A Pan-Canadian Consensus Statement on First-Line PARP Inhibitor Maintenance for Advanced,High-Grade Serous and Endometrioid Tubal,Ovarian, and Primary Peritoneal Cancers

The majority of patients with advanced, high-grade epithelial-tubo ovarian cancer (EOC) respond well to initial treatment with platinum-based chemotherapy; however, up to 80% of patients will experience a recurrence. Poly(ADP-ribose) Polymerase (PARP) inhibitors have been established as a standard of care maintenance therapy to prolong remission and prevent relapse following a response to first-line platinum-chemotherapy. Olaparib and niraparib are the PARP inhibitors currently approved for use in the first-line maintenance setting in Canada. Selection of maintenance therapy requires consideration of patient and tumour factors, presence of germline and somatic mutations, expected drug toxicity profile, and treatment access. This paper discusses the current clinical evidence for first-line PARP inhibitor maintenance therapy in patients with advanced, high-grade EOC and presents consensus statements and a treatment algorithm to aid Canadian oncologists on the selection and use of PARP inhibitors within the Canadian EOC treatment landscape.     

Thyroid lesions incidentally detected by 18F-FDG PET-CT — a two centre retrospective study

Background.

Incidental ¹⁸F-FDG uptake in the thyroid on PET-CT examinations represents a diagnostic challenge. The maximal standardized uptake value (SUV_max) is one possible parameter that can help in distinguishing between benign and malignant thyroid PET lesions.

Patients and methods.

We retrospectively evaluated ¹⁸F-FDG PET-CT examinations of 5,911 patients performed at two different medical centres from 2010 to 2011. If pathologically increased activity was accidentally detected in the thyroid, the SUV_max of the thyroid lesion was calculated. Patients with incidental ¹⁸F-FDG uptake in the thyroid were instructed to visit a thyroidologist, who performed further investigation including fine needle aspiration cytology (FNAC) if needed. Lesions deemed suspicious after FNAC were referred for surgery.

Results.

Incidental ¹⁸F-FDG uptake in the thyroid was found in 3.89% — in 230 out of 5,911 patients investigated on PET-CT. Malignant thyroid lesions (represented with focal thyroid uptake) were detected in 10 of 66 patients (in 15.2%). In the first medical centre the SUV_max of 36 benign lesions was 5.6 ± 2.8 compared to 15.8 ± 9.2 of 5 malignant lesions (p < 0.001). In the second centre the SUV_max of 20 benign lesions was 3.7 ± 2.2 compared to 5.1 ± 2.3 of 5 malignant lesions (p = 0.217). All 29 further investigated diffuse thyroid lesions were benign.

Conclusions.

Incidental ¹⁸F-FDG uptake in the thyroid was found in 3.89% of patients who had a PET-CT examination. Only focal thyroid uptake represented a malignant lesion in our study — in 15.2% of all focal thyroid lesions. SUV_max should only serve as one of several parameters that alert the clinician on the possibility of thyroid malignancy.     

Pharmacokinetics,safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial

BackgroundThe poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide (TMZ) chemotherapy in preclinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side effects of TMZ. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib and assess the safety and tolerability of its combination with TMZ.MethodsPreclinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose TMZ in a 3 + 3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumor core and tumor margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines.ResultsOlaparib was a substrate for multidrug resistance protein 1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients; median, 496 nM) and 21/21 tumor margin specimens (9 patients; median, 512.3 nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150 mg (3 days/week) with TMZ 75 mg/m² daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression free at 6 months. Olaparib radiosensitized 6 glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM.ConclusionOlaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better preclinical models.     

Trabectedin in Advanced High-Grade Uterine Leiomyosarcoma: A Case Report Illustrating the Value of 18FDG-PET-CT in Assessing Treatment Response

We report the case of a 60-year-old woman with metastatic high-grade uterine leiomyosarcoma who achieved a delayed response to second-line therapy with the marine-derived drug trabectedin (Yondelis^®, PharmaMar). We used 2-deoxy-2-[¹⁸F] fluorodeoxyglucose (FDG)-positron emission tomography (PET-CT) imaging as a tool for response monitoring in parallel with conventional re-staging according to Response Evaluation Criteria in Solid Tumours (RECIST) using computed tomography (CT). We illustrate the role of serial ¹⁸FDG-PET-CT imaging in the functional assessment of tumour response. Three cycles after commencement of trabectedin treatment, a reduction of the maximum standardized uptake value (SUV_max) of the solid component of the pelvic mass was observed, indicating a cystic or necrotic response in the tumour to trabectedin. After 7 cycles of treatment, on ¹⁸FDG-PET-CT there was clear evidence of ongoing disease improvement: the solid pelvic components were at worst stable, with an unchanged SUV_max, and possibly marginally reduced in size, while the pulmonary metastases had further reduced in size and become FDG negative; the bony metastases were stable. After a total of 13 cycles of treatment, administered over 13 months, the patient showed signs of progression on an ¹⁸FDG-PET-CT scan. The safety profile of trabectedin remained manageable, showing no evidence of cumulative toxicity and being associated with a preserved quality of life. This report illustrates potential limitations of RECIST in response assessments and the critical role of serial ¹⁸FDG-PET-CT imaging in assessing response to trabectedin treatment. Therefore, we propose that ¹⁸FDG-PET-CT may improve the assessment of response to trabectedin in selected patients.Key words: Sarcoma, Trabectedin, Delayed response, ¹⁸FDG-PET-CT, Uterine leiomyosarcoma     

Synthetic lethal targeting of RNF20 through PARP1 silencing and inhibition

Purpose

The identification of novel therapeutic targets that exploit the aberrant genetics driving oncogenesis is critical to better combat cancer. RNF20 is somatically altered in numerous cancers, and its diminished expression drives genome instability, a driving factor of oncogenesis. Accordingly, we sought to determine whether PARP1 silencing and inhibition could preferentially kill RNF20-deficient cells using a synthetic lethal strategy.

Methods

RNF20 and PARP1 were silenced using RNAi-based approaches. Direct synthetic lethal tests were performed by silencing RNF20 with and without PARP1 and the impact on cell numbers was evaluated using semi-quantitative imaging microscopy. Next, Olaparib and BMN673 (PARP1 inhibitors) were evaluated for their ability to induce preferential killing in RNF20 silenced cells, while real-time cell analyses were used to distinguish cell cytotoxicity from cell cycle arrest. Finally, quantitative imaging microscopy was employed to evaluate marks associated with DNA double-strand breaks (γ-H2AX) and apoptosis (cleaved Caspase-3).

Results

We found that PARP1 silencing resulted in a decrease in number of RNF20 silenced cells relative to controls. We further found that Olaparib and BMN673 treatments also resulted in fewer RNF20 silenced cells relative to controls. Finally, we found by quantitative imaging microscopy that RNF20 silenced cells treated with BMN673 exhibited significant increases in γ-H2AX and cleaved Caspase-3, suggesting that these treatments induce DNA double-strand breaks that are not adequately repaired within RNF20-silenced cells.

Conclusions

Collectively, our data indicate that RNF20 and PARP1 are synthetic lethal interactors, suggesting that cancers with diminished RNF20 expression and/or function may be susceptible to PARP1 inhibitors.

     

Inhibition of PARP1‐dependent end‐joining contributes to Olaparib‐mediated radiosensitization in tumor cells

Poly‐ADP‐ribose‐polymerase inhibitors (PARPi) are considered to be optimal tools for specifically enhancing radiosensitivity. This effect has been shown to be replication‐dependent and more profound in HR‐deficient tumors. Here, we present a new mode of PARPi‐mediated radiosensitization which was observed in four out of six HR‐proficient tumor cell lines (responders) investigated, but not in normal cells. This effect is replication‐independent, as the radiosensitization remained unaffected following the inhibition of replication using aphidicolin. We showed that responders are radiosensitized by Olaparib because their DSB‐repair is switched to PARP1‐dependent end‐joining (PARP1‐EJ), as evident by (i) the significant increase in the number of residual γH2AX foci following irradiation with 3Gy and treatment with Olaparib, (ii) the enhanced enrichment of PARP1 at the chromatin after 3Gy and (iii) the inhibition of end‐joining activity measured by a specific reporter substrate upon Olaparib treatment. This is the first study which directly demonstrates the switch to PARP1‐EJ in tumor cells and its contribution to the response to Olaparib as a radiosensitizer, findings which could widen the scope of application of PARPi in tumor therapy.     

In vivo evaluation of percutaneous carbon dioxide treatment for improving intratumoral hypoxia using 18F-fluoromisonidazole PET-CT

Carbon dioxide (CO₂) treatment is reported to have an antitumor effect owing to the improvement in intratumoral hypoxia. Previous studies were based on histological analysis alone. In the present study, the improvement in intratumoral hypoxia by percutaneous CO₂ treatment in vivo was determined using ¹⁸F-fluoromisonidazole positron emission tomography-computed tomography (¹⁸F-FMISO PET-CT) images. Twelve Japanese nude mice underwent implantation of LM8 tumor cells in the dorsal subcutaneous area 2 weeks before percutaneous CO₂ treatment and ¹⁸F-FMISO PET-CT scans. Immediately after intravenous injection of ¹⁸F-FMISO, CO₂ and room air were administered transcutaneously in the CO₂-treated group (n=6) and a control group (n=6), respectively; each treatment was performed for 10 minutes. PET-CT was performed 2 h after administration of ¹⁸F-FMISO. ¹⁸F-FMISO tumor uptake was quantitatively evaluated using the maximum standardized uptake value (SUV_max), tumor-to-liver ratio (TLR), tumor-to-muscle ratio (TMR), metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Mean ± standard error of the mean (SEM) of the tumor volume was not significantly different between the two groups (CO₂-treated group, 1.178±0.450 cm³; control group, 1.368±0.295 cm3; P=0.485). Mean ± SEM of SUV_max, TLR, MTV (cm3) and TLG were significantly lower in the CO₂-treated group compared with the control group (0.880±0.095 vs. 1.253±0.071, P=0.015; 1.063±0.147361 vs. 1.455±0.078, P=0.041; 0.353±0.139 vs. 1.569±0.438, P=0.015; 0.182±0.070 vs. 1.028±0.338, P=0.015), respectively. TMR was not significantly different between the two groups (4.520±0.503 vs. 5.504±0.310; P=0.240). In conclusion, ¹⁸F-FMISO PET revealed that percutaneous CO₂ treatment improved intratumoral hypoxia in vivo. This technique enables assessment of the therapeutic effect in CO₂ treatment by imaging, and may contribute to its clinical application.     

Positron-Emission Tomographic Imaging of a Fluorine 18–Radiolabeled Poly(ADP-Ribose) Polymerase 1 Inhibitor Monitors the Therapeutic Efficacy of Talazoparib in SCLC Patient–Derived Xenografts

IntroductionInhibitors of poly-(ADP)-ribose polymerase (PARP) are promising therapeutics for SCLC. We tested whether PARP inhibitor (PARPi) target engagement as measured by a fluorine 18–radiolabeled PARPi ([¹⁸F]PARPi) has the potential to predict drug efficacy in vivo.MethodsTumor growth inhibition during daily talazoparib treatment was evaluated in mice engrafted with SCLC patient-derived xenografts to evaluate talazoparib efficacy at multiple doses. Mice were intravenously injected with [¹⁸F]PARPi radiotracer at multiple timepoints after single doses of oral talazoparib to quantitatively assess the extent to which talazoparib could reduce tumor radiotracer uptake and positron-emission tomographic (PET)/computer tomographic activity. Tumors were harvested and tumor poly-(ADP) ribose level was measured by enzyme-linked immunosorbent assay.ResultsA dose range of talazoparib with differential therapeutic efficacy was established, with significant delay in time to reach 1000 mm³ for tumors treated with 0.3 mg/kg (p = 0.02) but not 0.1 mg/kg talazoparib. On PET/computed tomography with [¹⁸F]PARPi, reduction in [¹⁸F]PARPi uptake after talazoparib dosing was consistent with talazoparib clearance, with reduction in PET activity attenuating over 24 hours. Talazoparib target engagement, measured by maximum tumor PET uptake, increased in a dose-dependent manner (3.9% versus 2.1% injected dose/g for 0.1 and 0.3 mg/kg at 3 hours post-talazoparib, p = 0.003) and correlated with PARP enzymatic activity among individual tumors as measured by total tumor poly-(ADP) ribose (p = 0.04, R = 0.62 at 1 hour post-talazoparib).ConclusionsPET imaging using [¹⁸F]PARPi has the potential to be a powerful tool in treatment monitoring by assessing PARPi target engagement in real-time.     

PARP inhibition sensitizes childhood high grade glioma, medulloblastoma and ependymoma to radiation

Poly ADP-ribose polymerase (PARP) is a protein involved in single strand break repair. Recently, PARP inhibitors have shown considerable promise in the treatment of several cancers, both in monotherapy and in combination with cytotoxic agents. Synthetic lethal action of PARP inhibitors has been observed in tumors with mutations in double strand break repair pathways. In addition, PARP inhibition potentially enhances sensitivity of tumor cells to DNA damaging agents, including radiotherapy. Aim of this study is to determine the radiosensitizing properties of the PARP inhibitor Olaparib in childhood medulloblastoma, ependymoma and high grade glioma (HGG). Increased PARP1 expression was observed in medulloblastoma, ependymoma and HGG, as compared to non-neoplastic brain tissue. Pediatric high grade glioma, medulloblastoma and ependymoma gene expression profiling revealed that high PARP1 expression is associated with poor prognosis. Cell growth inhibition assays with Olaparib resulted in differential sensitivity, with IC50 values ranging from 1.4 to 8.4 μM, irrespective of tumor type and PARP1 protein expression. Sensitization to radiation was observed in medulloblastoma, ependymoma and HGG cell lines with subcytotoxic concentrations of Olaparib, which coincided with persistence of double strand breaks. Combining PARP inhibitors with radiotherapy in clinical studies in childhood high grade brain tumors may improve therapeutic outcome.     

Noninvasive Multimodality Imaging of the Tumor Microenvironment: Registered Dynamic Magnetic Resonance Imaging and Positron Emission Tomography Studies of a Preclinical Tumor Model of Tumor Hypoxia

In vivo knowledge of the spatial distribution of viable, necrotic, and hypoxic areas can provide prognostic information about the risk of developing metastases and regional radiation sensitivity and may be used potentially for localized dose escalation in radiation treatment. In this study, multimodality in vivo magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging using stereotactic fiduciary markers in the Dunning R3327-AT prostate tumor were performed, focusing on the relationship between dynamic contrast-enhanced (DCE) MRI using Magnevist (Gd-DTPA) and dynamic ¹⁸F-fluoromisonidazole (¹⁸F-Fmiso) PET. The noninvasive measurements were verified using tumor tissue sections stained for hematoxylin/eosin and pimonidazole. To further validate the relationship between ¹⁸F-Fmiso and pimonidazole uptake, ¹⁸F digital autoradiography was performed on a selected tumor and compared with the corresponding pimonidazole-stained slices. The comparison of Akep values (kep = rate constant of movement of Gd-DTPA between the interstitial space and plasma and A = amplitude in the two-compartment model (Hoffmann U, Brix G, Knopp MV, Hess T and Lorenz WJ (1995). Magn Reson Med 33, 506–514) derived from DCE-MRI studies and from early ¹⁸F-Fmiso uptake PET studies showed that tumor vasculature is a major determinant of early ¹⁸F-Fmiso uptake. A negative correlation between the spatial map of Akep and the slope map of late (last 1 hour of the dynamic PET scan) ¹⁸F-Fmiso uptake was observed. The relationships between DCE-MRI and hematoxylin/eosin slices and between ¹⁸F-Fmiso PET and pimonidazole slices confirm the validity of MRI/PET measurements to image the tumor microenvironment and to identify regions of tumor necrosis, hypoxia, and well-perfused tissue.     

Can Fluorine-18 Fluoroestradiol Positron Emission Tomography–Computed Tomography Demonstrate the Heterogeneity of Breast Cancer In Vivo?

AimOur study was to investigate the heterogeneity of estrogen receptor (ER) expression among tumor sites by using fluorine-18 (¹⁸F) fluoroestradiol (FES) positron-emission tomography–computed tomography (PET-CT) imaging.MethodsThirty-two breast cancer patients underwent both ¹⁸F-FES and ¹⁸F fluorodeoxyglucose (FDG) PET-CTs from June 2010 to December 2011 in our center (mean age, 53 years; range, 27-77 years). We used the maximum standardized uptake value to quantify ER expression and a cutoff value of 1.5 to dichotomize results into ER⁺ and ER^?. The difference of heterogeneity between the initial patients and patients with recurrent or metastatic disease after treatments was assessed by using the χ² test. Also, the ¹⁸F-FES uptake was compared with the ¹⁸F-FDG uptake by use of Spearman correlation coefficients.ResultsA total number of 237 lesions in 32 patients were detected. Among them, most lesions (64.1% [152/237]) were bone metastasis. A striking 33.4-fold difference in ¹⁸F-FES uptake was observed among different patients (maximum standardized uptake value range, 0.5 to approximately 16.7), and a 8.2-fold difference was observed among lesions within the same individual (1.0 to approximately 8.2). As for ¹⁸F-FDG uptake, the difference was 11.6-fold (1.3 to approximately 15.1) and 9.9-fold (1.4 to approximately 13.8), respectively. In 28.1% (9/32) of the patients, both ¹⁸F-FES⁺ and ¹⁸F-FES^? metastases were present, which suggests partial discordant ER expression. After treatments, 37.5% (9/24) patients with recurrent or metastatic breast cancer showed heterogeneity, whereas no untreated patient was detected to exist discordant ER expression (χ², 4.174; P < .05). In addition, the ¹⁸F-FES uptake showed a weak correlation with the ¹⁸F-FDG uptake (ρ = 0.248; P < .05).Conclusion¹⁸F-FES and ¹⁸F-FDG uptake varied greatly both within and among patients. ¹⁸F-FES PET-CT demonstrated a conspicuous number of patients with the heterogeneity of ER expression.     

18FDG PET-CT for diagnosis of distant metastases in breast cancer patients. A meta-analysis

BackgroundWe performed a meta-analysis to evaluate the value of ¹⁸FDG PET-CT for diagnosis of distant metastases in breast cancer patients.MethodsStudies about PET-CT were systematically searched in the MEDLINE and EMBASE databases. We calculated sensitivities, specificities, likelihood ratios, and constructed summary receiver operating characteristic curves for PET-CT. We also compared the performance of PET-CT with that of conventional imaging by analyzing studies that had also used conventional imaging on the same patients.ResultsAcross 8 PET-CT studies (748 patients), sensitivity and specificity of PET-CT were 0.96 (95% confidence interval [CI] = 0.90–0.98) and 0.95 (95% CI = 0.92–0.97). Across 6 comparative studies (664 patients), sensitivity and specificity of PET-CT were 0.97 (95% CI = 0.84–0.99) and 0.95 (95% CI = 0.93–0.97), and of conventional imaging were 0.56 (95% CI = 0.38–0.74) and 0.91 (95% CI = 0.78–0.97), respectively.ConclusionsCompared with conventional imaging, ¹⁸FDG PET-CT has higher sensitivity for diagnosis of distant metastases in breast cancer patients.     

Complete pathological response (pCR) in gastroesophageal cancer: Correlation with metabolic response

PurposeNeoadjuvant chemoradiotherapy (nCRT) followed by surgery in patients with resectable esophageal or esophagogastric junctional (GEJ) (Siewert I) cancer is associated with long term overall survival benefits. Up to one third of all patients submitted to nCRT present pathological complete response (pCR). ¹⁸F-fluorodeoxyglucose positron emission tomography with CT (¹⁸F-FDG PET-CT) is an important tool for assessing treatment response. Purpose was to assess retrospectively the power of ¹⁸F-FDG PET-CT in predicting pCR to evaluate the feasibility of a “watch and wait” approach.Patients and methodsRetrospective analysis of a prospective database with esophageal or GEJ submitted to pre-operative chemoradiation. Pre and pos treatment ¹⁸F-FDG PET-CT were reviewed and classified using visual assessment and PERCIST criteria and the values of maximum standard uptake value were also recorded. Patients were classified as pCR or non-PCR. ¹⁸F-FDG PET-CT and pathological findings were compared against each other.ResultsForty-three patients were included. The median age was 67 years and 90.7% were male. All patients underwent preoperative CRT and were evaluated with ¹⁸F-FDG PET-CT pre and post treatment. Transthoracic surgery was performed in all patients. Histological type was adenocarcinoma in 37% and squamous cell carcinoma in 58%. pCR was achieved in 56% of cases. Visual assessment of ¹⁸F-FDG PET-CT showed overall sensitivity 57.9%, specificity 62.5% and PERCIST criteria had 100% sensibility and 16.7% specificity.Conclusions¹⁸F-FDG PET-CT is not an ideal predictor of pCR but if we use the PERCIST criteria we will have a high sensitivity and negative predictive value, avoiding false negative scans.     

Small Molecule,Multimodal, [18F]-PET and Fluorescence Imaging Agent Targeting Prostate-Specific Membrane Antigen: First-in-Human Study

BackgroundA first-in-human study of [¹⁸F]-BF3-Cy3-ACUPA, a small-molecule imaging agent that can be unimolecularly both positron emitting and fluorescent, is conducted to determine its safety, biodistribution, radiation dosimetry, feasibility in tumor detection by preoperative positron emission tomography (PET), as well as its intraoperative fluorescence imaging utility in patients with prostate-specific membrane antigen positive (PSMA⁺) tumors.MethodsTen patients aged 66 ± 7 years received a 6.5 ± 3.2 mCi intravenous injection of [¹⁸F]-BF3-Cy3-ACUPA and underwent PET/computed tomography (CT) imaging. Radiation dosimetry of [¹⁸F]-BF3-Cy3-ACUPA, normal organ biodistribution, and tumor uptakes were examined. Two patients were prescheduled for radical prostatectomy (RP) with extended pelvic lymphadenectomy approximately 24 hours following [¹⁸F]-BF3-Cy3-ACUPA injection and imaging. Without reinjection, intraoperative fluorescence imaging was performed on freshly excised tissue during RP. Frozen sections of excised tissue during RP were submitted for confirmatory histopathology and multiphoton fluorescence and brightfield microscopy.ResultsAbsorbed doses by organs including the kidneys and salivary glands were similar to 68Ga-PSMA-11 imaging. [¹⁸F]-BF3-Cy3-ACUPA physiologic radiotracer accumulation and urinary/biliary excretion closely resembled the distribution of other published PSMA tracers including [¹⁸F]-JK-PSMA-7, [¹⁸F]-PSMA-1007, [¹⁸F]-DCFPyL, and [¹⁸F]-DCFBC. ¹⁹F-BF3-Cy3-ACUPA was retained in PSMA⁺ cancer tissues in patients for at least 24 hours, allowing for intraoperative fluorescence assessment of the prostate and of the embedded prostate cancer without contrast reinjection. After 24 hours, the imaging agent mostly decayed or cleared from the blood pool. Preoperative PET and fluorescence imaging findings were confirmed with final histopathology and multiphoton microscopy.ConclusionOur first-in-human results demonstrate that [¹⁸F]-BF3-Cy3-ACUPA is safe and feasible in humans. Larger trials with this PET tracer are expected to further define its capabilities and its clinical role in the management of PSMA⁺ tumors, especially in prostate cancer.     

18F-fluorodeoxyglucose positron-emission tomography-computed tomography to diagnose recurrent cancer

Background:

Sometimes the diagnosis of recurrent cancer in patients with a previous malignancy can be challenging. This prospective cohort study assessed the clinical utility of ¹⁸F-fluorodeoxyglucose positron-emission tomography-computed tomography (¹⁸F-FDG PET-CT) in the diagnosis of clinically suspected recurrence of cancer.

Methods:

Patients were eligible if cancer recurrence (non-small-cell lung (NSCL), breast, head and neck, ovarian, oesophageal, Hodgkin''s or non-Hodgkin''s lymphoma) was suspected clinically, and if conventional imaging was non-diagnostic. Clinicians were asked to indicate their management plan before and after ¹⁸F-FDG PET-CT scanning. The primary outcome was change in planned management after ¹⁸F-FDG PET-CT.

Results:

Between April 2009 and June 2011, 101 patients (age, median 65 years; 55% female) were enroled from four cancer centres in Ontario, Canada. Distribution by primary tumour type was: NSCL (55%), breast (19%), ovarian (10%), oesophageal (6%), lymphoma (6%), and head and neck (4%). Of the 99 subjects who underwent ¹⁸F-FDG PET-CT, planned management changed after ¹⁸F-FDG PET-CT in 52 subjects (53%, 95% confidence interval (CI), 42–63%); a major change in plan from no treatment to treatment was observed in 38 subjects (38%, 95% CI, 29–49%), and was typically associated with ¹⁸F-FDG PET-CT findings that were positive for recurrent cancer (37 subjects). After 3 months, the stated post-¹⁸F-FDG PET-CT management plan was actually completed in 88 subjects (89%, 95% CI, 81–94%).

Conclusion:

In patients with suspected cancer recurrence and conventional imaging that is non-diagnostic, ¹⁸F-FDG PET-CT often provides new information that leads to important changes in patient management.     

PACE4-Based Molecular Targeting of Prostate Cancer Using an Engineered 64Cu-Radiolabeled Peptide Inhibitor

The potential of PACE4 as a pharmacological target in prostate cancer has been demonstrated as this proprotein convertase is strongly overexpressed in human prostate cancer tissues and its inhibition, using molecular or pharmacological approaches, results in reduced cell proliferation and tumor progression in mouse tumor xenograft models. We developed a PACE4 high-affinity peptide inhibitor, namely, the multi-leucine (ML), and sought to determine whether this peptide could be exploited for the targeting of prostate cancer for diagnostic or molecular imaging purposes. We conjugated a bifunctional chelator 1,4,7-triazacyclononane-1,4,7- triacetic acid (NOTA) to the ML peptide for copper-64 (⁶⁴Cu) labeling and positron emission tomography (PET)– based prostate cancer detection. Enzyme kinetic assays against recombinant PACE4 showed that the NOTA-modified ML peptide displays identical inhibitory properties compared to the unmodified peptide. In vivo biodistribution of the ⁶⁴Cu/NOTA-ML peptide evaluated in athymic nude mice bearing xenografts of two human prostate carcinoma cell lines showed a rapid and high uptake in PACE4-expressing LNCaP tumor at an early time point and in PACE4-rich organs. Co-injection of unlabeled peptide confirmed that tumor uptake was target-specific. PACE4-negative tumors displayed no tracer uptake 15 minutes after injection, while the kidneys, demonstrated high uptake due to rapid renal clearance of the peptide. The present study supports the feasibility of using a ⁶⁴Cu/NOTA-ML peptide for PACE4-targeted prostate cancer detection and PACE4 status determination by PET imaging but also provides evidence that ML inhibitor–based drugs would readily reach tumor sites under in vivo conditions for pharmacological intervention or targeted radiation therapy.Abbreviations: ACN, acetonitrile; Ac, acetyl; ⁶⁴Cu, copper-64; DCM, dichloromethane; [¹⁸F]-FDG, [¹⁸F]-fluoro-2-deoxy-d-glucose; HR-MS, high-resolution mass spectrometry; K_i, inhibitory constant; ML, multi-leucine; DMF, N,N′-dimethylformamide; NOTA, 1,4,7-triazacyclononane-1,4,7-triacetic acid; PC, proprotein convertase; PET, positron emission tomography     

Imaging the distribution of an antibody-drug conjugate constituent targeting mesothelin with 89Zr and IRDye 800CW in mice bearing human pancreatic tumor xenografts

Mesothelin is a tumor differentiation antigen expressed by epithelial tumors, including pancreatic cancer. Currently, mesothelin is being targeted with an antibody-drug conjugate (ADC) consisting of a mesothelin-specific antibody coupled to a highly potent chemotherapeutic drug. Considering the toxicity of the ADC and reduced accessibility of pancreatic tumors, non-invasive imaging could provide necessary information. We therefore developed a zirconium-89 (⁸⁹Zr) labeled anti-mesothelin antibody (⁸⁹Zr-AMA) to study its biodistribution in human pancreatic tumor bearing mice. Biodistribution and dose-finding of ⁸⁹Zr-AMA were studied 144 h after tracer injection in mice with subcutaneously xenografted HPAC. MicroPET imaging was performed 24, 72 and 144 h after tracer injection in mice bearing HPAC or Capan-2. Tumor uptake and organ distribution of ⁸⁹Zr-AMA were compared with nonspecific ¹¹¹In-IgG. Biodistribution analyses revealed a dose-dependent ⁸⁹Zr-AMA tumor uptake. Tumor uptake of ⁸⁹Zr-AMA was higher than ¹¹¹In-IgG using the lowest tracer dose. MicroPET showed increased tumor uptake over 6 days, whereas activity in blood pool and other tissues decreased. Immunohistochemistry showed that mesothelin was expressed by the HPAC and CAPAN-2 tumors and fluorescence microscopy revealed that AMA-800CW was present in tumor cell cytoplasm. ⁸⁹Zr-AMA tumor uptake is antigen-specific in mesothelin-expressing tumors. ⁸⁹Zr-AMA PET provides non-invasive, real-time information about AMA distribution and tumor targeting.     

MicroPET Imaging of Breast Cancer Using Radiolabeled Bombesin Analogs Targeting the Gastrin-releasing Peptide Receptor

Mammography is a well-established method for detecting primary breast cancer; however, it has some limitations that may be overcome using nuclear imaging methods. Current radiopharmaceuticals have limited sensitivity for detecting small primary lesions and it has been suggested that novel radiopharmaceuticals are necessary for detection of primary breast cancer, as well as for detecting metastases and recurrence, or for monitoring therapy. The gastrin-releasing peptide receptor (GRPR) is a seven-transmembrane G-protein coupled receptor that is overexpressed on primary breast cancer and lymph node metastases. Bombesin (BN) is a tetradecapeptide that binds with high affinity to GRPR and can be radiolabeled with the positron-emitter, copper-64 (⁶⁴Cu) for imaging with positron-emission tomography (PET). The goal of this study was to evaluate BN analogs that could be radiolabeled with ⁶⁴Cu for PET imaging of breast cancer. A series of BN analogs containing 4, 5, 6, 8, and 12- carbon linkers were evaluated with regard to their binding and internalization into T-47D human breast cancer cells. The ⁶⁴Cu-labeled analogs were then evaluated in mice bearing T-47D xenografts by tissue biodistribution and microPET imaging. These studies showed that all of the analogs had IC₅₀ values <100 nM and were all internalized into T-47D cells. Biodistribution studies showed that the BN analog with the 8-carbon linker not only had the highest tumor uptake but also had high normal tissue uptake in the liver. The analogs containing the 6- or 8-carbon linkers demonstrated good tumor uptake as determined by microPET imaging. Overall, this study shows the feasibility of using positron-labeled BN analogs for PET detection of GRPR-expressing breast cancer.     

18F-FDG PET-CT CT 在诊断乳腺癌腋窝淋巴结转移状态的对比研究*

目的:通过与CT对比,探讨18F-FDG PET-CT 在诊断乳腺癌患者腋窝淋巴结转移中的价值。方法:回顾性分析22例行乳腺癌改良根治术患者的术前18F-FDG PET-CT 、CT图像。在CT图像上分别以淋巴结最短径>0.5cm（A 标准）、最短径≥1.0cm（B 标准）及最长径≥1.0cm（C 标准）为判定淋巴结转移的标准;在PET-CT 图像上,分别以目测腋窝淋巴结出现18F-FDG 异常放射性浓聚为判定淋巴结阳性的标准（D 标准）及半定量分析法异常放射性浓聚灶最大标准化摄取值（maximum standard uptake value ,SUV max）≥1.0 为判定淋巴结转移标准（E 标准）。 以术后病理为金标准,比较不同影像方法诊断腋窝淋巴结转移状态的价值。结果:乳腺癌患者腋窝阳性与阴性淋巴结在大小及SUV max 方面的差异均具有统计学意义。不同诊断标准中,以PET-CT 的总体诊断准确率及与病理吻合度Kappa 值最高,其中A 标准灵敏度最高（59.3%）而特异度最低（83.5%）;B 标准特异度和阳性预测值最高（分别为98.2% 、72.7%）,而灵敏度和阴性预测值最低（27.1% 、88.4%）;C 标准各项诊断指标相对较差,无突出项;PET-CT 图像目测与半定量诊断结果相同,其诊断准确性（90.1%）、阴性预测值（92.5%）均优于单独CT诊断,且与病理诊断吻合度较好（Kappa 值为0.57）,在诊断灵敏度（55.9%）、特异度（96.1%）及阳性预测值（71.7%）方面与单独CT比较也具较高诊断价值,阳性组SUV max 较阴性组明显为高,二者差异有统计学意义（P=0.000）。 不同影像方法在诊断腋窝淋巴结转移时差异有统计学意义（P<0.05）。 结论:18F-FDG PET-CT 是一种直观有效的评价乳腺癌腋窝淋巴结转移状态的方法。      

131碘-组胺-吲哚美辛对小鼠荷Lewis肺癌的治疗效果及其作用机制的研究

目的:通过放射自显影技术(ARG)、血管内皮生长因子(VEGF)含量测定及18F-FDG PET-CT显像等方式观察131碘-组胺-吲哚美辛(131I-His-IN)对小鼠荷Lewis肺癌的治疗效果及作用机制.方法:小鼠灌胃给予131I-His-IN后,于不同时间点测定肿瘤组织及其它非肿瘤器官放射性计数,制成ARG切片及HE病理切片.给予不同药物治疗前、后均行18F-FDG PET-CT显像,获半定量最大标准摄取值(SUVmax)及抑瘤率.应用ELISA免疫分析法分析血清标本VEGF含量.结果:ARG显示:131I-His-IN选择性浓聚于肿瘤组织,黑色银颗粒主要在肿瘤细胞浆及细胞核分布.给药后8h肿瘤组织与肝脏、肾脏、肌肉、血液的放射性摄取比差异显著(F=3.46,P＜0.05),肿瘤组织放射性强度达到最大值(52％).病理显示肿瘤坏死组织随时间推移逐渐增多;18F-FDG PET-CT显像,治疗后的肿瘤组织SUVmax值降低,差异具有统计学意义(F=6.54,P＜0.05),抑瘤率以131I-His-IN降低最为显著达54.8％;血清中VEGF含量随时间推移逐渐下降,以131I-His-IN及His-IN组下降明显,差异具有统计学意义(F=7.74,P＜0.05).结论:放射自显影观察到131I-His-IN选择性浓聚于肿瘤组织上,作用靶点以胞核、胞浆为主,胞膜也有部分存在;随时间推移瘤组织坏死逐渐增加、抑瘤率升高、血清中VEGF水平逐渐下降,证明131I-His-IN具有明显的抗肿瘤作用.18F-FDGPET-CT显像通过SUVmax值动态变化,可用于监测抗肿瘤药物的疗效.