Pazopanib in Patients with Osteosarcoma Metastatic to the Lung: Phase 2 Study Results and the Lessons for Tumor Measurement

Background. This single-arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable, pulmonary metastatic osteosarcoma. Patients and Methods. Patients with pulmonary metastatic osteosarcoma unresponsive to chemotherapy were eligible. Patients who received prior tyrosine kinase inhibitor therapy were excluded. Pazopanib at 800 mg once daily was administered for 28-day cycles. Tumor responses were evaluated by local radiology assessment 1 month prior to and after initiation of treatment to calculate tumor doubling time and after every even numbered cycle. The primary endpoints were progression-free survival at 4 months, concomitant with a demonstrated 30% increase in tumor doubling time relative to the pretreatment growth rate. Results. 12 patients (7 female) were enrolled. The study was terminated prematurely due to withdrawal of financial support by the sponsor. 8 subjects were eligible for the primary analysis, whereas 4 patients were in a predefined exploratory “slow-growing” cohort. In the “fast-growing” cohort, 3 of the 8 patients (37.5%) eligible for first-stage analysis were deemed “success” by the preplanned criteria, adequate to proceed to second-stage accrual. In addition, 1 of the 4 patients in the “slow-growing” cohort experienced a partial remission. Grade 1-2 diarrhea was the most common adverse event, and grade 3 events were infrequent. Conclusion. This study illustrates a novel method of demonstrating positive drug activity in osteosarcoma by increasing tumor doubling time, and this is further supported by a partial response in a patient with “slow-growing” disease. This trial is registered with NCT01759303.

Tumor Doubling Time Using CT Volumetric Segmentation in Metastatic Adrenocortical Carcinoma

Adrenocortical carcinoma (ACC) is a rare malignancy with an overall unfavorable prognosis. Clinicians treating patients with ACC have noted accelerated growth in metastatic liver lesions that requires rapid intervention compared to other metastatic locations. This study measured and compared the growth rates of metastatic ACC lesions in the lungs, liver, and lymph nodes using volumetric segmentation. A total of 12 patients with metastatic ACC (six male; six female) were selected based on their medical history. Computer tomography (CT) exams were retrospectively reviewed and a sampling of ≤5 metastatic lesions per organ were selected for evaluation. Lesions in the liver, lung, and lymph nodes were measured and evaluated by volumetric segmentation. Statistical analyses were performed to compare the volumetric growth rates of the lesions in each organ system. In this cohort, 5/12 had liver lesions, 7/12 had lung lesions, and 5/12 had lymph node lesions. A total of 92 lesions were evaluated and segmented for lesion volumetry. The volume doubling time per organ system was 27 days in the liver, 90 days in the lungs, and 95 days in the lymph nodes. In this series of 12 patients with metastatic ACC, liver lesions showed a faster growth rate than lung or lymph node lesions.

A novel tumor doubling time-related immune gene signature for prognosis prediction in hepatocellular carcinoma

Background Hepatocellular carcinoma (HCC) has become a global health issue of wide concern due to its high prevalence and poor therapeutic efficacy. Both tumor doubling time (TDT) and immune status are closely related to the prognosis of HCC patients. However, the association between TDT-related genes (TDTRGs) and immune-related genes (IRGs) and the value of their combination in predicting the prognosis of HCC patients remains unclear. The current study aimed to discover reliable biomarkers for anticipating the future prognosis of HCC patients based on the relationship between TDTRGs and IRGs. Methods Tumor doubling time-related genes (TDTRGs) were acquired from GSE54236 by using Pearson correlation test and immune-related genes (IRGs) were available from ImmPort. Prognostic TDTRGs and IRGs in TCGA-LIHC dataset were determined to create a prognostic model by the LASSO-Cox regression and stepwise Cox regression analysis. International Cancer Genome Consortium (ICGC) and another cohort of individual clinical samples acted as external validations. Additionally, significant impacts of the signature on HCC immune microenvironment and reaction to immune checkpoint inhibitors were observed. Results Among the 68 overlapping genes identified as TDTRG and IRG, a total of 29 genes had significant prognostic relevance and were further selected by performing a LASSO-Cox regression model based on the minimum value of λ. Subsequently, a prognostic three-gene signature including HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), C-type lectin domain family 1 member B (CLEC1B), and Collectin sub-family member 12 (COLEC12) was finally identified by stepwise Cox proportional modeling. The signature exhibited superior accuracy in forecasting the survival outcomes of HCC patients in TCGA, ICGC and the independent clinical cohorts. Patients in high-risk subgroup had significantly increased levels of immune checkpoint molecules including PD-L1, CD276, CTLA4, CXCR4, IL1A, PD-L2, TGFB1, OX40 and CD137, and are therefore more sensitive to immune checkpoint inhibitors (ICIs) treatment. Finally, we first found that overexpression of CLEC1B inhibited the proliferation and migration ability of HuH7 cells. Conclusions In summary, the prognostic signature based on TDTRGs and IRGs could effectively help clinicians classify HCC patients for prognosis prediction and individualized immunotherapies.

Duration of lead time in screening for gastric cancer

Objective: Estimates of lead time (LT), i.e., from detection of cancer in asymptomatic persons to manifestations of the disease, can be obtained by follow-up of populations at risk, reviews of the past histories of patients with cancer, estimates of tumor doubling time, and from the ratio between the prevalence of cancer at the first round of screening and its annual incidence on subsequent screening rounds. Aim of this study is to derive the LT of gastric cancer (GC) from published studies. Material and Methods: An overview of longitudinal studies and screening trials of GC; search of the reference sections of the retrieved papers for additional relevant studies; and calculation of the LT derived from these studies. Results: LT was 2.8 – 7.3 years if derived from prospective follow-up studies; 1.0 - 4.0 years if derived from retrospective reviews of the patients' histories before the clinical diagnosis of GC; 5.9 - 8.6 years if derived from tumor doubling time; and 1.8 - 4.3 years if derived from prevalence / /incidence ratios. Conclusions: There is wide variability in estimates of the LT of GC. Since an LT exceeding 6 six years may explain the improved survival of patients with screen-detected GS, the present survey does not obviate the need for randomized clinical trials of the effect of screening on gastric cancer mortality.

Expression of p53 Protein Associates with Anti-PD-L1 Treatment Response on Human-Derived Xenograft Model of GATA3/CR5/6-Negative Recurrent Nonmuscular Invasive Bladder Urothelial Carcinoma

Background: The possible involvement of p53 signaling, FGFR3 expression, and FGFR3 mutation rates in the prediction of the NMIBC anti-PD-L1 treatment response needs to be clarified. The main aim of our study was to explore predictive value of p53 expression, FGFR3 expression, and its gene mutation status for the therapeutic success of anti-PD-L1 treatment in the patient-derived murine model of recurrent high-PD-L1(+) GATA3(-)/CR5/6(-) high-grade and low-grade NMIBC. Methods: twenty lines of patient-derived xenografts (PDXs) of relapsed high-PD-L1(+) double-negative NMIBC were developed, of which 10 lines represented high-grade tumors and the other ones—low-grade bladder cancer. Acceptors of each grade-related branch received specific anti-PD-L1 antibodies. Animals’ survival, tumor-doubling time, and remote metastasis were followed during the post-interventional period. PD-L1, GATA3, CR5/6, and p53 protein expressions in engrafted tumors were assessed by immunohistochemistry. The FGFR3 expression and FGFR3 mutations in codons 248 and 249 were detected by real-time polymerase chain reaction. Results: The expression of p53 protein is an independent factor affecting the animals’ survival time [HR = 0.036, p = 0.031] of anti-PD-L1-treated mice with low-grade high-PD-L1(+) double-negative NMIBC PDX. The FGFR3 expression and FGFR3 mutation rate have no impact on the anti-PD-L1 treatment response in the interventional groups. Conclusions: p53 expression may be considered as a prognostic factor for the anti-PD-L1 treatment efficacy of low-grade high-PD-L1-positive GATA3(-)/CR5/6(-)-relapsed noninvasive bladder cancer.

Tumor perfusion evaluation using dynamic contrast-enhanced ultrasound after electrochemotherapy and IL-12 plasmid electrotransfer in murine melanoma

Electrochemotherapy with bleomycin (ECT BLM) is an effective antitumor treatment already used in clinical oncology. However, ECT alone is still considered a local antitumor therapy because it cannot induce systemic immunity. When combined with adjuvant gene electrotransfer of plasmid DNA encoding IL-12 (GET pIL-12), the combined therapy leads to a systemic effect on untreated tumors and distant metastases. Although the antitumor efficacy of both therapies alone or in combination has been demonstrated at both preclinical and clinical levels, data on the predictors of efficacy of the treatments are still lacking. Herein, we evaluated the results of dynamic contrast-enhanced ultrasound (DCE-US) as a predictive factor for ECT BLM and GET pIL-12 in murine melanoma. Melanoma B16F10 tumors grown in female C57Bl/6NCrl mice were treated with GET pIL-12 and ECT BLM. Immediately after therapy, 6 h and 1, 3, 7 and 10 days later, tumors were examined by DCE-US. Statistical analysis was performed to inspect the correlation between tumor doubling time (DT) and DCE-US measurements using semilinear regression models and Bland–Altman plots. Therapeutic groups in which DCE-US showed reduced tumor perfusion had longer tumor DTs. It was confirmed that the DCE-US parameter peak enhancement (PE), reflecting relative blood volume, had predictive value for the outcome of therapy: larger PE correlated with shorter DT. In addition, perfusion heterogeneity was also associated with outcome: tumors that had more heterogeneous perfusion had faster growth, i.e., shorter DTs. This study demonstrates that DCE-US can be used as a method to predict the efficacy of electroporation-based treatment.

Growth rate and site of pulmonary metastasis to predict lung relapse and overall survival in patients affected by bone and soft tissue sarcomas (B-STS).

11571 Background: Despite surgically resectable pulmonary metastases may lead to cure patients with B-STS (Chudgar NP 2017), a substantial proportion of patients will eventually relapse. Presently, patient selection is based on unique organ involvement, number of metastases, interval between previous surgery and pulmonary progression or relapse. We assessed the impact of anatomical site of metastasis into the lung (as if the pleural site might ease further tumor spreading) and nodule growth rate as additional predictive/prognostic factors of lung progression-free survival (L-PFS) and overall survival (OS). Methods: In our prospectively collected database, we retrospectively evaluated patients operated for B-STS pulmonary progression at 3 different centers from 2005 to 2019. Beyond patients’ clinical features at both baseline and disease progression in the lungs, we focused on whether the relapse occurred into the parenchyma or nearby the pleura (Welter S 2012); secondly, we estimated lung metastasis growth rate, defined as tumor doubling time (TDT) (Nakamura T 2011). Statistical analyses were carried out with IBM SPSS (v. 20.0). Survival outcomes were estimated by Kaplan-Meier method. Hazard ratios (HR) were estimated by Cox regression. Multivariate analysis was performed for both L-PFS and OS according to Cox proportional hazard model. All tests were 2-sided with their corresponding 95% confidence intervals (CI95%). Results: We identified 138 patients who underwent lung metastasectomy [(F=66 (48%); median age at surgery 50 (14-78)]. Median PFS and L-PFS were 8.7 months (CI95% 6.6-10.9) and 8.6 months (CI95% 6.2-11.0), respectively. Median OS was 40.6 months (CI 95% 32.8-48.5). Univariate analysis showed a statistically significant impact of the following variables for both L-PFS and OS: ECOG 0, nodule number <3, being disease-free after first-line treatment, no pleural involvement, and TDT >40 days. Disease-free interval ≤ 24 months and absence of metastases at diagnosis showed significant correlation with L-PFS and OS, respectively. At multivariate analyses the following variables retained statistical significance for L-PFS: TDT >40 days (HR 0.53, CI95% 0.31-0.93, p=0.028); nodule number <3 (HR 0.54, 95%CI 0.29-0.99, p=0.048), no pleural involvement (HR 0.39, CI95% 0.22-0.70, p=0.001); and for OS: TDT >40 days (HR 0.36, CI95% 0.18-0.72, p=0.004), nodule number <3 (HR 0.35, 95%CI 0.18-0.71, p=0.004), no pleural involvement (HR 0.49, CI95% 0.24-0.98, p=0.045), and ECOG 0 (HR 0.29, 95%CI 0.14-0.59, p=0.001). Conclusions: Acknowledging its retrospective nature and the need for an external validation, our series highlights the key-role of the anatomical site of relapse within the lung and the impact of tumor growth rate. If confirmed, these two clinical parameters should be factored in the decision making on performing pulmonary metastasectomy.