Tumor Volume Doubling Time Research Articles

Earlier Diagnosis Not Self-Evidently Beneficial: Natural History of Subcentimeter Lung Cancers.

OBJECTIVE. We estimated the natural history of subcentimeter stage I non-small cell lung cancers detected on screening CT using a computed mean 230-day tumor volume doubling time and exponential growth. CONCLUSION. We found that the majority of patients with subcentimeter, non-small cell lung cancers would survive for more than 5 years without treatment. The benefit of cancer interdiction would be offset to some extent by the combined effects of surgical mortality and materially diminished longer-term disease-free survival among the more than 40% of patients who would be overdiagnosed.

Tumor Volume Doubling Time in Active Surveillance of Papillary Thyroid Carcinoma.

Background: Tumor volume (TV) of papillary thyroid carcinoma (PTC) increases exponentially during active surveillance, and the growth rate differs for each patient. TV doubling time (TVDT) is considered a strong dynamic marker for the prediction of the growth rate and progression of the tumor. Methods: This cohort study analyzed 273 PTC patients who underwent active surveillance for more than one year rather than immediate thyroid surgery. TVDT was calculated in each patient, and patients were divided into two groups: rapid-growing (TVDT <5 years) and stable (TVDT ≥5 years). Clinical and initial ultrasonography (US) features between the two groups were compared. Results: The median patient age was 51.1 years (interquartile range [IQR] 42.2-61.0 years), and 76% of the patients were women. The initial TV of PTC was 62.1 mm3 (IQR 28.1-122.8 mm3). During a median of 42 months (IQR 29-61 months) of active surveillance, 10.3% of the patients had a TVDT of less than two years, 5.1% had a TVDT between two and three years, 6.2% had a TVDT between three and four years, 6.6% had a TVDT between four and five years, and 71.8% had a TVDT of five years or more. Patients in the rapid-growing group (77 patients; 28.2%) were significantly younger (p = 0.004) than those in the stable group (196 patients; 71.8%). Being younger than 50 years of age was significantly associated with rapid tumor growth of PTC (odds ratio = 2.31 [confidence interval 1.30-4.31], p = 0.004) in multivariate analysis. In ultrasound findings, macrocalcification was independently associated with rapid tumor growing of PTCs (odds ratio = 4.98 [confidence interval 2.19-11.69], p < 0.001). Conclusions: TVDT is a good indicator for presenting the growing velocity of PTCs during active surveillance. Younger age and macrocalcification in the initial US were associated with rapid-growing PTCs. Determination of TVDT during the early phase of active surveillance may be helpful for the prediction of rapidly progressing PTCs and deciding whether to adopt an early surgical approach.

Prolongation of tumour volume doubling time (midDT) is associated with improvement in disease-specific survival in patients with rapidly progressive radioactive iodine refractory differentiated thyroid cancer selected for molecular targeted therapy.

To assess molecular targeted therapy (MTT)'s ability to affect tumour volume doubling time (TVDT) and disease-specific survival (DSS) in patients presenting with lung metastasis from radioactive iodine refractory progressive thyroid cancer. In this retrospective study, we examined the clinical characteristics, average tumour volume doubling times of lung metastasis and disease-specific survival of patients with lung metastasis from differentiated thyroid cancer who were treated with MTT. The 5-year DSS from the distant metastasis (DM) diagnosis was 72% with median survival of 8years (95% CI: 6.6-9.5). The median survival was 2.9years after MTT start (95% CI: 2.1-3.6). On MTT, lung average tumour volume doubling time (midDT) was prolonged to midDT ≥3years in 75% of patients with baseline midDT ≤1year and 100% of patients with midDT 1-3years. In patients with rapidly progressive thyroid cancer (midDT ≤1year at baseline), the median survival was 4.5years in those with MTT-achieved midDT ≥3years (95% CI: 2.9-6.2), as opposed to 2.3years (95% CI: 0.3-4.3) and 0.7years (95% CI: 0.2-1.3) in those with MTT-achieved midDT of 1-3years and MTT-achieved midDT ≤1year, respectively (log rank P<0.001). Lung midDT is a useful and important clinical marker of disease-specific survival for patients with progressive radioactive iodine refractory (RAIR) metastatic thyroid cancer. In patients with rapidly progressive metastatic RAIR thyroid cancer, molecular targeted therapy prolongs lung tumour volume doubling time and is associated with improved disease-specific survival.

Acoustic feedback enables safe and reliable carboplatin delivery across the blood-brain barrier with a clinical focused ultrasound system and improves survival in a rat glioma model.

The blood-brain barrier (BBB) restricts delivery of most chemotherapy agents to brain tumors. Here, we investigated a clinical focused ultrasound (FUS) device to disrupt the BBB in rats and enhance carboplatin delivery to the brain using the F98 glioma model.Methods: In each rat, 2-3 volumetric sonications (5 ms bursts at 1.1 Hz for 75s) targeted 18-27 locations in one hemisphere. Sonication was combined with Definity microbubbles (10 µl/kg) and followed by intravenous carboplatin (50 mg/kg). Closed-loop feedback control was performed based on acoustic emissions analysis.Results: Safety and reliability were established in healthy rats after three sessions with carboplatin; BBB disruption was induced in every target without significant damage evident in MRI or histology. In tumor-bearing rats, concentrations of MRI contrast agent (Gadavist) were 1.7 and 3.3 times higher in the tumor center and margin, respectively, than non-sonicated tumors (P<0.001). Tissue-to-plasma ratios of intact carboplatin concentrations were increased by 7.3 and 2.9 times in brain and tumor respectively, at one hour after FUS and 4.2 and 2.4 times at four hours. Tumor volume doubling time in rats receiving FUS and carboplatin increased by 96% and 126% compared to rats that received carboplatin alone and non-sonicated controls, respectively (P<0.05); corresponding increases in median survival were 48% and 66% (P<0.01).Conclusion: Overall, this work demonstrates that actively-controlled BBB disruption with a clinical device can enhance carboplatin delivery without neurotoxicity at level that reduces tumor growth and improves survival in an aggressive and infiltrative rat glioma model.

Mathematical determination of some oncological parameters and their therapeutic implications in dogs

Cancer is a serious life-threatening disease with increased morbidity and mortality in dogs. A number of cancers are diagnosed after metastasis has taken place when therapeutic intervention would have been useless. In view of this, mammary gland tumors and adenocarcinoma of the lungs were calculated using some established and revised formulas. The reported fundamental parameters were calculated using macroscopy. But the mathematical oncological analysis revealed that tumor doubling time (82.1–123.1 days) of adenocarcinoma of the lung was lower than that of complex mammary adenoma (101.3–151.9 days), complex carcinoma of the lung (215.5–323.2 days), and benign mammary gland tumor (810–1215 days), respectively, suggesting that adenocarcinoma of the lung proliferates faster than the remaining cancers. Cancer cells per year for adenocarcinoma (1.21 × 108), benign mammary gland tumor (1.35 × 109), complex mammary adenoma (1.4–3.3 × 108), and complex carcinoma of the lung (3.4 × 108) with benign mammary gland tumor metastasized and others were about to metastasize. Therefore, the formulas can be used in estimation of some oncological parameters such as tumor volume, tumor weight, and tumor doubling time. All the investigated tumors can be managed chemotherapeutically if detected early enough. However, adenocarcinoma of the lung may be proven very difficult to treat because of low tumor doubling, doubling time followed by complex mammary adenoma, and complex carcinoma of the lung. Hence, oncological parameters could serve as indices of successful therapeutic interventions.

MS32.02 Patient Derived Models (PDX and CTC-Derived)

Patient-derived xenograft (PDX) models are a powerful preclinical tool for studying small cell lung cancer (SCLC) biology and therapeutic vulnerabilities. SCLC PDX models can be generated from biopsies or circulating tumor cells (CTCs), though these approaches can be limited by scarcity of tissue and low efficiency of tumor growth. Applying an established clinical-translational pipeline for tissue collection and an automated microfluidic platform for CTC-enrichment, we have generated over 40 PDX models. In a 24-month period, we initiated 17 biopsy-derived PDXs and 17 CTC-derived PDXs, at 89% and 38% efficiency, respectively (Drapkin et al., Cancer Discovery 2018). Whole exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs. Early-passage PDXs maintain the genomic and transcriptional profiles of the founder PDX. We have standardized quantitative measurements of efficacy of in vivo treatments, utilizing both depth of tumor shrinkage (response) and time to tumor volume doubling (time to progression). With these approaches, we have assessed responses to both standard of care and experimental therapies across a large panel of mice. We find that sensitivity to etoposide and platinum (EP) corresponds with the treatment history of patients, and that resistance to EP corresponded to increased expression of a MYC gene signature. Similarly, responses of the PDXs to an experimental combination, olaparib and temozolomide, mirrors the responses seen in patients treated on a clinical trial (Farago et al., ASCO 2018). Biomarker analysis in this panel reveals that basal PARylation is a highly sensitive and specific predictor of response to olaparib and temozolomide. Collectively, this experience highlights the utility of PDX models in SCLC for biomarker discovery and assessment of novel therapeutic strategies. 1. Drapkin BJ, George J, Christensen CL, Mino-Kenudson M, Dries R, Sundaresan T, Phat S, Myers DT, Zong J, Igo P, Hazar-Rethinam MH, Licausi JA, Gomez-Caraballo M, Kem M, Jani KN, Azimi R, Abedpour N, Menon R, Lakis S, Heist RS, Buttner R, Haas S, Sequist LV, Shaw AT, Wong K-K, Hata A, Toner M, Maheswaran S, Haber DA, Peifer M, Dyson N, Thomas RK, Farago AF. Genomic and functional fidelity of small cell lung cancer patient-derived xenografts. Cancer Discovery 2018 May 8(5):600-615. PMID: 29483136 2. Farago AF, Drapkin BJ, Charles A, Yeap B, Heist RS, Azzoli CG, Jackman D, Marcoux P, Barbie D, Myers DT, Phat S, Zhong J, Grinnell JB, Sequist LV, Mino-Kenudson M, Maheswaran S, Haber D, Hata A, Dyson N, Shaw AT. Safety and efficacy of combination olaparib (O) and temozolomide (T) in small cell lung cancer (SCLC). American Society of Clinical Oncology Annual Meeting, June 1-5 2018. Poster presentation

Impact of hepatocellular carcinoma aetiology and liver function on the benefit of surveillance: A novel approach for the adjustment of lead-time bias.

Surveillance reportedly has benefit on survival in patients with hepatocellular carcinoma (HCC), even after adjustment for lead-time bias. However, previous adjustment for lead-time bias using tumour volume doubling time (TVDT) had inherent problem in accuracy. We evaluated survival benefit of HCC surveillance with newly developed approach for adjusting lead-time bias. In addition, survival benefit was evaluated according to HCC aetiology and liver function. A total of 3899 patients were studied. TVDT was calculated in 255 study patients with ≥2 tumour size measurements before the diagnosis of HCC. Adjusted survival time was calculated based on TVDT, as the time from when HCC was assumed to be 5mm to death or last follow-up. Survival rates based on this adjusted survival time were compared between the surveillance and nonsurveillance groups and categorized by HCC aetiology and liver function. Calculated TVDT varied widely by study patients (median 141.9, IQR, 73.1-261.7days). Survival rates based on adjusted survival time were higher in the surveillance group overall and by patients HCC aetiology. Whereas adjusted survival rates were higher in the surveillance group in Child-Pugh class A patients, the survival benefit was smaller in Child-Pugh class B patients and not statistically significant in Child-Pugh class C patients. The survival benefit of surveillance for patients with HCC was demonstrated after adjustment for lead-time bias with novel, more accurate methodology. However, the benefits differed based on liver function and may vary largely by patients because of wide variation in TVDT.

Consolidated mathematical growth model of the primary tumor and secondary distant metastases of breast cancer (CoMPaS).

The goal of this research is to improve the accuracy of predicting the breast cancer (BC) process using the original mathematical model referred to as CoMPaS. The CoMPaS is the original mathematical model and the corresponding software built by modelling the natural history of the primary tumor (PT) and secondary distant metastases (MTS), it reflects the relations between the PT and MTS. The CoMPaS is based on an exponential growth model and consists of a system of determinate nonlinear and linear equations and corresponds to the TNM classification. It allows us to calculate the different growth periods of PT and MTS: 1) a non-visible period for PT, 2) a non-visible period for MTS, and 3) a visible period for MTS. The CoMPaS has been validated using 10-year and 15-year survival clinical data considering tumor stage and PT diameter. The following are calculated by CoMPaS: 1) the number of doublings for the non-visible and visible growth periods of MTS and 2) the tumor volume doubling time (days) for the non-visible and visible growth periods of MTS. The diameters of the PT and secondary distant MTS increased simultaneously. In other words, the non-visible growth period of the secondary distant MTS shrinks, leading to a decrease of the survival of patients with breast cancer. The CoMPaS correctly describes the growth of the PT for patients at the T1aN0M0, T1bN0M0, T1cN0M0, T2N0M0 and T3N0M0 stages, who does not have MTS in the lymph nodes (N0). Additionally, the CoMPaS helps to consider the appearance and evolution period of secondary distant MTS (M1). The CoMPaS correctly describes the growth period of PT corresponding to BC classification (parameter T), the growth period of secondary distant MTS and the 10-15-year survival of BC patients considering the BC stage (parameter M).

Abstract 4106: Hyperpolarized [1-13C]-pyruvate/lactate magnetic resonance spectroscopic imaging of prostate cancer in vivo predicts response to lactate dehydrogenase inhibition

Abstract Purpose: Non-invasive magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized (HP) 13C-labeled pyruvate and its metabolite lactate is being used to monitor the metabolic flux in solid tumors. In this study, we evaluate the potential of MRSI of HP [1-13C]-pyruvate and [1-13C]-lactate, in prostate cancer as a predictive biomarker for targeting lactate dehydrogenase. Experimental Design: Two human prostate cancer cell lines (DU145 and PC3) were grown as xenografts. The conversion of pyruvate to lactate in xenografts was measured, after intravenous delivery of hyperpolarized [1-13C] pyruvic acid, by MRSI. Steady state metabolomic analysis of xenograft tumors was performed by mass spectrometry and steady state lactate levels were measured with proton (1H) MRS. Perfusion and oxygenation of xenografts were measured with electron paramagnetic resonance (EPR) imaging. Tumor growth was assessed after lactate dehydrogenase (LDH) inhibition with FX-11 (42 µg/mouse/day for 5 days x 2 weekly cycles). Lactate production, pyruvate uptake, extracellular acidification rates and oxygen consumption of the prostate cancer cell lines was analyzed in vitro. Protein levels of glycolysis regulators were assessed with immunoblotting. Results: DU145 tumors demonstrated an enhanced conversion of pyruvate to lactate with HP [1-13C] MRSI relative to PC3 tumors (21% higher 13C-lactate/pyruvate p&amp;lt;0.05). In addition, DU145 xenografts have a 42% (p&amp;lt;0.05) reduction in 13C-lactate/pyruvate after FX-11 treatment while PC3 xenografts demonstrate no sensitivity to FX-11 treatment. In correlation FX-11 significantly delayed DU145 tumor volume doubling time by 3.4 days (p&amp;lt;0.05). By comparison no difference was observed between DU145 and PC3 xenografts in steady state measures of lactate, oxygenation, or perfusion. The two cell lines also exhibited similar pyruvate uptake, lactate production, extracellular acidification and oxygen consumption rates and sensitivity to FX-11 in vitro. Difference in the expression of glycolysis regulators such as Hif-1α, LDHA, MCT1, MCT4, HK2 and PFKP were observed in vitro but did not correlate with HP [13C]-lactate/pyruvate MRSI results or FX-11 sensitivity. Conclusions: Hyperpolarized [1-13C]-pyruvate MRSI of prostate cancer xenografts predicted the efficacy of targeting LDH when steady state markers of glycolysis, in vivo and in vitro, did not. Citation Format: Bradley T. Scroggins, Masayuki Matsuo, Ayla O. White, Keita Saito, Jeeva P. Munasinghe, Carole Sourbier, Kazutoshi Yamamoto, Vivian Diaz, James B. Mitchell, Murali C. Krishna, Deborah E. Citrin. Hyperpolarized [1-13C]-pyruvate/lactate magnetic resonance spectroscopic imaging of prostate cancer in vivo predicts response to lactate dehydrogenase inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4106.

Abstract B35: An innovative in vivo model of metastasizing prostate cancer using orthotopic xenografts

Abstract Introduction: In this study, we aimed to develop a versatile in vivo model of prostate cancer using orthotopic xenografts, which adequately represents intraprostatic tumor growth as well as the natural routes of metastatic spread. Materials and Methods: 5x105 VCaP-, LuCaP136-, and LuCaP147 cells were injected into the prostate of male CB17-SCID mice (n=8 for each cell line; VCaP cultured as monolayer, LuCaP136 and LuCaP147 as three-dimensional spheroid culture). During 12 weeks of follow-up, orthotopic tumor growth and the development of metastases was monitored by repetitive serum-PSA measurements and imaging studies (ultrasonography, CT, MRI). At autopsy, primary tumors and metastases were harvested and examined by conventional histology (H&amp;E) and immunohistochemistry (CK5, CK8, AMACR, AR, Ki67, ERG, PSA). From the results of the imaging studies and PSA measurements, tumor volume doubling time, tumor-specific growth rate, and PSA-density were calculated for each cell line. Results: All 24 mice developed orthotopic tumors, whose growth could be reliably monitored by ultrasonography, CT, MRI, and serum-PSA measurements. 4 animals died during follow-up (1 in the VCaP group, 1 in the LuCaP136 group, 2 in the LuCaP147 group). Mean PSA-density was 433.9 ng/ml per ml tumor in the VCaP group, 6.5 ng/ml per ml tumor in the LuCaP136 group, and 11.2 ng/ml per ml tumor in the LuCaP147 group. Tumor-specific growth rate and tumor volume doubling time were 3.87% per day and 21.24 days in the VCaP group, 3.11% and 27.57 days in the LuCaP136 group, and 4.47% and 16.2 days in the LuCaP147 group, respectively. In up to 100% of animals, lymph node metastases could be detected after 12 weeks (5/7 in the VCaP group, 6/7 in the LuCaP136 group, 6/6 in the LuCaP147 group). These could also be visualized by ultrasonography and MRI. Immunohistochemistry showed positive CK8, AR, and AMACR as well as negative CK5 reactions in all tumors. ERG-straining was positive in VCaP and negative in both LuCaP tumors, Ki67 proliferation indices were &amp;gt;90% in all groups. Conclusions: By using different monolayer as well as 3D spheroid cell cultures in an orthotopic xenograft model, we could establish an innovative, versatile in vivo model of prostate cancer, which enables the study of both intraprostatic tumor growth as well as metastatic spread to regional lymph nodes. Citation Format: Johannes Linxweiler, Christina Körbel, Andreas Müller, Markus Hammer, Michael Stöckle, Kerstin Junker, Michael D. Menger. An innovative in vivo model of metastasizing prostate cancer using orthotopic xenografts [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B35.

Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

Multiscale systems pharmacological analysis of everolimus action in hepatocellular carcinoma.

Dysregulation of mTOR pathway is common in hepatocellular carcinoma (HCC). A translational quantitative systems pharmacology (QSP), pharmacokinetic (PK), and pharmacodynamic (PD) model dissecting the circuitry of this pathway was developed to predict HCC patients' response to everolimus, an mTOR inhibitor. The time course of key signaling proteins in the mTOR pathway, HCC cells viability, tumor volume (TV) and everolimus plasma and tumor concentrations in xenograft mice, clinical PK of everolimus and progression free survival (PFS) in placebo and everolimus-treated patients were extracted from literature. A comprehensive and multiscale QSP/PK/PD model was developed, qualified, and translated to clinical settings. Model fittings and simulations were performed using Monolix software. The S6-kinase protein was identified as critical in the mTOR signaling pathway for describing everolimus lack of efficacy in HCC patients. The net growth rate constant (kg) of HCC cells was estimated at 0.02h-1 (2.88%RSE). The partition coefficient of everolimus into the tumor (kp) was determined at 0.06 (12.98%RSE). The kg in patients was calculated from the doubling time of TV in naturally progressing HCC patients, and was determined at 0.004day-1. Model-predicted and observed PFS were in good agreement for placebo and everolimus-treated patients. In conclusion, a multiscale QSP/PK/PD model elucidating everolimus lack of efficacy in HCC patients was successfully developed and predicted PFS reasonably well compared to observed clinical findings. This model may provide insights into clinical response to everolimus-based therapy and serve as a valuable tool for the clinical translation of efficacy for novel mTOR inhibitors.

PD51-12 COMPARISON OF MID-TERM ONCOLOGICAL OUTCOMES OF ACTIVE SURVEILLANCE AND PERCUTANEOUS CRYOABLATION OF SMALL RENAL MASSES

You have accessJournal of UrologyKidney Cancer: Localized: Active Surveillance1 Apr 2018PD51-12 COMPARISON OF MID-TERM ONCOLOGICAL OUTCOMES OF ACTIVE SURVEILLANCE AND PERCUTANEOUS CRYOABLATION OF SMALL RENAL MASSES Paolo Umari, Michele Rizzo, Michele Billia, Nicola Pavan, Gaetano Chiapparrone, Giovanni Liguori, Fulvio Stacul, Monica Zacchero, Paolo De Angelis, Alessandro Volpe, and Carlo Trombetta Paolo UmariPaolo Umari More articles by this author , Michele RizzoMichele Rizzo More articles by this author , Michele BilliaMichele Billia More articles by this author , Nicola PavanNicola Pavan More articles by this author , Gaetano ChiapparroneGaetano Chiapparrone More articles by this author , Giovanni LiguoriGiovanni Liguori More articles by this author , Fulvio StaculFulvio Stacul More articles by this author , Monica ZaccheroMonica Zacchero More articles by this author , Paolo De AngelisPaolo De Angelis More articles by this author , Alessandro VolpeAlessandro Volpe More articles by this author , and Carlo TrombettaCarlo Trombetta More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2352AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Partial nephrectomy (PN) is considered the standard approach for small renal masses (SRMs). Active surveillance (AS) and ablative therapies represent emerging strategies for older and comorbid patients due to the indolent behaviour of most SRMs and to the high competing risk mortality. Aim of this study was to compare the mid-term oncological outcomes of AS and percutaneous cryoablation (PCA) of small renal masses (SRMs). METHODS Data regarding PCA and AS in patients with a single T1a renal tumors were collected prospectively at two large academic centers. 60 patients underwent PCA and 77 were enrolled in a AS protocol. The minimum follow-up period was 6 months. The most frequent indications for AS were severe comorbidities (48,1%), <15 mm renal masses (23,4%) and advanced age (15,6%). All patients in AS were followed with a standardized protocol including serial imaging (US, CT or MRI) every 6 months during the first 3 years and yearly thereafter. Tumor progression was defined as the reach of a 4 cm threshold in maximum diameter or a tumor volume doubling time <12 months. All PCA procedures were performed with a percutaneous approach. A double freeze-thaw cycle was performed using a mean of 2 sealed argon 17G cryoprobes per patient. Tumor progression after PCA was defined as a new nodular enhancement in the ablation zone or the enlargement of the ablated tumor 3 months after the treatment. RESULTS 14 masses showed dimensional progression during AS and 9 were surgically removed after a median follow-up of 30 months. 3 patients in the PCA group experienced progression and underwent a repeat ablation with a median follow-up of 24 months. Progression free survival (PFS) at 2 years was 94,8% and 95,0% for AS and PCA group, respectively. None of the patients progressed to metastatic disease. Overall survival at 2 years was 93,5% and 95,0% in the AS and PCA group, respectively. In the PCA group the complication rate was 5% (Clavien grade 1-2). CONCLUSIONS There are no good quality studies comparing the oncological outcomes of AS and PCA. Comparing AS to an active treatment is not an easy task due to the different definitions of the oncological endpoints such as PFS. With these limitations this study shows that both AS and PCA represent viable and safe treatment options for elderly and comorbid patients with SRMs. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e980 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Paolo Umari More articles by this author Michele Rizzo More articles by this author Michele Billia More articles by this author Nicola Pavan More articles by this author Gaetano Chiapparrone More articles by this author Giovanni Liguori More articles by this author Fulvio Stacul More articles by this author Monica Zacchero More articles by this author Paolo De Angelis More articles by this author Alessandro Volpe More articles by this author Carlo Trombetta More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

177 (PB-078) - Tumor volume doubling time of invasive breast cancer in women with a BRCA1 mutation; A retrospective study

177 (PB-078) - Tumor volume doubling time of invasive breast cancer in women with a BRCA1 mutation; A retrospective study

A novel mouse model of human prostate cancer to study intraprostatic tumor growth and the development of lymph node metastases

In this study, we aimed to establish a versatile in vivo model of prostate cancer, which adequately mimics intraprostatic tumor growth, and the natural routes of metastatic spread. In addition, we analyzed the capability of high-resolution ultrasonography (hrUS), in vivo micro-CT (μCT), and 9.4T MRI to monitor tumor growth and the development of lymph node metastases. A total of 5 × 105 VCaP cells or 5 × 105 cells of LuCaP136- or LuCaP147 spheroids were injected into the prostate of male CB17-SCID mice (n = 8 for each cell type). During 12 weeks of follow-up, orthotopic tumor growth, and metastatic spread were monitored by repetitive serum-PSA measurements and imaging studies including hrUS, μCT, and 9.4T MRI. At autopsy, primary tumors and metastases were harvested and examined by histology and immunohistochemistry (CK5, CK8, AMACR, AR, Ki67, ERG, and PSA). From imaging results and PSA-measurements, tumor volume doubling time, tumor-specific growth rate, and PSA-density were calculated. All 24 mice developed orthotopic tumors. The tumor growth could be reliably monitored by a combination of hrUS, μCT, MRI, and serum-PSA measurements. In most animals, lymph node metastases could be detected after 12 weeks, which could also be well visualized by hrUS, and MRI. Immunohistochemistry showed positive signals for CK8, AMACR, and AR in all xenograft types. CK5 was negative in VCaP- and focally positive in LuCaP136- and LuCaP147-xenografts. ERG was positive in VCaP- and negative in LuCaP136- and LuCaP147-xenografts. Tumor volume doubling times and tumor-specific growth rates were 21.2 days and 3.9 %/day for VCaP-, 27.6 days and 3.1 %/day for LuCaP136- and 16.2 days and 4.5 %/day for LuCaP147-xenografts, respectively. PSA-densities were 433.9 ng/mL per milliliter tumor for VCaP-, 6.5 ng/mL per milliliter tumor for LuCaP136-, and 11.2 ng/mL per milliliter tumor for LuCaP147-xenografts. By using different monolayer and 3D spheroid cell cultures in an orthotopic xenograft model, we established an innovative, versatile in vivo model of prostate cancer, which enables the study of both intraprostatic tumor growth as well as metastatic spread to regional lymph nodes. HrUS and MRI are feasible tools to monitor tumor growth and the development of lymph node metastases while these cannot be visualized by μCT.

Estimating Breast Cancer Survival by Molecular Subtype in the Absence of Screening and Adjuvant Treatment.

As molecular subtyping of breast cancer influences clinical management, the evaluation of screening and adjuvant treatment interventions at the population level needs to account for molecular subtyping. Performing such analyses are challenging because molecular subtype-specific, long-term outcomes are not readily accessible; these markers were not historically recorded in tumor registries. We present a modeling approach to estimate historical survival outcomes by estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status. Our approach leverages a simulation model of breast cancer outcomes and integrates data from two sources: the Surveillance Epidemiology and End Results (SEER) databases and the Breast Cancer Surveillance Consortium (BCSC). We not only produce ER- and HER2-specific estimates of breast cancer survival in the absence of screening and adjuvant treatment but we also estimate mean tumor volume doubling time (TVDT) and mean mammographic detection threshold by ER/HER2-status. In general, we found that tumors with ER-negative and HER2-positive status are associated with more aggressive growth, have lower TVDTs, are harder to detect by mammography, and have worse survival outcomes in the absence of screening and adjuvant treatment. Our estimates have been used as inputs into model-based analyses that evaluate the effects of screening and adjuvant treatment interventions on population outcomes by ER and HER2 status developed by the Cancer Intervention and Surveillance Modeling Network (CISNET) Breast Cancer Working Group. In addition, our estimates enable a re-assessment of historical trends in breast cancer incidence and mortality in terms of contemporary molecular tumor characteristics. Our approach can be generalized beyond breast cancer and to more complex molecular profiles.

Reduced Expression of Mismatch Repair Genes MSH6/MSH2 Directly Promotes Pituitary Tumor Growth via the ATR-Chk1 Pathway.

The mechanisms of pituitary adenoma (PA) pathogenesis and proliferation remain largely unknown. To clarify the role of mismatch repair (MMR) genes in the molecular mechanism of PA proliferation. We performed quantitative analyses by real-time polymerase chain reaction and immunohistochemistry to detect MMR gene and protein expression in human PAs (n = 47). We also performed correlation analyses of expression levels and tumor volume doubling time (TVDT; n = 31). Specifically, correlation analyses were performed between genes with significant correlation and ataxiatelangiectasia and Rad3-related (ATR) expression in cell-cycle regulatory mechanism ATR-checkpoint kinase 1 (Chk1) pathway (n = 93). We investigated the effect of reduced gene expression on cell proliferation and ATR gene expression in AtT-20ins cells and primary cultures of human PAs. Expression of mutS homologs 6 and 2 (MSH6 and MSH2) was positively associated with TVDT (R = 0.52, P = 0.003, and R = 0.44, P = 0.01), as were the corresponding protein levels. Gene expression was positively associated with ATR expression (R = 0.47, P < 0.00001, and R = 0.49, P < 0.00001). In AtT-20ins, the reduction of MSH6 and/or MSH2 expression by small interfering RNA significantly promoted cell proliferation by decreasing ATR expression. This effect was also observed in primary culture. Reduction of MSH6 and MSH2 expression at the messenger RNA and protein levels could be involved in direct PA proliferation by promoting cell-cycle progression or decreasing the rate of apoptosis through interference with the function of the ATR-Chk1 pathway.

Spontaneous Slowing and Regressing of Tumor Growth in Childhood/Adolescent Papillary Thyroid Carcinomas Suggested by the Postoperative Thyroglobulin-Doubling Time.

Background Children and adolescents with papillary thyroid carcinomas (PTCs) have generally excellent prognoses despite their frequent extended disease. The tumor growth of young patients' PTCs might show spontaneous slowing postoperatively. We compared young PTC patients' postoperative thyroglobulin-doubling time (Tg-DT) with their preoperative hypothetical tumor volume-doubling time (hTV-DT). Methods Fourteen PTC patients aged ≤18 years who underwent total thyroidectomy at Kuma Hospital in 1998–2016 had biochemically persistent disease postoperatively. We calculated their Tg-DTs and estimated their preoperative TV-DTs with the tumor size and the patient's age at surgery, presuming that a single cancer cell was present at the patient's birth. Results Twelve patients had positive Tg-DTs ranging from 2.0 to 147 years, and the remaining two had negative Tg-DTs, indicating slow growth or even regression. The hTV-DTs were 0.3–0.6 years (median 0.5 years), which were significantly shorter than the Tg-DTs (p < 0.001), indicating much faster growth preoperatively. The analyses of the nine patients without radioactive iodine administration (RAI) gave similar results (p < 0.01). Conclusions Irrespective of RAI, the patients' postoperative Tg-DTs were significantly longer than their preoperative hTV-DTs and were negative values in two patients, indicating that the growth of these young patients' PTCs had spontaneously slowed or even regressed postoperatively.

Gene expression profiling of fast- and slow-growing non-functioning gonadotroph pituitary adenomas.

Reliable biomarkers associated with aggressiveness of non-functioning gonadotroph adenomas (GAs) are lacking. As the growth of tumor remnants is highly variable, molecular markers for growth potential prediction are necessary. We hypothesized that fast- and slow-growing GAs present different gene expression profiles and reliable biomarkers for tumor growth potential could be identified, focusing on the specific role of epithelial-mesenchymal transition (EMT). Eight GAs selected for RNA sequencing were equally divided into fast- and slow-growing group by the tumor volume doubling time (TVDT) median (27.75 months). Data were analyzed by tophat2, cufflinks and cummeRbund pipeline. 40 genes were selected for RT-qPCR validation in 20 GAs based on significance, fold-change and pathway analyses. The effect of silencing MTDH (metadherin) and EMCN (endomucin) on in vitro migration of human adenoma cells was evaluated. 350 genes were significantly differentially expressed (282 genes upregulated and 68 downregulated in the fast group, P-adjusted <0.05). Among 40 selected genes, 11 showed associations with TVDT (-0.669<R<-0.46, P < 0.05). These were PCDH18, UNC5D, EMCN, MYO1B, GPM6A and six EMT-related genes (SPAG9, SKIL, MTDH, HOOK1, CNOT6L and PRKACB). MTDH, but not EMCN, demonstrated involvement in cell migration and association with EMT markers. Fast- and slow-growing GAs present different gene expression profiles, and genes related to EMT have higher expression in fast-growing tumors. In addition to MTDH, identified as an important contributor to aggressiveness, the other genes might represent markers for tumor growth potential and possible targets for drug therapy.

Abstract 36: Preclinical models of multiple myeloma

Abstract Multiple myeloma is a clonal B-cell malignancy characterized by the accumulation of terminally differentiated, antibody-producing plasma cells in the bone marrow. Genetic mutations within the myeloma cells and their interaction with various cytokines and growth factors contribute to the invasiveness of the disease and enhanced drug resistance. Patients are generally asymptomatic until very late-state disease. However, once disease is present, localization in the bones, especially the spine, is common. There are few preclinical models that recapitulate human disease. In this work, we have evaluated the human MM.1S model and the murine 5TGM-1 model. MM.1S was derived from a 42-year-old African American woman and has been documented to express CD25, CD38, CD52, and CD59. It also expresses the glucocorticoid receptor and is dexamethasone sensitive. To more effectively monitor in vivo disease progression, we transfected the MM.1S line with luciferase (MM.1S-pMMP-LucNeo). With bioluminescence imaging (BLI) we track and monitor disseminated disease progression over time and find reproducible in vivo growth in SCID beige mice. The median tumor volume doubling time is ~2 days and median time to morbidity/mortality endpoint is 35-45 days. MM.1S-pMMP-LucNeo was also evaluated in NSG mice which show more aggressive disease onset (staging 7 days post implant vs. 15 days in SCID mice). In NSG mice the tumor volume doubling time is ~1.8 days and median time to endpoint is ~21 days, roughly half the overall survival time observed in the SCID mouse. In all mouse strains we have investigated, the animals are relatively asymptomatic throughout the lifetime of the study and only begin to present symptoms at late-stage disease, similar to how the disease manifests itself in humans. Common, late-stage clinical signs in the mice include lethargy and paralysis. BLI on these animals shows localization of the signal in the spine, long bones, and mandible. As in the clinic, bortezomib (Velcade®) has limited effect on disease progression in this model. Expression of CD138 is a hallmark of plasma cells and multiple myeloma cells. In the NSG study we determined, by flow cytometry, that &amp;gt;85% of the CD45- gate in the bone marrow was CD138+ 21 days post-implant, suggesting significant engraftment of the tumor cells within the bone marrow. 5TGM-1 is a syngeneic model generated from the C57BL/KaLwRij mouse which is predisposed to develop several monoclonal B-cell proliferative disorders, including a low percentage (0.5%) of the mice developing multiple myeloma. From this strain, several cell clones were isolated and called the 5TMM series, which included the 5T33MM clone. 5TGM-1 is a sub-clone of 5T33MM cells and we have used 5TGM-1-luc to monitor disease progression and localization in vivo. The 5TGM-1-luc model is aggressive and BLI has shown localization of disease in the long bones. We have compared this model in both the syngeneic C57BL/KaLwRij strain and the immune-deficient NIH III (triple deficient) strain. Disease progression behaves similarly in both strains of mice, with significant tumor cells localizing in the spine and the long bones. The model is sensitive to traditional chemotherapies like doxorubicin and cyclophosphamide, but bortezomib (Velcade) only produces modest activity and carfilzomib has shown little activity at the dose and schedule tested. A greater understanding of the preclinical behavior of these models, including response to standard of care and molecular profiling, will provide critical insight into designing more clinically relevant preclinical experiments. Citation Format: Erin Trachet, Maryland Rosenfeld Franklin. Preclinical models of multiple myeloma [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 36.