspection of the gamma index distribution and calculation of the dose difference to assess whether there may be a clinical impact in failed regions.

A study of the reproducibility of a fluorescence in situ hybridization bladder cancer detection assay.

OBJECTIVE: To assess the reproducibility of the UroVysion fluorescence in situ hybridization (FISH) bladder cancer detection assay. STUDY DESIGN: Thirteen specimens (2 negative, 3 low-level positive [1-10% abnormal cells], 5 mid-level positive [11-75%], and 3 high-level positive [>75%]) were analyzed by 7 cytotechnologists. Each cytotechnologist rendered an overall diagnosis of positive or negative and determined the percentage of abnormal urothelial cells for all positive specimens. RESULTS: The interobserver reproducibility of the assay was 100% for mid-level and high-level positive specimens, 93% for negative specimens, and 78% for low-level positive specimens. The range of percent abnormal determinations was highest for mid-level positive specimens, with mean SDs of 1.8%, 16.4% and 10.1% for the low-, mid-, and high-level positives, respectively. CONCLUSION: There was a high level of reproducibility among the mid- and high-level positive specimens. The reproducibility for low-level positive specimens was lowest, suggesting that such specimens should be reviewed by a second technologist to ensure an accurate diagnosis. The findings of this study are important for further elucidating the clinical value of quantitative FISH analysis in the management of patients undergoing FISH testing for bladder cancer.

Intensity Modulated Radiotherapy (IMRT) in locally advanced thyroid cancer: acute toxicity results of a phase I study.

BACKGROUND AND PURPOSE: This phase 1 study was designed to determine the toxicity of accelerated fractionation IMRT in locally advanced thyroid cancer. METHODS: Patients with high risk locally advanced thyroid cancer who required post-operative EBRT were recruited. A single-phase inverse-planned-simultaneous-boost was delivered by IMRT: 58.8 Gy/28F (daily) to the primary tumour and involved nodes and 50 Gy/28F to the elective nodes. Acute (NCICTCv.2.0) and late toxicity (RTOG and modified LENTSOM) was collected. RESULTS: Thirteen patients were treated (7 medullary thyroid, 2 Hurthle cell and 4 well differentiated thyroid cancer). G3 and G2 radiation dermatitis rates were 38.5% and 31%; G3 and G2 mucositis rates 8% and 53% and G3 and G2 pain 23% and 54%. Thirty-one percentage required enteral feeding. G3 and G2 xerostomia rates were 0% and 31%. Recovery was seen, with 62% patients having dysphagia G< or =1 2 months after IMRT. Thirty percent of patients developed L'Hermitte's syndrome. No grade 4 toxicity was observed. No dose limiting toxicity was found. CONCLUSIONS: Accelerated fractionation IMRT in this group of patients is feasible and safe. The acute toxicity appeared acceptable and early indicators of late toxicity moderate and similar to what would be expected with conventional RT. Longer follow up is required to quantify late side effects.