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1.
Artigo em Inglês | MEDLINE | ID: mdl-33524546

RESUMO

PURPOSE/OBJECTIVES: We hypothesized that dose-intensified chemoradiation (chemoRT) targeting adversely prognostic hypercellular (TVHCV) and hyperperfused (TVCBV) tumor volumes would improve outcomes in patients with glioblastoma (GBM). MATERIALS/METHODS: This single-arm phase II trial enrolled adult patients with newly diagnosed GBM. Patients with >1cc TVHCV/TVCBV identified using high b-value diffusion-weighted MRI and dynamic contrast-enhanced perfusion MRI were treated over 30 fractions to 75 Gy to the TVHCV/TVCBV with temozolomide. The primary objective was to estimate improvement in 12-month overall survival (OS) versus historical control. Secondary objectives included evaluating the effect of 3-month TVHCV/TVCBV reduction on OS using Cox proportional-hazard regression, and characterizing coverage (95%IDL) of metabolic tumor volumes (MTV) identified using correlative 11C-Methionine PET. Clinically meaningful change was assessed for quality of life (QOL) by EORTC-QLQ-C30, symptom burden by MDASI-BT, and neurocognitive function (NCF) by COWA, Trail Making Test A/B, and HVLT-R. RESULTS: Between 2016-2018, 26 patients were enrolled. Initial patients were boosted to TVHCV alone, and 13 patients to both TVHCV/TVCBV. Gross or subtotal resection was performed in 87% of patients, 22% were MGMT methylated. With 26-month follow-up (95%CI 19-NR), among patients boosted to the combined TVHCV/TVCBV 12-month OS was 92% (95%CI 78-100%, p=0.03) and median OS was 20 months (95%CI 18-NR), and OS 20 months (95%CI 14-29) for the whole study cohort. Patients whose 3-month TVHCV/TVCBV decreased to

2.
Neuro Oncol ; 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33599755

RESUMO

BACKGROUND: Adversely prognostic hypercellular and hyperperfused regions of glioblastoma (GBM) predict progression-free survival, and are a novel target for dose-intensified chemoradiation (chemoRT) recently implemented in a phase II clinical trial. As a secondary aim, we hypothesized that dose-intensified chemoRT would induce greater mid-treatment response of hypercellular/hyperperfused tumor regions versus standard chemoradiation, and that early response would improve overall survival (OS). METHODS: Forty-nine patients with newly diagnosed GBM underwent prospective, multiparametric high b-value diffusion-weighted (DW-MRI) and perfusion dynamic contrast-enhanced MRI (DCE-MRI) pre-RT and 3-4 weeks into RT. The hypercellular tumor volume (TVHCV, mean contralateral normal brain+2SD) and hyperperfused tumor volume (TVCBV, contralateral normal frontal grey matter+1SD) were generated using automated thresholding. Twenty-six patients were enrolled on a dose-escalation trial targeting TVHCV/TVCBV with 75 Gy in 30 fractions, and 23 non-trial patients comprised the control group. OS was estimated using Kaplan-Meier method and compared using log-rank test. The effect of TVHCV/TVCBV and Gd-enhanced tumor volume on OS were assessed using multivariable Cox proportional-hazard regression. RESULTS: Most patients had gross total (47%) or subtotal resection (37%), 25% were MGMT methylated. Patients treated on the dose-escalation trial had significantly greater reduction in TVHCV/TVCBV (41% reduction, IQR 17-75%) vs non-trial patients (6% reduction, IQR 6-22%, p=0.002). An increase in TVHCV/TVCBV during chemoRT was associated with worse OS (AHR 1.2, 95%CI 1.0-1.4, p=0.02), while pre-treatment tumor volumes (p>0.5) and changes in Gd-enhanced volume (p=0.9) were not. CONCLUSIONS: Multiparametric MRI permits identification of therapeutic resistance during chemoRT and supports adaptive strategies in future trials.

3.
Nat Med ; 27(1): 152-164, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33398162

RESUMO

Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8+ T cells from systemic circulation. Within the liver, activated antigen-specific Fas+CD8+ T cells undergo apoptosis following their interaction with FasL+CD11b+F4/80+ monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+ T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.


Assuntos
Imunoterapia , Neoplasias Hepáticas Experimentais/secundário , Neoplasias Hepáticas Experimentais/terapia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Macrófagos/imunologia , Linfócitos T/imunologia , Animais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma Pulmonar de Células não Pequenas/terapia , Linhagem Celular Tumoral , Estudos de Coortes , Terapia Combinada , Feminino , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas Experimentais/imunologia , Ativação Linfocitária , Masculino , Melanoma/imunologia , Melanoma/secundário , Melanoma/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Radioterapia Adjuvante , Linfócitos T/classificação , Linfócitos T/patologia , Falha de Tratamento , Resultado do Tratamento , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiação
4.
5.
Int J Radiat Oncol Biol Phys ; 109(2): 332-334, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33422276
6.
Mol Cancer Ther ; 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33268569

RESUMO

PARP inhibitor monotherapy (olaparib) was recently FDA-approved for the treatment of BRCA1/2 mutant, HR (homologous recombination repair)-deficient pancreatic cancer. Most pancreatic cancers, however, are HR-proficient and thus resistant to PARP inhibitor monotherapy. We tested the hypothesis that combined therapy with radiation and ATR inhibitor (AZD6738) would extend the therapeutic indication of olaparib to HR-proficient pancreatic cancers. We show that olaparib combined with AZD6738 significantly reduced radiation survival relative to either agent alone, regardless of HR status. While catalytic inhibition of PARP with low concentrations of olaparib radiosensitized HR-deficient models, maximal sensitization in HR-proficient models required concentrations of olaparib that induce formation of PARP1-DNA complexes. Furthermore, CRISPR-Cas9-mediated PARP1 deletion failed to recapitulate the effects of olaparib on radiosensitivity and negated the combinatorial efficacy of olaparib and AZD6738 on radiosensitization, suggesting that PARP1-DNA complexes, rather than PARP catalytic inhibition, were responsible for radiosensitization. Mechanistically, therapeutic concentrations of olaparib in combination with radiation and AZD6738 increased DNA double strand breaks. DNA fiber combing revealed that high concentrations of olaparib did not stall replication forks but instead accelerated replication fork progression in association with an ATR-mediated replication stress response that was antagonized by AZD6738. Finally, in HR-proficient tumor xenografts, the combination of olaparib, radiation and AZD6738 significantly delayed tumor growth compared to all other treatments. These findings suggest that PARP1-DNA complexes are required for the therapeutic activity of olaparib combined with radiation and ATR inhibitor in HR-proficient pancreatic cancer and support the clinical development of this combination for tumors intrinsically resistant to PARP inhibitors.

7.
Phys Med Biol ; 2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33361579

RESUMO

Abdominal organs are subject to a variety of physiological forces that superimpose their effects to influence local motion and configuration. These forces not only include breathing, but can also arise from cyclic antral contractions and a range of slow configuration changes. To elucidate each individual motion pattern as well as their combined effects, a hierarchical motion model was built for characterization of these 3 motion modes (characterized as deformation maps between states) using golden angle radial MR signals. Breathing motions are characterized first. Antral contraction states are then reconstructed after breathing motion-induced deformation are corrected; slow configuration change states are further extracted from breathing motion-corrected image reconstructions. The hierarchical model is established based on these multimodal states, which can be either individually shown or combined to demonstrate any arbitrary composited motion patterns. The model was evaluated using 20 MR scans acquired from 9 subjects. Poor reproducibility of breathing motions both within as well as between scan sessions was observed, with an average intra-subject difference of 1.6 cycles/min for average breathing frequencies of 12.0 cycles/min. Antral contraction frequency distributions were more stable than breathing, but also presented poor reproducibility between scans with an average difference of 0.3 cycles/min for average frequencies of 3.2 cycles/min. The magnitudes of motions beyond breathing were found to be significant, with 14.4 and 33.8mm maximal motions measured from antral contraction and slow configuration changes, respectively. Hierarchical motion models have potential in multiple applications in radiotherapy, including improving the accuracy of dose delivery estimation, providing guidance for margin creation, and supporting advanced decisions and strategies for immobilization, treatment monitoring and gating. Keywords: abdominal motion, modeling, Magnetic Resonance Imaging.

8.
JCO Clin Cancer Inform ; 4: 1002-1013, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33136432

RESUMO

PURPOSE: Hepatocellular carcinoma (HCC) is characterized by a poor prognosis and a high recurrence rate. The tumor immune microenvironment in HCC has been characterized as shifted toward immunosuppression. We conducted a genomic data-driven classification of immune microenvironment HCC subtypes. In addition, we demonstrated their prognostic value and suggested a potential therapeutic targeting strategy. METHODS: RNA sequencing data from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma was used (n = 366). Abundance of immune cells was imputed using CIBERSORT and visualized using unsupervised hierarchic clustering. Overall survival (OS) was analyzed using Kaplan-Meier estimates and Cox regression. Differential expression and gene set enrichment analyses were conducted on immune clusters with poor OS and high programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) coexpression. A scoring metric combining differentially expressed genes and immune cell content was created, and its prognostic value and immune checkpoint blockade response prediction was evaluated. RESULTS: Two clusters were characterized by macrophage enrichment, with distinct M0Hi and M2Hi subtypes. M2Hi (P = .038) and M0Hi (P = .018) were independently prognostic for OS on multivariable analysis. Kaplan-Meier estimates demonstrated that patients in M0Hi and M2Hi treated with sorafenib had decreased OS (P = .041), and angiogenesis hallmark genes were enriched in the M0Hi group. CXCL6 and POSTN were overexpressed in both the M0Hi and the PD-1Hi/PD-L1Hi groups. A score consisting of CXCL6 and POSTN expression and absolute M0 macrophage content was discriminatory for OS (intermediate: hazard ratio [HR], 1.59; P ≤ .001; unfavorable: HR, 2.08; P = .04). CONCLUSION: Distinct immune cell clusters with macrophage predominance characterize an aggressive HCC phenotype, defined molecularly by angiogenic gene enrichment and clinically by poor prognosis and sorafenib response. This novel immunogenomic signature may aid in stratification of unresectable patients to receive checkpoint inhibitor and antiangiogenic therapy combinations.

9.
Artigo em Inglês | MEDLINE | ID: mdl-33130332

RESUMO

The incidence of esophageal adenocarcinoma (EAC) and other gastrointestinal (GI) cancers have risen dramatically, thus defining the oncogenic drivers to develop effective therapies are necessary. Patients with Barrett's Esophagus (BE), have an elevated risk of developing EAC. Around 70%-80% of BE cases that progress to dysplasia and cancer have detectable TP53 mutations. Similarly, in other GI cancers higher rates of TP53 mutation are reported, which provide a significant survival advantage to dysplastic/cancer cells. Targeting molecular chaperones that mediate mutant p53 stability may effectively induce mutant p53 degradation, and improve cancer outcomes. Statins can achieve this via disrupting the interaction between mutant p53 and the chaperone DNAJA1, promoting CHIP-mediated degradation of mutant p53, and statins are reported to significantly reduce the risk of BE progression to EAC. However, statins demonstrated sub-optimal efficacy depending on cancer types and TP53 mutation specificity. Besides the well-established role of MDM2 in p53 stability, we reported that individual isoforms of the E3 ubiquitin ligase GRAIL (RNF128) are critical, tissue-specific regulators of mutant p53 stability in BE progression to EAC and targeting the interaction of mutant p53 with these isoforms may help mitigate EAC development. In this review, we discuss the critical ubiquitin-proteasome and chaperone regulation of mutant p53 stability in EAC and other GI cancers with future insights as to how to affect mutant p53 stability, further noting how the precise p53 mutation may influence the efficacy of treatment strategies and identifying necessary directions for further research in this field.

10.
Nat Commun ; 11(1): 3811, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732914

RESUMO

Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance. Treatments that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we find that purine metabolites, especially guanylates, strongly correlate with radiation resistance. Inhibiting GTP synthesis radiosensitizes GBM cells and patient-derived neurospheres by impairing DNA repair. Likewise, administration of exogenous purine nucleosides protects sensitive GBM models from radiation by promoting DNA repair. Neither modulating pyrimidine metabolism nor purine salvage has similar effects. An FDA-approved inhibitor of GTP synthesis potentiates the effects of radiation in flank and orthotopic patient-derived xenograft models of GBM. High expression of the rate-limiting enzyme of de novo GTP synthesis is associated with shorter survival in GBM patients. These findings indicate that inhibiting purine synthesis may be a promising strategy to overcome therapy resistance in this genomically heterogeneous disease.


Assuntos
Neoplasias Encefálicas/radioterapia , Reparo do DNA/genética , Glioblastoma/radioterapia , Guanosina Monofosfato/metabolismo , Tolerância a Radiação/genética , Animais , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Feminino , Glioblastoma/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos SCID , Nucleosídeos de Purina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Artigo em Inglês | MEDLINE | ID: mdl-32853708

RESUMO

PURPOSE: Previous reports of stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) suggest unacceptably high rates of toxicity in patients with Child-Turcotte-Pugh (CTP) B liver disease. We hypothesized that an individualized adaptive treatment approach based on midtreatment liver function would maintain good local control while limiting toxicity in this population. METHODS AND MATERIALS: Patients with CTP-B liver disease and HCC were treated on prospective trials of individualized adaptive SBRT between 2006 and 2018. Patients underwent pre- and midtreatment liver function assessments using indocyanine green. Treatment-related toxicity was defined as a ≥2-point increase in CTP score from pretreatment within 6 months of treatment. In addition, we performed analyses with a longitudinal model to assess changes in CTP score over 12 months after SBRT. RESULTS: Eighty patients with CTP-B (median tumor size, 2.5 cm) were treated: 37 patients were CTP-B-7, 28 were CTP-B-8, and 15 were CTP-B-9. The median treatment dose was 36 Gy in 3 fractions. One-year local control was 92%. In a multivariate model controlling for tumor size, treatment dose, and baseline CTP score, higher treatment dose was associated with improved freedom from local progression (hazard ratio: 0.97; 95% confidence interval, 0.94-1.00; P = .04). Eighteen patients (24%) had a ≥2-point increase in CTP score within 6 months of SBRT. In a longitudinal model assessing changes in CTP score over 12 months after SBRT, controlling for baseline CTP and tumor size, increasing mean liver dose was associated with larger increases in CTP score (P = .04). CONCLUSIONS: An individualized adaptive treatment approach allows for acceptable toxicity and effective local control in patients with HCC and CTP-B liver disease. Because increasing dose may increase both local control and toxicity, further work is needed to optimize treatment in patients with compromised liver function.

12.
Mol Cancer Ther ; 19(10): 2163-2174, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32796101

RESUMO

New approaches are needed to overcome intrinsic therapy resistance in glioblastoma (GBM). Because GBMs exhibit sexual dimorphism and are reported to express steroid hormone receptors, we reasoned that signaling through the androgen receptor (AR) could mediate therapy resistance in GBM, much as it does in AR-positive prostate and breast cancers. We found that nearly half of GBM cell lines, patient-derived xenografts (PDX), and human tumors expressed AR at the transcript and protein level-with expression levels overlapping those of primary prostate cancer. Analysis of gene expression datasets also revealed that AR expression is higher in GBM patient samples than normal brain tissue. Multiple clinical-grade antiandrogens slowed the growth of and radiosensitized AR-positive GBM cell lines and PDXs in vitro and in vivo Antiandrogens blocked the ability of AR-positive GBM PDXs to engage adaptive transcriptional programs following radiation and slowed the repair of radiation-induced DNA damage. These results suggest that combining blood-brain barrier permeable antiandrogens with radiation may have promise for patients with AR-positive GBMs.

13.
Nat Metab ; 2(8): 775-792, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32694827

RESUMO

Branched-chain amino acids (BCAAs) supply both carbon and nitrogen in pancreatic cancers, and increased levels of BCAAs have been associated with increased risk of pancreatic ductal adenocarcinomas (PDACs). It remains unclear, however, how stromal cells regulate BCAA metabolism in PDAC cells and how mutualistic determinants control BCAA metabolism in the tumour milieu. Here, we show distinct catabolic, oxidative and protein turnover fluxes between cancer-associated fibroblasts (CAFs) and cancer cells, and a marked reliance on branched-chain α-ketoacid (BCKA) in PDAC cells in stroma-rich tumours. We report that cancer-induced stromal reprogramming fuels this BCKA demand. The TGF-ß-SMAD5 axis directly targets BCAT1 in CAFs and dictates internalization of the extracellular matrix from the tumour microenvironment to supply amino-acid precursors for BCKA secretion by CAFs. The in vitro results were corroborated with circulating tumour cells (CTCs) and PDAC tissue slices derived from people with PDAC. Our findings reveal therapeutically actionable targets in pancreatic stromal and cancer cells.

14.
Clin Cancer Res ; 26(19): 5246-5257, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32718999

RESUMO

PURPOSE: Treatment approaches using Hsp90 inhibitors at their maximum tolerated doses (MTDs) have not produced selective tumor toxicity. Inhibition of Hsp90 activity causes degradation of client proteins including those involved in recognizing and repairing DNA lesions. We hypothesized that if DNA repair proteins were degraded by concentrations of an Hsp90 inhibitor below those required to cause nonspecific cytotoxicity, significant tumor-selective radiosensitization might be achieved. EXPERIMENTAL DESIGN: Tandem mass tagged-mass spectrometry was performed to determine the effect of a subcytotoxic concentration of the Hsp90 inhibitor, AT13387 (onalespib), on global protein abundance. The effect of AT13387 on in vitro radiosensitization was assessed using a clonogenic assay. Pharmacokinetics profiling was performed in mice bearing xenografts. Finally, the effect of low-dose AT13387 on the radiosensitization of three tumor models was assessed. RESULTS: A subcytotoxic concentration of AT13387 reduced levels of DNA repair proteins, without affecting the majority of Hsp90 clients. The pharmacokinetics study using one-third of the MTD showed 40-fold higher levels of AT13387 in tumors compared with plasma. This low dose enhanced Hsp70 expression in peripheral blood mononuclear cells (PBMCs), which is a biomarker of Hsp90 inhibition. Low dose monotherapy was ineffective, but when combined with radiotherapy, produced significant tumor growth inhibition. CONCLUSIONS: This study shows that a significant therapeutic ratio can be achieved by a low dose of Hsp90 inhibitor in combination with radiotherapy. Hsp90 inhibition, even at a low dose, can be monitored by measuring Hsp70 expression in PBMCs in human studies.

15.
J Biol Chem ; 295(36): 12661-12673, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32669362

RESUMO

The discovery of activating epidermal growth factor receptor (EGFR) mutations spurred the use of EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib, as the first-line treatment of lung cancers. We previously reported that differential degradation of TKI-sensitive (e.g. L858R) and resistant (T790M) EGFR mutants upon erlotinib treatment correlates with drug sensitivity. We also reported that SMAD ubiquitination regulatory factor 2 (SMURF2) ligase activity is important in stabilizing EGFR. However, the molecular mechanisms involved remain unclear. Here, using in vitro and in vivo ubiquitination assays, MS, and superresolution microscopy, we show SMURF2-EGFR functional interaction is important for EGFR stability and response to TKI. We demonstrate that L858R/T790M EGFR is preferentially stabilized by SMURF2-UBCH5 (an E3-E2)-mediated polyubiquitination. We identified four lysine residues as the sites of ubiquitination and showed that replacement of one of them with acetylation-mimicking glutamine increases the sensitivity of mutant EGFR to erlotinib-induced degradation. We show that SMURF2 extends membrane retention of EGF-bound EGFR, whereas SMURF2 knockdown increases receptor sorting to lysosomes. In lung cancer cell lines, SMURF2 overexpression increased EGFR levels, improving TKI tolerance, whereas SMURF2 knockdown decreased EGFR steady-state levels and sensitized lung cancer cells. Overall, we propose that SMURF2-mediated polyubiquitination of L858R/T790M EGFR competes with acetylation-mediated receptor internalization that correlates with enhanced receptor stability; therefore, disruption of the E3-E2 complex may be an attractive target to overcome TKI resistance.

16.
Transl Oncol ; 13(11): 100834, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32688248

RESUMO

The Unfolded Protein Response (UPR) plays a key role in the adaptive response to loss of protein homeostasis within the endoplasmic reticulum (ER). The UPR has an adaptive function in protein homeostasis, however, sustained activation of the UPR due to hypoxia, nutrient deprivation, and increased demand for protein synthesis, alters the UPR program such that additional perturbation of ER homeostasis activates a pro-apoptotic program. Since ubiquitination followed by proteasomal degradation of misfolded proteins within the ER is a central mechanism for restoration of ER homeostasis, inhibitors of this pathway have proven to be valuable anti-cancer therapeutics. Ubiquitin activating enzyme 1(UAE1), activates ubiquitin for transfer to target proteins for proteasomal degradation in conjunction with E2 and E3 enzymes. Inhibition of UAE1 activity in response to TAK-243, leads to an accumulation of misfolded proteins within the ER, thereby aggravating ER stress, leading to DNA damage and arrest of cells in the G2/M phase of the cell cycle. Persistent drug treatment mediates a robust induction of apoptosis following a transient cell cycle arrest. These biological effects of TAK-243 were recapitulated in mouse models of PDAC demonstrating antitumor activity at a dose and schedule that did not exhibit obvious normal tissue toxicity. In vitro as well as studies in mouse models failed to show enhanced efficacy when TAK-243 was combined with ionizing radiation or gemcitabine, providing an impetus for future studies to identify agents that synergize with this class of agents for improved tumor control in PDAC. SIGNIFICANCE: The UAE1 inhibitor TAK-243, mediates activation of the unfolded protein response, accumulation of DNA breaks and apoptosis, providing a rationale for the use as a safe and efficacious anti-cancer therapeutic for PDAC.

17.
Semin Radiat Oncol ; 30(3): 242-252, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32503790

RESUMO

Definitive reirradiation using a stereotactic technique is an effective local treatment option for both recurrent liver metastases and recurrent primary liver cancers. The tolerance of the liver, bile ducts, and surrounding gastrointestinal luminal organs must be respected to ensure safe retreatment. The risks associated with retreatment to these organs must be carefully balanced with the probability of clinical benefit. We present 2 cases for consideration of repeat irradiation along with the opinions of 4 experts, along with conclusions about recommendations.

18.
Eur J Cancer ; 134: 41-51, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32460180

RESUMO

BACKGROUND: Stereotactic Body Radiation Therapy (SBRT) is a non-invasive ablative treatment for hepatocellular carcinoma (HCC). This report aimed to address the limited availability of long-term outcomes after SBRT for HCC from North America. METHODS: Localized HCC patients without vascular invasion, who were ineligible for other liver-directed therapies and treated with SBRT at the University of Toronto or University of Michigan, were pooled to determine overall survival (OS), cumulative recurrence rates, and ≥ grade-3 toxicity. Multivariable analysis determined factors affecting OS and local recurrence rates. RESULTS: In 297 patients with 436 HCCs (42% > 3 cm), one-, three- and five-year OS was 77·3%, 39·0% and 24·1%, respectively. On Cox proportional hazards regression analysis, liver transplant after SBRT, Child-Pugh A liver function, alpha-fetoprotein ≤ 10 ng/ml, and Eastern Co-operative Oncology Group performance status 0 significantly improved OS (hazard ratio [HR] = 0·06, 95% confidence interval [CI- 0·02-0·25; p<0·001; HR = 0·42, 95% CI = 0·29-0·60, p<0·001; HR = 0·61, 95% CI- 0·44-0·83; p=0·002 and HR = 0·71, 95% CI = 0·51-0·97, p=0·034, respectively). Cumulative local recurrence was 6·3% (95% CI = 0.03-0.09) and 13·3% (95% CI = 0.06-0.21) at one and three years, respectively. Using Cox regression modelling, local control was significantly higher using breath-hold motion management and in HCC smaller than 3 cm (HR = 0.52, 95% CI = 0.58-0.98; p=0.042 and HR = 0.53, 95% CI = 0.26-0.98; p=0.042, respectively). Worsening of Child-Pugh score by ≥2 points three months after SBRT was seen in 15.9%. CONCLUSIONS: SBRT confers high local control and long-term survival in a substantial proportion of HCC patients unsuitable for, or refractory to standard loco-regional treatments. Liver transplant should be considered if appropriate downsizing occurs after SBRT.


Assuntos
Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/mortalidade , Recidiva Local de Neoplasia/mortalidade , Radiocirurgia/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Fracionamento da Dose de Radiação , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
19.
Phys Med Biol ; 65(12): 125001, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32330923

RESUMO

Magnetic resonance imaging (MRI) is gaining popularity in guiding radiation treatment for intrahepatic cancers due to its superior soft tissue contrast and potential of monitoring individual motion and liver function. This study investigates a deep learning-based method that generates synthetic CT volumes from T1-weighted MR Dixon images in support of MRI-based intrahepatic radiotherapy treatment planning. Training deep neutral networks for this purpose has been challenged by mismatches between CT and MR images due to motion and different organ filling status. This work proposes to resolve such challenge by generating 'semi-synthetic' CT images from rigidly aligned CT and MR image pairs. Contrasts within skeletal elements of the 'semi-synthetic' CT images were determined from CT images, while contrasts of soft tissue and air volumes were determined from voxel-wise intensity classification results on MR images. The resulting 'semi-synthetic' CT images were paired with their corresponding MR images and used to train a simple U-net model without adversarial components. MR and CT scans of 46 patients were investigated and the proposed method was evaluated for 31 patients with clinical radiotherapy plans, using 3-fold cross validation. The averaged mean absolute errors between synthetic CT and CT images across patients were 24.10 HU for liver, 28.62 HU for spleen, 47.05 HU for kidneys, 29.79 HU for spinal cord, 105.68 HU for lungs and 110.09 HU for vertebral bodies. VMAT and IMRT plans were optimized using CT-derived electron densities, and doses were recalculated using corresponding synthetic CT-derived density grids. Resulting dose differences to planning target volumes and various organs at risk were small, with the average difference less than 0.15 Gy for all dose metrics evaluated. The similarities in both image intensity and radiation dose distributions between CT and synthetic CT volumes demonstrate the accuracy of the method and its potential in supporting MRI-only radiotherapy treatment planning.


Assuntos
Neoplasias Hepáticas/radioterapia , Imagem por Ressonância Magnética/métodos , Planejamento da Radioterapia Assistida por Computador/métodos , Tomografia Computadorizada por Raios X/métodos , Abdome/diagnóstico por imagem , Humanos , Dosagem Radioterapêutica
20.
Cancers (Basel) ; 12(4)2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32326109

RESUMO

Improvement in pancreatic cancer treatment represents an urgent medical goal that has been hampered by the lack of predictive biomarkers. Circulating Tumor Cells (CTCs) may be able to overcome this issue by allowing the monitoring of therapeutic response and tumor aggressiveness through ex vivo expansion. The successful expansion of CTCs is challenging, due to their low numbers in blood and the high abundance of blood cells. Here, we explored the utility of pancreatic CTC cultures as a preclinical model for treatment response. CTCs were isolated from ten patients with locally advanced pancreatic cancer using the Labyrinth, a biomarker independent, size based, inertial microfluidic separation device. Three patient-derived CTC samples were successfully expanded in adherent and spheroid cultures. Molecular and functional characterization was performed on the expanded CTC lines. CTC lines exhibited KRAS mutations, consistent with pancreatic cancers. Additionally, we evaluated take rate and metastatic potential in vivo and examined the utility of CTC lines for cytotoxicity assays. Patient derived expanded CTCs successfully generated patient derived xenograft (PDX) models with a 100% take rate. Our results demonstrate that CTC cultures are possible and provide a valuable resource for translational pancreatic cancer research, while also providing meaningful insight into the development of distant metastasis, as well as treatment resistance.

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