Patient Tumor Characteristics Research Articles

Activity quantification and dosimetry in radiopharmaceutical therapy with reference to 177Lutetium.

Radiopharmaceutical therapy has been widely adopted owing primarily to the development of novel radiopharmaceuticals. To fully utilize the potential of these RPTs in the era of precision medicine, therapy must be optimized to the patient's tumor characteristics. The vastly disparate dosimetry methodologies need to be harmonized as the first step towards this. Multiple factors play a crucial role in the shift from empirical activity administration to patient-specific dosimetry-based administrations from RPT. Factors such as variable responses seen in patients with presumably similar clinical characteristics underscore the need to standardize and validate dosimetry calculations. These efforts combined with ongoing initiatives to streamline the dosimetry process facilitate the implementation of radiomolecular precision oncology. However, various challenges hinder the widespread adoption of personalized dosimetry-based activity administration, particularly when compared to the more convenient and resource-efficient approach of empiric activity administration. This review outlines the fundamental principles, procedures, and methodologies related to image activity quantification and dosimetry with a specific focus on 177Lutetium-based radiopharmaceuticals.

Lean body mass index is a marker of advanced tumor features in patients with hepatocellular carcinoma.

Obesity is an independent risk factor for the development of hepatocellular carcinoma (HCC) and may influence its outcomes. However, after diagnosis of HCC, like other malignancies, the obesity paradox may exist where higher body mass index (BMI) may in fact confer a survival benefit. This is frequently observed in patients with advanced HCC and cirrhosis, who often present late with advanced tumor features and cancer related weight loss. To explore the relationship between BMI and survival in patients with cirrhosis and HCC. This is a retrospective cohort study of over 2500 patients diagnosed with HCC between 2009-2019 at two United States academic medical centers. Patient and tumor characteristics were extracted manually from medical records of each institutions' cancer registries. Patients were stratified according to BMI classes: < 25 kg/m2 (lean), 25-29.9 kg/m2 (overweight), and > 30 kg/m2 (obese). Patient and tumor characteristics were compared according to BMI classification. We performed an overall survival analysis using Kaplan Meier by the three BMI classes and after adjusting for Milan criteria. A multivariable Cox regression model was then used to assess known risk factors for survival in patients with cirrhosis and HCC. A total of 2548 patients with HCC were included in the analysis of which 11.2% (n = 286) were classified as non-cirrhotic. The three main BMI categories: Lean (n = 754), overweight (n = 861), and obese (n = 933) represented 29.6%, 33.8%, and 36.6% of the total population overall. Within each BMI class, the non-cirrhotic patients accounted for 15% (n = 100), 12% (n = 94), and 11% (n = 92), respectively. Underweight patients with a BMI < 18.5 kg/m2 (n = 52) were included in the lean cohort. Of the obese cohort, 42% (n = 396) had a BMI ≥ 35 kg/m2. Out of 2262 patients with cirrhosis and HCC, 654 (29%) were lean, 767 (34%) were overweight, and 841 (37%) were obese. The three BMI classes did not differ by age, MELD, or Child-Pugh class. Chronic hepatitis C was the dominant etiology in lean compared to the overweight and obese patients (71%, 62%, 49%, P < 0.001). Lean patients had significantly larger tumors compared to the other two BMI classes (5.1 vs 4.2 vs 4.2 cm, P < 0.001), were more likely outside Milan (56% vs 48% vs 47%, P < 0.001), and less likely to undergo transplantation (9% vs 18% vs 18%, P < 0.001). While both tumor size (P < 0.0001) and elevated alpha fetoprotein (P < 0.0001) were associated with worse survival by regression analysis, lean BMI was not (P = 0.36). Lean patients with cirrhosis and HCC present with larger tumors and are more often outside Milan criteria, reflecting cancer related cachexia from delayed diagnosis. Access to care for hepatitis C virus therapy and liver transplantation confer a survival benefit, but not overweight or obese BMI classifications.

The influence of the initial clinical presentation of upper tract urothelial carcinoma on histopathological tumor features.

To investigate the influence of the initial clinical presentation (symptomatic vs. asymptomatic) on histopathological tumor features in patients with upper tract urothelial carcinoma (UTUC). We conducted a single-center, cross-sectional, and retrospective study that enrolled 72 adults with primary UTUC who underwent radical nephroureterectomy at our institution over a period of 4 years (April 2019-April 2023). Symptomatic patients exhibited significantly higher frequencies of high-grade UTUC (73.6% vs. 36.8%, p = 0.006), ≥ T2 stage UTUC (60.4% vs. 26.3%, p = 0.007), and larger tumor sizes (median 5 vs. 4cm, p = 0.015) compared to asymptomatic patients. Multiple regression analyses demonstrated significant associations between symptomatic presentation and the presence of high-grade UTUC (OR 6.35, 95% CI 1.81-22.27, p = 0.004), ≥ T2 stage UTUC (OR 5.98, 95% CI 1.62-22.08, p = 0.007), and larger tumor size (B 3.14, 95% CI 0.62-5.66, p = 0.015). A subset of patients with hematuria was separately analyzed to assess the influence of hematuria severity (gross vs. microscopic) on UTUC characteristics. Patients with gross hematuria exhibited significantly higher frequencies of high-grade UTUC (72.9% vs. 33.3%, p = 0.048) and ≥ T2 stage UTUC (58.3% vs. 22.2%, p = 0.001). Multiple regression analyses showed significant associations between gross hematuria and the presence of high-grade UTUC (OR 6.34, 95% CI 1.15-34.95, p = 0.034) and ≥ T2 stage UTUC (OR 6.54, 95% CI 1.11-38.93, p = 0.039). Initial symptomatic presentation was independently associated with adverse histopathological UTUC characteristics, potentially attributed to earlier detection of UTUC in asymptomatic patients, before the onset of symptoms.

Can Axillary Ultrasound Identify Node Positive Patients Who can Avoid an Axillary Dissection After Neoadjuvant Chemotherapy?

IntroductionAxillary lymph node dissection (ALND) is recommended for patients with invasive breast cancer with axillary metastasis treated with neoadjuvant chemotherapy (NAC) who do not have a nodal pathologic complete response (n-pCR). We hypothesized that patients with a single, ultrasound-suspicious, nonpalpable lymph node (LN) at diagnosis, who do not achieve an n-pCR, will have ypN1 disease on surgical pathology. MethodsThis retrospective study identified breast cancer patients in our institution from 2012 to 2020 with axillary metastasis treated with NAC who did not achieve an n-pCR and had an ALND. Patient's tumor characteristics, axillary ultrasound, and lymph node disease burden at the time of surgery were reviewed. ResultsFifty five patients met the criteria and 36% had one suspicious LN on ultrasound, 25% had 2, and 38% had >3. After chemotherapy, 64% had ypN1 disease, 29% had ypN2 disease, and 7% had ypN3 disease. Of the 20 patients with one abnormal LN on initial ultrasound, 17 (85%, 95% CI 61-96%) had ypN1 disease. Eleven patients with one abnormal LN on initial ultrasound also had no suspicious LNs on prechemotherapy physical exam; among these patients, 100% had ypN1 disease. ConclusionsFor breast cancer patients who do not achieve an n-pCR after NAC, pretreatment normal clinical axillary exam and prechemotherapy ultrasound showing only one abnormal LN is associated with ypN1 disease. It may be reasonable to consider omitting completion ALND in this subset of patients while awaiting the results of the Alliance A011202 trial.

The Value of Epidermal Growth Factor Receptor Expression in Predicting Aggressive Behaviors of Bladder Neoplasms

Background: It has been shown that some cancers express the epidermal growth factor receptor (EGFR). Several variables influence bladder cancer prognosis, including stage, grade, and gene expression. Objectives: We used immunohistochemistry to measure the prevalence and prognostic significance of EGFR expression in bladder tumors in our population. Methods: Thirty bladder tumors were the subjects of this cross-sectional study. To evaluate the biological behavior of the tumors, histopathological analysis was performed. We carried out EGFR immunohistochemical staining to evaluate gene expression. Results: EGFR was expressed in 25 (83.3%) patients. Expression of this biomarker was independent of tumor characteristics such as lymphatic invasion, muscle invasion, and tumor grade and stage (P value &gt; 0.05). Conclusions: Remembering each patient's tumor characteristics determine that prognosis is crucial. The prognostic value of EGFR expression in predicting aggressive behavior in bladder tumors is marginal, but it is necessary to evaluate therapeutic response.

Molecular characteristics of breast tumors in patients screened for germline predisposition from a population-based observational study

BackgroundPathogenic germline variants (PGVs) in certain genes are linked to higher lifetime risk of developing breast cancer and can influence preventive surgery decisions and therapy choices. Public health programs offer genetic screening based on criteria designed to assess personal risk and identify individuals more likely to carry PGVs, dividing patients into screened and non-screened groups. How tumor biology and clinicopathological characteristics differ between these groups is understudied and could guide refinement of screening criteria.MethodsSix thousand six hundred sixty breast cancer patients diagnosed in South Sweden during 2010–2018 were included with available clinicopathological and RNA sequencing data, 900 (13.5%) of which had genes screened for PGVs through routine clinical screening programs. We compared characteristics of screened patients and tumors to non-screened patients, as well as between screened patients with (n = 124) and without (n = 776) PGVs.ResultsBroadly, breast tumors in screened patients showed features of a more aggressive disease. However, few differences related to tumor biology or patient outcome remained significant after stratification by clinical subgroups or PAM50 subtypes. Triple-negative breast cancer (TNBC), the subgroup most enriched for PGVs, showed the most differences between screening subpopulations (e.g., higher tumor proliferation in screened cases). Significant differences in PGV prevalence were found between clinical subgroups/molecular subtypes, e.g., TNBC cases were enriched for BRCA1 PGVs. In general, clinicopathological differences between screened and non-screened patients mimicked those between patients with and without PGVs, e.g., younger age at diagnosis for positive cases. However, differences in tumor biology/microenvironment such as immune cell composition were additionally seen within PGV carriers/non-carriers in ER + /HER2 − cases, but not between screening subpopulations in this subgroup.ConclusionsCharacterization of molecular tumor features in patients clinically screened and not screened for PGVs represents a relevant read-out of guideline criteria. The general lack of molecular differences between screened/non-screened patients after stratification by relevant breast cancer subsets questions the ability to improve the identification of screening candidates based on currently used patient and tumor characteristics, pointing us towards universal screening. Nevertheless, while that is not attained, molecular differences identified between PGV carriers/non-carriers suggest the possibility of further refining patient selection within certain patient subsets using RNA-seq through, e.g., gene signatures.Trial registrationThe Sweden Cancerome Analysis Network – Breast (SCAN-B) was prospectively registered at ClinicalTrials.gov under the identifier NCT02306096.

Combined Modality Stereotactic Body Radiotherapy vs. Salvage Stereotactic Body Radiotherapy in the Management of Patients with Hepatocellular Carcinoma

<h3>Purpose/Objective(s)</h3> The management of hepatocellular carcinoma (HCC) is complex and requires careful consideration of the patient's tumor characteristics and underlying liver function. Local therapies including stereotactic body radiation therapy (SBRT), trans-arterial chemoembolization, trans-arterial radioembolization, trans-arterial embolization, and microwave ablation have been shown to be safe and effective. Limited data exist characterizing the outcomes of combined modality therapy (CMT), defined as thermal ablative or transarterial liver directed therapy followed by consolidative SBRT. We hypothesized that upfront CMT would result in better outcomes compared to local therapy followed by SBRT for local salvage. <h3>Materials/Methods</h3> Patients with HCC who were treated with SBRT were prospectively enrolled into an institutional database from 2012-2021. Patients treated with upfront CMT or local therapy followed by salvage SBRT were identified. Overall survival (OS) and local control (LC) were evaluated using the Kaplan-Meier method. Local control was evaluated using both radiographic and pathologic data when available. <h3>Results</h3> 67 patients with a total of 77 tumors were included in our analysis with a median follow up of 31.8 months. Median tumor size was 3.3 cm. Median dose delivered was 45 Gy in a median of 5 fractions. 27 (40%) patients received CMT and 40 (60%) patients received salvage SBRT. The groups were comparable in terms of baseline characteristics including age, Child Pugh score, Milan eligibility, and radiation dose. There was a significantly greater proportion of CMT patients who were listed for transplant (60% 16/27 versus 30% 12/40 in the salvage SBRT group, <i>p</i> = .01). The estimated 1-year LC rate were similar between the two cohorts with 100% LC in the CMT group and 94.3% LC in the salvage SBRT group (<i>p</i> =0.62). OS was also similar between cohorts with an estimated 1-year OS of 92.59% in the CMT group and 89.5% in the salvage SBRT group (<i>p</i> =0.3). Radiographic response rates between the CMT and salvage SBRT cohorts were comparable with a radiographic complete response (rCR) of 73% (19/26) in the CMT group and 67% (29/43) in the salvage SBRT group. Of the tumors that were pathologically analyzed either at explant or autopsy, pathologic complete response rates (pCR) were similar with 50% (7/14) of CMT patients and 67% (8/12) of salvage SBRT patients achieving a pCR. Toxicity rates were low with only 3 patients (11.1%) in the CMT cohort and 3 patients (7.5%) in the salvage SBRT cohort who had grade 3+ adverse events. Regardless of treatment type, 56% had stable or improved CPT scores by 6 months post SBRT. <h3>Conclusion</h3> Both upfront CMT and salvage SBRT following local failure provide excellent local control, are associated with similar overall survival, and have acceptable rates of toxicity. Further studies are needed to evaluate the role of CMT with SBRT in patients with HCC to avoid over treatment and maximize cost efficiency.

Pituitary adenomas in the elderly: Retrospective comparative analysis of clinical/tumor features and surgical data by age group.

The increase in life expectancy along with technological advances has translated into a higher number of pituitary adenomas (PA) diagnosed from the age of 65. In the elderly, symptoms related to comorbidities might overlap with endocrine dysfunction, in addition to increasing anesthetic and surgical risks. This study aimed to compare baseline clinical and tumor features between patients with PA from different age groups: younger adults (YA), 18 to 64 years, and older adults (OA), ≥65 years. As secondary outcomes, we also intended to assess: clinical characteristics and tumor features in patients undergoing surgical intervention and surgical data and complications in patients undergoing transphenoidal surgery (TSS). This retrospective cohort study included patients diagnosed with PA in adulthood divided into YA and OA groups. The secondary outcomes were evaluated in the subgroups: patients who underwent pituitary surgery and patients specifically submitted to TSS, who had completed postoperative follow-up ≥ 6 months until July/2020. A total of 401 patients were included, 327 (81.5%) in the YA and 74 (18.5%) in the OA group. Hormone-secreting effects were more common in the YA group (P < .001) and mass effects in the OA group (P = .070). The prevalence of hypertension and diabetes was higher in the OA group (P = .002, P = .011). A larger proportion of nonfunctioning (NF) PA and prolactinomas was found in OA (P < .001) and YA (P = .012), respectively. Macroadenomas were more common in the OA group (P < .001). No differences were found in terms of invasiveness. In the secondary outcome analysis, there was a higher prevalence of NF-PA in those who underwent pituitary surgery. The rate of TSS-related complications was similar between the groups for major, minor and endocrine/electrolyte complications. OA-PA clinically differ from the younger: tend to present more frequently with chronic comorbidities and less frequently with hormone-secreting effects, are more often NF and larger in size without a significant increase in invasiveness. The TSS results were reassuring, proving to be equally safe for the elderly.

Factors associated with artificial airway retention after skull base chordoma resection: A retrospective cohort study.

BackgroundChordoma is a malignant bone and soft tissue tumor derived from embryonic notochord remnants, and skull base chordoma accounts for ~1/3 of all chordoma cases. Skull base chordoma is closely related to the brainstem and cranial nerves and has a high recurrence rate. The purpose of this study was to investigate the influence of the timing of tracheal extubation on perioperative pulmonary complications. We also aimed to explore predictors of postoperative artificial airway (AA) retention in patients with skull base chordoma.MethodsThis was a single-center, retrospective cohort study. The study population included all skull base chordoma patients undergoing surgical treatment between January 2019 and December 2021 at Beijing Tiantan Hospital. The primary outcome was the incidence of postoperative pulmonary complications. Several patient characteristics were evaluated for potential associations with AA retention.ResultsA total of 310 patients with skull base chordoma were enrolled. The frequency of AA retention after surgery for skull base chordoma was 30.97%. The incidence of postoperative pulmonary complications was much lower in those without AA retention (3.74 vs. 39.58%, P < 0.001). Factors with the highest point estimates for the odds of AA retention included body mass index, cranial nerve involvement, maximum tumor diameter, operative method, hemorrhage volume, operative duration and intraoperative mechanical ventilation duration.ConclusionsIn this retrospective cohort study, most of the factors associated with postoperative airway retention were closely related to the patient's tumor characteristics. These data demonstrate that respiratory management in patients with skull base chordoma remains an ongoing concern.

Abstract 2743: Tumor growth modeling and its applications in preclinical pharmacology studies to improve translatability of animal models

Abstract Successful oncology drug development hinges on proper use of preclinical xenograft and allograft mouse models that faithfully reflect histopathology and genomic features of patient tumors and exhibit clinically similar drug response. For in vivo pharmacology studies, tumor-bearing mice are treated by drugs and efficacy is monitored by continuingly measuring tumor volumes over weeks or even months, resulting in mouse-specific tumor growth data. In our previous study, we used linear mixed model (LMM) to fit tumor growth data and demonstrated its superiority to simple readouts, such as tumor growth inhibition (TGI), in discovering biomarkers and exploring mechanism of action for drugs. Here we extended the study to more parametric statistical models on an expanded dataset with over 100 thousand tumor growth curves. Six parametric models (exponential, exponential square, Gompertz, Logistic, Monomolecular, and von Bertalanffy) were fit to tumor growth curves within a single-treatment group, by the least square method after variance stabilization transformation. Best models were selected by Akaike information criterion (AIC)-based confidence set. In the Irinotecan case study, logarithmic transformation of tumor volume converts exponential or exponential square models to mixed-effects linear models that integrate random effect of mouse difference within a treatment group, and are used to identify predictive biomarkers for drug efficacy. We compared three variance stabilization transformations and found that log transformation of tumor volume is appropriate for majority of tumor growth curves. In log transformed data, exponential or exponential square model can satisfactorily fit nearly all tumor growth curves, as 96.1% of best model confidence sets contain exponential or exponential square model, followed by von Bertalanffy (92.5%), Gompertz (92.1%), Logistic (90.5%), and Monomolecular (58.9%). The percentage of studies, in which all treatment groups can be best fit by exponential or exponential square model, is 91.3% (82.4% for von Bertalanffy, 81.4% for Gompertz, 79.1% for Logistic, 37.3% for Monomolecular). Thus, exponential or exponential square model can be applied to most in vivo mouse studies, and should be preferred for their mathematical simplicity and interpretability. We further demonstrated the utility of the modeling method on a 16-PDX-model study for Irinotecan to identify biological processes and pathways related to its mechanism of action. Citation Format: Huajun Zhou, Binchen Mao, Sheng Guo. Tumor growth modeling and its applications in preclinical pharmacology studies to improve translatability of animal models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2743.

Endometrial Cancer Patient-Derived Xenograft Models: A Systematic Review.

Background: Because patient-derived xenograft (PDX) models resemble the original tumors, they can be used as platforms to find target agents for precision medicine and to study characteristics of tumor biology such as clonal evolution and microenvironment interactions. The aim of this review was to identify articles on endometrial cancer PDXs (EC-PDXs) and verify the methodology and outcomes. Methods: We used PubMed to research and identify articles on EC-PDX. The data were analyzed descriptively. Results: Post literature review, eight studies were selected for the systematic review. Eighty-five EC-PDXs were established from 173 patients with EC, with a total success rate of 49.1%. A 1–10 mm3 fragment was usually implanted. Fresh-fragment implantation had higher success rates than using overnight-stored or frozen fragments. Primary tumors were successfully established with subcutaneous implantation, but metastasis rarely occurred; orthotopic implantation via minced tumor cell injection was better for metastatic models. The success rate did not correspond to immunodeficiency grades, and PDXs using nude mice reduced costs. The tumor growth period ranged from 2 weeks to 13 months. Similar characteristics were observed between primary tumors and PDXs, including pathological findings, gene mutations, and gene expression. Conclusion: EC-PDXs are promising tools for translational research because they closely resemble the features of tumors in patients and retain molecular and histological features of the disease.

High mitochondrial content is associated with breast cancer aggressiveness.

Mitochondria are relevant for cancer initiation and progression. Antibodies against mitochondrially encoded cytochrome c oxidase II (MTCO2), targeting a mitochondria specific epitope, can be used to quantitate the mitochondria content of tumor cells. The present study evaluated the impact of the cellular mitochondrial content on the prognosis of patients with breast cancer using immunohistochemical analysis on 2,197 arrayed breast cancer specimens. Results were compared with histological tumor parameters, patient overall survival, tumor cell proliferation using Ki67 labeling index (Ki67LI) and various other molecular features. Tumor cells exhibited stronger MTCO2 expression than normal breast epithelial cells. MTCO2 immunostaining was largely absent in normal breast epithelium, but was observed in 71.9% of 1,797 analyzable cancer specimens, including 34.6% tumors with weak expression, 22.3% with moderate expression and 15.0% with strong expression. High MTCO2 expression was significantly associated with advanced tumor stage, high Bloom-Richardson-Elston/Nottingham (BRE) grade, nodal metastasis and shorter overall survival (P<0.0001 each). In multivariate analysis, MTCO2 expression did not provide prognostic information independent of BRE grade, pathological tumor and pathological lymph node status. Additionally, significant associations were observed for high MTCO2 expression and various molecular features, including high Ki67LI, amplifications of HER2, MYC, CCND1 and MDM2, deletions of PTEN, 8p21 and 9p, low estrogen receptor expression (P<0.0001 each) and progesterone receptor expression (P<0.0001). The present study demonstrated that high MTCO2 expression was strongly associated with a poor prognosis and unfavorable phenotypical and molecular tumor features in patients with breast cancer. This suggests that the mitochondrial content may have a pivotal role in breast cancer progression.

Retrospective Evaluation of The Cases with Malignant Pheochromocytoma: A Single Center Experience

IIntroduction&#x0D; &#x0D; The aim of this study was to evaluate the clinicodemographic factors and features of tumors in patients with malignant pheochromocytoma.&#x0D; &#x0D; Methods:&#x0D; &#x0D; We retrospectively evaluated the data of 5 cases admitted to our department between 2013 and 2020 and diagnosed with malignant pheochromocytoma.&#x0D; &#x0D; Results:&#x0D; &#x0D; The patients included three females with mean age of 45 years at presentation. Three cases were diagnosed with pheochromocytoma after hypertensive attack and two cases were diagnosed after detection of adrenal mass. The average diameter of the adrenal mass of the cases was 58 mm. Extesion to periadrenal adipose tissue was detected in two patients, vascular invasion in one patient, and capsule invasion in 1 patient in the surgery-resected specimen. Intraabdominal lymph node metastasis was found in 1 patient and metastatic focus was seen in the liver in 1 patient at the time of the diagnosis. During follow-up, perirenal region metastasis was detected in 1 patient. Bone metastasis was seen in 3 patients, lymph node metastasis in 2 patients and lung metastasis in 1 patient. Transperitoneal surrenalectomy was performed in all cases. Lutetium-177, radiotherapy and surgery were the preferred adjuvant therapies. Three patients died because of progression of the disease or acute complications and the other 2 patients are still under follow-up in our clinic.&#x0D; &#x0D; Conclusion:&#x0D; &#x0D; Malignant pheochromocytoma is rare and definitive criteria for malignancy is not established. Prognosis is poor and there is no curative treatment. Resection of malignant pheochromocytoma with intent to cure, which may improve symptoms and possibly survival is important.

Abstract IA16: The International Human Cancer Models Initiative is generating models annotated with clinical and molecular data

Abstract For the past 60 years, cancer research has relied heavily on established cancer cell lines. Their genomes are known to have evolved in vitro and therefore may not reflect well the various salient features of patient tumors (e.g., sensitivity/resistance to cancer therapeutics, etc.). Novel model generation technologies promise to create the next-generation cancer models (NGCMs) to facilitate and enhance studies in various areas of cancer research. The Human Cancer Models Initiative (HCMI) is an international consortium that is developing ~1,000 NGCMs for use in a wide range of cancer-relevant discoveries, from genomic research, cell biology or bio/chemistry studies, to improvements in preclinical and clinical applications. Our goal is to make these models available broadly to the academic and industry researchers (community resource). Therefore, we established a process that ensures the quality of the models and the data associated with them. In my presentation I will describe the Initiative’s pipeline, status (e.g., tumor types, molecular characterization), challenges encountered, and how to obtain the models and associated data. Citation Format: Daniela S. Gerhard. The International Human Cancer Models Initiative is generating models annotated with clinical and molecular data [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA16.

Sonographic features of the testicular adrenal rests tumors in patients with congenital adrenal hyperplasia: a single-center experience and literature review

PurposeTesticular adrenal rests tumor (TART) is a rare kind of benign tumor in the testis. It usually occurred secondary to congenital adrenal hyperplasia (CAH), a hormonal disorder caused by hydroxylase deficiency. As the first-line examination method, ultrasound provides crucial diagnostic information for TART, although misdiagnosis to malignancy is quite common because of its rare prevalence. We aimed to summarize the sonographic manifestations of TART to improve the diagnostic accuracy and specificity.MethodsEight CAH patients with TART identified by ultrasound in our medical center were retrospectively reviewed. Clinical and hormonal profile, semen analysis and treatment choices were collected. Sonographic examinations were performed at the first evaluation and interpreted by experienced radiologists individually. All patients received regular follow-up, and 5 patients undertook repeated scrotal ultrasound. A literature review of TART in CAH patients was conducted, with 123 patients from 23 articles since 1990 included.ResultsA total of 8 patients aged between 4 to 27 years old were enrolled. 7 of 8 (87.5%) patients exhibited bilateral testicular lesions. The sizes of the testicular lesions were between 0.18 ml to 5.68 ml, and all showed a clear boundary. 10/15 (66.7%) lesions were homogenously hypoechoic, 4/15 (26.7%) were heterogeneously iso-hypoechoic, and 1/15 (6.7%) were homogenously isoechoic. 10/15 (66.7%) lesions were hyper-vascular. The longitudinal follow-up of 5 patients showed testicular lesions changed in terms of size, echogenicity, and vascularity after steroid treatment. A potential correlation may exist between ACTH levels and tumor size (p = 0.066). From the literature review, 100/123 (81%) patients got bilateral lesions, and 95% of them were located near the mediastinum. 80/103 (78%) lesions exhibited a clear boundary, and predominant lesions (74%) were hypoechogenic. Vascularity was with great diversity. Seventy-nine lesions of 44 patients were followed-up by scrotal ultrasound, among which 29 (37%) remained unchanged, 29(37%) shrank, and 21(27%) disappeared.ConclusionsKey sonographic characteristics of TART are: resembled lesions on both testes, located near the mediastinum, clear boundary, and changed in size or echogenicity after steroid treatment. These features can help radiologists to make an accurate diagnosis of TART.

Functional Characterization of Brain Tumor-Initiating Cells: Implications for Preclinical Models and Drug Development

Abstract INTRODUCTION Glioblastoma (GBM) is the deadliest and most common primary brain cancer in adults. Brain tumor-initiating cells (BTICs) are a heterogeneous subset of stem-like, invasive cells that play a critical role in treatment failure and recurrence. METHODS Here, we propose a system to functionally characterize patient-derived BTICs to identify features that will guide assessment of therapeutics in a BTIC subpopulation-specific manner. We established and evaluated 5 BTIC populations based on (1) proliferation, (2) stemness, (3) migration, (4) tumorigenesis, (5) clinical characteristics, and (6) therapeutic sensitivity. RESULTS Overall, in Vitro growth trends reflected in Vivo growth rates. However, a significant difference was found between tumor growth in male versus female mice in 3 BTIC lines (QNS108 P = .0011; QNS120 P &lt; .0001; QNS 140 P &lt; .0001). Differences in survival were observed, where BTICs derived from male and female patients produced faster morbidity in mice of the opposite sex (male derived QNS108 male vs female P = .0039; female derived QNS203 male vs female P = .029). QNS203, which was isolated from a tumor in contact with the anterior subventricular zone, decreased survival at a faster rate compared to other cell lines (n = 10 per line, 5 males/5 females, P &lt; .0001). Stem-like properties of BTICs were assessed via differentiation marker expression, sphere-forming capacity, and detection of canonical marker CD133. Higher CD133 expression correlated with faster in Vitro doubling time and greater tumor burden. Histology reflected similar patient tumor features such as migration across the corpus callosum and cystic formation. BTICs revealed varying responses to therapies (TMZ, Radiation, TRAIL, BMP4) and varied competence to retroviral transduction. CONCLUSION By studying the functional features of BTICs within our model of GBM heterogeneity, it was shown that several factors influenced tumorigenesis and survival. These included original tumor location, stemness, variation in therapeutic sensitivity, and a critical finding for the role of sex, an unexplored area for creating next-generation, sex-specific, and BTIC-specific therapeutics.

Leveraging a robust patient-derived xenograft platform to characterize predictors for engraftment and oncologic outcomes in renal cell carcinoma patients.

e16100 Background: Patient-derived xenograft (PDX) models of renal cell carcinoma (RCC) preserve the biological features of patient tumors, providing a platform for biomarker identification and preclinical drug testing. We sought to identify predictors of successful tumor engraftment and evaluate the prognostic value of engraftment in patients with RCC using a robust murine PDX platform. Methods: 1,200 specimens derived from nephrectomy, thrombectomy, metastasectomy, or biopsy were orthotopically (renally) implanted into NOD/SCID mice between 2008-2018. Non-RCC pathology was excluded. Stable engraftment was defined by successful passage of tumor tissue at least twice with histologic confirmation. Clinicopathologic characteristics were stratified by engraftment status, and multivariate (MVA) logistic regression was used to identify predictors of engraftment. Kaplan-Meier and Cox regression analyses were used to assess the prognostic value of engraftment on patient overall (OS) and disease-free (DFS) survival. Results: 1,003 independent PDX lines derived from 770 RCC patients were included. 157 (15.6%) lines successfully engrafted and exhibited higher tumor grade, stage, size, and presence of sarcomatoid or rhabdoid components. 79.3% of all tumors were of clear cell histology, and histologic distribution did not vary by engraftment status. We have completed whole exome sequencing and RNAseq on 197 and 213 PDX lines, respectively, and downstream analyses will be reported. On MVA, sarcomatoid (OR 5.71, p &lt; 0.001), rhabdoid (OR 2.79, p = 0.046), and advanced stage (OR 1.72, p = 0.049) were significant predictors for engraftment, while high grade and metastatic tumor source were significant only on UVA. Engraftment was associated with poor OS (HR 2.11, p &lt; 0.001) and DFS (HR 1.85, p = 0.020) in patients after controlling for sarcomatoid, rhabdoid, grade, stage, and age on MVA. Conclusions: Aggressive RCC biology correlates with successful engraftment in PDX models. Engraftment remains independently predictive of OS and DFS even after controlling for adverse pathologic features. Engraftment in mice may illuminate aspects of tumor biology not captured by clinicopathologic variables and provide insight into novel determinants of tumor aggressiveness and metastasis.

Leveraging a robust patient-derived xenograft platform to characterize predictors for engraftment and oncologic outcomes in renal cell carcinoma patients.

651 Background: Patient-derived xenograft (PDX) models of renal cell carcinoma (RCC) preserve the biological features of patient tumors, providing a platform for biomarker identification and preclinical drug testing. We sought to identify predictors of successful tumor engraftment and evaluate the prognostic value of engraftment in patients with RCC using a robust murine PDX platform. Methods: 1,200 specimens derived from nephrectomy, thrombectomy, metastasectomy, or biopsy were orthotopically (renally) implanted into NOD/SCID mice between 2008-2018. Non-RCC pathology was excluded. Stable engraftment was defined by successful passage of tumor tissue at least twice with histologic confirmation. Clinicopathologic characteristics were stratified by engraftment status, and multivariate (MVA) logistic regression was used to identify predictors of engraftment. Kaplan-Meier and Cox regression analyses were used to assess the prognostic value of engraftment on patient overall (OS) and disease-free (DFS) survival. Results: 1,003 independent PDX lines derived from 770 RCC patients were included. 157 (15.6%) lines successfully engrafted and exhibited higher tumor grade, stage, size, and presence of sarcomatoid or rhabdoid components. Whole exome sequencing was performed on 230 PDX lines. On MVA, sarcomatoid (OR 5.71, p &lt; 0.001), rhabdoid (OR 2.79, p = 0.046), and advanced stage (OR 1.72, p = 0.049) were significant predictors for engraftment, while high grade and metastatic tumor source were significant only on UVA. Engraftment was associated with poor OS (HR 2.11, p &lt; 0.001) and DFS (HR 1.85, p = 0.020) in patients after controlling for sarcomatoid, rhabdoid, grade, stage, and age on MVA. Conclusions: Aggressive RCC biology correlates with successful engraftment in PDX models. Engraftment remains independently predictive of OS and DFS even after controlling for adverse pathologic features. Engraftment in mice may illuminate aspects of tumor biology not captured by clinicopathologic variables and provide insight into novel determinants of tumor aggressiveness and metastasis. Efforts are underway to elucidate genomic drivers of engraftment.

Abstract P5-05-01: A molecularly annotated collection of breast cancer patient-derived xenograft models aligned with ongoing clinical trials built from fine needle aspiration samples throughout neoadjuvant treatment

Abstract BACKGROUND: Patient-derived xenograft (PDX) models of breast cancer replicate the diverse histologic and molecular features of patient tumors and provide a renewable source of human tumor tissue. However, collection of tissue by core needle biopsy is problematic due to patient discomfort, bleeding risk and the limited number of passes a patient can tolerate. Several studies have catalogued the maintenance of molecular features of patient tumors in PDX models of breast cancer. METHODS: To support the neoadjuvant molecular diagnostic and drug development program in triple negative breast cancer (TNBC), a pilot study was conducted to determine if fine needle aspiration (FNA) could be used for building PDX models. Subsequently, PDX models are being established in alignment with ongoing clinical trials at MDACC. The molecular evolution of patient's tumors, matched with PDXs engrafted from their tumors, is under study throughout the neoadjuvant treatment of TNBC using RNA sequencing, whole-exome sequencing, deep sequencing of cancer genes, and histologic analyses. RESULTS: To date, 20 established PDX models have been developed and stable PDX models continue to be generated at a rate of 2-3 per month. Several of these models are derived from serial FNAs derived from patients throughout neoadjuvant treatment. These models retain histologic and molecular features of the original patient tumors. Serial patient biopsies, matched with PDX models, have enabled measurement of the mutational and transcriptomic evolution in vivo of TNBC undergoing neoadjuvant treatment. We have standardized the use of FNAs to generate PDX models both pre- and post-neoadjuvant therapy in the following ongoing neoadjuvant clinical trials: 1. MDACC 2014-0185 (PI Stacy Moulder, 360 patients), 'ARTEMIS: A Randomized TNBC-Enrolling trial to confirm Molecular profiling Improves Survival' 2. MDACC 2014-0045 (PI Jennifer Litton, 20+ patients), 'A pilot study of BMN673 as a neoadjuvant study in patients with a diagnosis of invasive breast cancer and a deleterious BRCA mutation' CONCLUSION: We demonstrated that PDX models from tissue collected by FNA recapitulate the biology and clinical course of the patient's tumor. Sequencing analyses revealed that neoadjuvant chemotherapy and PDX engraftment enrich for cancer gene mutations. We observe association of the rate of successful PDX engraftment with clinical parameters such as the patient's residual cancer burden (RCB) status at the time of surgery (upon completion of neoadjuvant treatment). In addition, we observe that PDX models derived from serial patient biopsies throughout treatment are more resistant to chemotherapy treatment. These models recapitulate the variety of chemotherapy responses observed in patients with TNBC and serve as powerful tools for preclinical biomarker and discovery studies. Citation Format: Echeverria GV, Cai S, Tu Y, McCoy A, Lau R, Redwood A, Rauch G, Adrada B, Candelaria R, Santiago L, Thompson A, Litton J, Moulder S, Symmans F, Chang JT, Piwnica-Worms H. A molecularly annotated collection of breast cancer patient-derived xenograft models aligned with ongoing clinical trials built from fine needle aspiration samples throughout neoadjuvant treatment [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-05-01.

Understanding the Relationship Between Interactive Optimisation and Visual Analytics in the Context of Prostate Brachytherapy.

The fields of operations research and computer science have long sought to find automatic solver techniques that can find high-quality solutions to difficult real-world optimisation problems. The traditional workflow is to exactly model the problem and then enter this model into a general-purpose "black-box" solver. In practice, however, many problems cannot be solved completely automatically, but require a "human-in-the-loop" to iteratively refine the model and give hints to the solver. In this paper, we explore the parallels between this interactive optimisation workflow and the visual analytics sense-making loop. We assert that interactive optimisation is essentially a visual analytics task and propose a problem-solving loop analogous to the sense-making loop. We explore these ideas through an in-depth analysis of a use-case in prostate brachytherapy, an application where interactive optimisation may be able to provide significant assistance to practitioners in creating prostate cancer treatment plans customised to each patient's tumour characteristics. However, current brachytherapy treatment planning is usually a careful, mostly manual process involving multiple professionals. We developed a prototype interactive optimisation tool for brachytherapy that goes beyond current practice in supporting focal therapy - targeting tumour cells directly rather than simply seeking coverage of the whole prostate gland. We conducted semi-structured interviews, in two stages, with seven radiation oncology professionals in order to establish whether they would prefer to use interactive optimisation for treatment planning and whether such a tool could improve their trust in the novel focal therapy approach and in machine generated solutions to the problem.