Liposomal formulations entrapping a vast number of molecules have improved cancer therapies overcoming certain pharmacokinetic (PK) and pharmacodynamic limitations, many of which are associated with ...tumor characteristics. In this context, immunoliposomes represent a new strategy that has been widely investigated in preclinical cancer models with promising results, although few have reached the stage of clinical trials. This contrasts with the emerging clinical application of monoclonal antibodies (mAbs). This formulation allows the conjugation of different mAbs or antibody derivatives, such as monovalent variable fragments Fab’, to the polymers covering the surface of liposomes. The combination of this targeting strategy together with drug encapsulation in a single formulation may contribute to enhance the efficacy of these associated agents, reducing their toxicities.
In this paper we will consider how factors such as particle size, lipid composition and charge, lipid-polymer conjugation, method of production and type of ligand for liposome coupling influence the efficacy of these formulations. Furthermore, the high inter-individual variability in the tumor microenvironment, as well as the poor experimental designs for the PK characterization of liposomes, make the establishment of the relationship between plasma or tumor concentrations and efficacy difficult. Thus, adequate dosing regimens and patient stratification regarding the target expression may contribute to enhance the possibility of incorporating these immunoliposomes into the therapeutic arsenal for cancer treatments. All these issues will be briefly dealt with here, together with a section showing the state of the art of those targeted liposomes that are coming up for testing in clinical trials. Finally, some insights into future developments such as the combination of specificity and controlled release, based on the application of different stimuli, for the manipulation of stability and cargo release, will be offered. This has been included in order to highlight the new opportunities for targeted liposomes, including immunoliposomes.
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High-grade serous ovarian carcinoma is characterised by TP53 mutations, DNA repair defects, and genomic instability. We hypothesised that prexasertib (LY2606368), a cell cycle checkpoint kinase 1 and ...2 inhibitor, would be active in BRCA wild-type disease.
In an open-label, single-centre, two-stage, proof-of-concept phase 2 study, we enrolled women aged 18 years or older with measurable, recurrent high-grade serous or high-grade endometrioid ovarian carcinoma. All patients had a negative family history of hereditary breast and ovarian cancer or known BRCA wild-type status, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status score 0–2, and adequate haematological, renal, hepatic, and bone-marrow function. Patients received intravenous prexasertib 105 mg/m2 administered over 1 h every 14 days in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint of investigator-assessed tumour response, based on RECIST version 1.1, was assessed per protocol (assessable patients who had undergone CT imaging at baseline and attended at least one protocol-specified follow-up) and by intention to treat. The final analysis of this cohort of patients with BRCA wild-type high-grade serous ovarian carcinoma is reported here. This ongoing trial is registered with ClinicalTrials.gov, number NCT02203513, and continues to enrol patients for the BRCA-mutated ovarian cancer cohort.
Between Jan 20, 2015, and Nov 2, 2016, we enrolled 28 women with a median age of 64 years (IQR 58·0–69·5) who had previously received a median of 5·0 (IQR 2·5–5·0) systemic therapies. Most patients (22 79%) had platinum-resistant or platinum-refractory disease. All women received at least one dose of prexasertib, but four (14%) of 28 patients were not assessable for RECIST response. Eight (33%, 95% CI 16–55) of 24 patients assessable per protocol had partial responses. In the intention-to-treat population, eight (29%, 95% CI 13–49) of 28 had a partial responses. The most common (in >10% patients) grade 3 or 4 treatment-emergent adverse events were neutropenia in 26 (93%) of 28 patients, reduced white blood cell count in 23 (82%), thrombocytopenia in seven (25%), and anaemia in three (11%). Grade 4 neutropenia was reported in 22 (79%) patients after the first dose of prexasertib and was transient (median duration 6 days IQR 4–8) and recovered without growth-factor support in all cases. The treatment-related serious adverse event of grade 3 febrile neutropenia was reported in two (7%) patients. One patient died during the study due to tumour progression.
Prexasertib showed clinical activity and was tolerable in patients with BRCA wild-type high-grade serous ovarian carcinoma. This drug warrants further development in this setting, especially for patients with platinum-resistant or platinum-refractory disease.
Intramural Research Program of the National Institutes of Health and National Cancer Institute.
Purpose To characterize clinically important prostate cancers missed at multiparametric (MP) magnetic resonance (MR) imaging. Materials and Methods The local institutional review board approved this ...HIPAA-compliant retrospective single-center study, which included 100 consecutive patients who had undergone MP MR imaging and subsequent radical prostatectomy. A genitourinary pathologist blinded to MP MR findings outlined prostate cancers on whole-mount pathology slices. Two readers correlated mapped lesions with reports of prospectively read MP MR images. Readers were blinded to histopathology results during prospective reading. At histopathologic examination, 80 clinically unimportant lesions (<5 mm; Gleason score, 3+3) were excluded. The same two readers, who were not blinded to histopathologic findings, retrospectively reviewed cancers missed at MP MR imaging and assigned a Prostate Imaging Reporting and Data System (PI-RADS) version 2 score to better understand false-negative lesion characteristics. Descriptive statistics were used to define patient characteristics, including age, prostate-specific antigen (PSA) level, PSA density, race, digital rectal examination results, and biopsy results before MR imaging. Student t test was used to determine any demographic differences between patients with false-negative MP MR imaging findings and those with correct prospective identification of all lesions. Results Of the 162 lesions, 136 (84%) were correctly identified with MP MR imaging. Size of eight lesions was underestimated. Among the 26 (16%) lesions missed at MP MR imaging, Gleason score was 3+4 in 17 (65%), 4+3 in one (4%), 4+4 in seven (27%), and 4+5 in one (4%). Retrospective PI-RADS version 2 scores were assigned (PI-RADS 1, n = 8; PI-RADS 2, n = 7; PI-RADS 3, n = 6; and PI-RADS 4, n = 5). On a per-patient basis, MP MR imaging depicted clinically important prostate cancer in 99 of 100 patients. At least one clinically important tumor was missed in 26 (26%) patients, and lesion size was underestimated in eight (8%). Conclusion Clinically important lesions can be missed or their size can be underestimated at MP MR imaging. Of missed lesions, 58% were not seen or were characterized as benign findings at second-look analysis. Recognition of the limitations of MP MR imaging is important, and new approaches to reduce this false-negative rate are needed.
RSNA, 2017 Online supplemental material is available for this article.
Hereditary cases account for about 5% of all cases of renal cell carcinoma (RCC). With advances in next-generation sequencing, several new hereditary syndromes have been described in the last few ...years.
To review and summarise the recent preclinical and clinical literature in hereditary renal cancer.
A systematic review of the literature was performed in November 2018 using PubMed and OMIM databases, with an emphasis on kidney cancer, genetics and genomics, clinical criteria, and management.
Several autosomal dominant hereditary RCC syndromes have been described, including those related to germline pathogenic variants in VHL, MET, FH, TSC1/TSC2, FLCN, SDHA/B/C/D, BAP1, CDC73, and MITF. Clinical spectrum of SDH, BAP1, and MITF is still being defined, although these appear to be associated with a lower incidence of RCC. FH and likely BAP1 RCC are associated with more aggressive disease. Preclinical and clinical studies show that using systemic therapy that exploits specific genetic pathways is a promising strategy.
There are several well-described hereditary RCC syndromes, as well as recently identified ones, for which the full clinical spectrum is yet to be defined. In the new era of precision medicine, identification of these syndromes may play an important role in management and systemic treatment selection.
This review covers updates in the diagnosis and management of familial kidney cancer syndromes. We describe updates in testing and management of the most common syndromes such as von Hippel-Lindau, and hereditary leiomyomatosis and renal cell carcinoma. We also provide insights into recently described familial kidney cancer syndromes.
In the last few years, there have been significant advances in our knowledge about the familial kidney cancer syndromes, with updated recommendations on work-up and management. Additionally, there are more recently described familial kidney cancer syndromes that may be under-recognised.
Purpose
Multiparametric MRI (mpMRI) improves the detection of clinically significant prostate cancer, but is limited by interobserver variation. The second version of theProstate Imaging Reporting ...and Data System (PIRADSv2) was recently proposed as a standard for interpreting mpMRI. To assess the performance and interobserver agreement of PIRADSv2 we performed a multi‐reader study with five radiologists of varying experience.
Materials and Methods
Five radiologists (n = 2 prostate dedicated, n = 3 general body) blinded to clinicopathologic results detected and scored lesions on prostate mpMRI using PIRADSv2. The endorectal coil 3 Tesla MRI included T2W, diffusion‐weighted imaging (apparent diffusion coefficient, b2000), and dynamic contrast enhancement. Thirty‐four consecutive patients were included. Results were correlated with radical prostatectomy whole‐mount histopathology produced with patient‐specific three‐dimensional molds. An index lesion was defined on pathology as the lesion with highest Gleason score or largest volume if equivalent grades. Average sensitivity and positive predictive values (PPVs) for all lesions and index lesions were determined using generalized estimating equations. Interobserver agreement was evaluated using index of specific agreement.
Results
Average sensitivity was 91% for detecting index lesions and 63% for all lesions across all readers. PPV was 85% for PIRADS ≥ 3 and 90% for PIRADS ≥ 4. Specialists performed better only for PIRADS ≥ 4 with sensitivity 90% versus 79% (P = 0.01) for index lesions. Index of specific agreement among readers was 93% for the detection of index lesions, 74% for the detection of all lesions, and 85% for scoring index lesions, and 58% for scoring all lesions.
Conclusion
By using PIRADSv2, general body radiologists and prostate specialists can detect high‐grade index prostate cancer lesions with high sensitivity and agreement.
Level of Evidence: 1
J. Magn. Reson. Imaging 2017;45:579–585.
Purpose To validate the dominant pulse sequence paradigm and limited role of dynamic contrast material-enhanced magnetic resonance (MR) imaging in the Prostate Imaging Reporting and Data System ...(PI-RADS) version 2 for prostate multiparametric MR imaging by using data from a multireader study. Materials and Methods This HIPAA-compliant retrospective interpretation of prospectively acquired data was approved by the local ethics committee. Patients were treatment-naïve with endorectal coil 3-T multiparametric MR imaging. A total of 163 patients were evaluated, 110 with prostatectomy after multiparametric MR imaging and 53 with negative multiparametric MR imaging and systematic biopsy findings. Nine radiologists participated in this study and interpreted images in 58 patients, on average (range, 56-60 patients). Lesions were detected with PI-RADS version 2 and were compared with whole-mount prostatectomy findings. Probability of cancer detection for overall, T2-weighted, and diffusion-weighted (DW) imaging PI-RADS scores was calculated in the peripheral zone (PZ) and transition zone (TZ) by using generalized estimating equations. To determine dominant pulse sequence and benefit of dynamic contrast-enhanced (DCE) imaging, odds ratios (ORs) were calculated as the ratio of odds of cancer of two consecutive scores by logistic regression. Results A total of 654 lesions (420 in the PZ) were detected. The probability of cancer detection for PI-RADS category 2, 3, 4, and 5 lesions was 15.7%, 33.1%, 70.5%, and 90.7%, respectively. DW imaging outperformed T2-weighted imaging in the PZ (OR, 3.49 vs 2.45; P = .008). T2-weighted imaging performed better but did not clearly outperform DW imaging in the TZ (OR, 4.79 vs 3.77; P = .494). Lesions classified as PI-RADS category 3 at DW MR imaging and as positive at DCE imaging in the PZ showed a higher probability of cancer detection than did DCE-negative PI-RADS category 3 lesions (67.8% vs 40.0%, P = .02). The addition of DCE imaging to DW imaging in the PZ was beneficial (OR, 2.0; P = .027), with an increase in the probability of cancer detection of 15.7%, 16.0%, and 9.2% for PI-RADS category 2, 3, and 4 lesions, respectively. Conclusion DW imaging outperforms T2-weighted imaging in the PZ; T2-weighted imaging did not show a significant difference when compared with DW imaging in the TZ by PI-RADS version 2 criteria. The addition of DCE imaging to DW imaging scores in the PZ yields meaningful improvements in probability of cancer detection.
RSNA, 2017 An earlier incorrect version of this article appeared online. This article was corrected on July 27, 2017. Online supplemental material is available for this article.
IMPORTANCE: Targeted magnetic resonance (MR)/ultrasound fusion prostate biopsy has been shown to detect prostate cancer. The implications of targeted biopsy alone vs standard extended-sextant biopsy ...or the 2 modalities combined are not well understood. OBJECTIVE: To assess targeted vs standard biopsy and the 2 approaches combined for the diagnosis of intermediate- to high-risk prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 1003 men undergoing both targeted and standard biopsy concurrently from 2007 through 2014 at the National Cancer Institute in the United States. Patients were referred for elevated level of prostate-specific antigen (PSA) or abnormal digital rectal examination results, often with prior negative biopsy results. Risk categorization was compared among targeted and standard biopsy and, when available, whole-gland pathology after prostatectomy as the “gold standard.” INTERVENTIONS: Patients underwent multiparametric prostate magnetic resonance imaging to identify regions of prostate cancer suspicion followed by targeted MR/ultrasound fusion biopsy and concurrent standard biopsy. MAIN OUTCOMES AND MEASURES: The primary objective was to compare targeted and standard biopsy approaches for detection of high-risk prostate cancer (Gleason score ≥4 + 3); secondary end points focused on detection of low-risk prostate cancer (Gleason score 3 + 3 or low-volume 3 + 4) and the biopsy ability to predict whole-gland pathology at prostatectomy. RESULTS: Targeted MR/ultrasound fusion biopsy diagnosed 461 prostate cancer cases, and standard biopsy diagnosed 469 cases. There was exact agreement between targeted and standard biopsy in 690 men (69%) undergoing biopsy. Targeted biopsy diagnosed 30% more high-risk cancers vs standard biopsy (173 vs 122 cases, P < .001) and 17% fewer low-risk cancers (213 vs 258 cases, P < .001). When standard biopsy cores were combined with the targeted approach, an additional 103 cases (22%) of mostly low-risk prostate cancer were diagnosed (83% low risk, 12% intermediate risk, and 5% high risk). The predictive ability of targeted biopsy for differentiating low-risk from intermediate- and high-risk disease in 170 men with whole-gland pathology after prostatectomy was greater than that of standard biopsy or the 2 approaches combined (area under the curve, 0.73, 0.59, and 0.67, respectively; P < .05 for all comparisons). CONCLUSIONS AND RELEVANCE: Among men undergoing biopsy for suspected prostate cancer, targeted MR/ultrasound fusion biopsy, compared with standard extended-sextant ultrasound-guided biopsy, was associated with increased detection of high-risk prostate cancer and decreased detection of low-risk prostate cancer. Future studies will be needed to assess the ultimate clinical implications of targeted biopsy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00102544
Purpose Prostate Imaging Reporting and Data System version 2 was developed to standardize the interpretation and reporting of multiparametric prostate magnetic resonance imaging and provide ...guidelines for biopsy of multiparametric magnetic resonance imaging findings. We prospectively evaluated the cancer detection rate at each overall PI-RADSv2 score. Materials and Methods This prospective study included 62 consecutive patients with 116 lesions who underwent multiparametric prostate magnetic resonance imaging at 3T with PI-RADSv2 evaluation and subsequent targeted magnetic resonance imaging/ transrectal ultrasound fusion guided biopsy and concurrent 12-core systematic prostate biopsy between May and September 2015. Median patient age and prostate specific antigen values were 65.5 years (range 50.3 to 76.6) and 7.10 ng/ml (range 0.47 to 863.0), respectively. Mean lesion size was 12.7 mm overall. Lesion based cancer detection rates for all tumors and for Gleason 3+4 or greater tumors at each PI-RADSv2 score were calculated. Univariate analysis was performed to assess differences in the cancer detection rate among PI-RADSv2 scores. Results A total of 116 lesions in 62 patients were evaluated prospectively (0 PI-RADS 1, 18 PI-RADS 2, 19 PI-RADS 3, 47 PI-RADS 4, 32 PI-RADS 5), and the patients underwent magnetic resonance/transrectal ultrasound fusion guided biopsy and systematic biopsy. Histopathology revealed 55 of 116 (47.4%) cancers (17 Gleason 3+3, 16 Gleason 3+4, 6 Gleason 4+3, 12 Gleason 4+4, 3 Gleason 4+5 and 1 Gleason 5+4). Based on targeted biopsy on a per lesion basis, the overall cancer detection rates of PI-RADS 2, 3, 4 and 5 scores for all tumors was 22.2%, 15.8%, 29.8% and 78.1%, respectively. The cancer detection rate of PI-RADS 2, 3, 4, and 5 scores for Gleason 3+4 or greater tumors was 5.6%, 0%, 21.3% and 75%, respectively. Differences in the cancer detection rate between overall PI-RADS 4 and 5 scores were significant (p <0.001 for Gleason greater than 3+3 and Gleason 3+4 or greater cancers). Conclusions A PI-RADS score of 5 had the highest prospective cancer detection rate (78%). A PI-RADS score of 4 had only a 30% cancer detection rate, which is lower than expected. Surprisingly, no or few significant cancers were detected at a PI-RADS score of 3 (16%). These early prospective data suggest that current criteria result in a high false-positive rate that lowers the cancer detection rate. Therefore, stricter criteria may be needed in the future to decrease false-positives and increase the cancer detection rate for PI-RADS scores of 3, 4 and 5.
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