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Peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTA-TATE has recently been evaluated for the treatment of meningioma patients. However, current knowledge of the underlying radiation biology is limited, in part due to the lack of appropriate in vitro models. Here, we demonstrate proof-of-concept of a meningioma patient-derived 3D culture model to assess the short-term response to radiation therapies such as PRRT and external beam radiotherapy (EBRT). We established short-term cultures (1 week) for 16 meningiomas with high efficiency and yield. In general, meningioma spheroids retained characteristics of the parental tumor during the initial days of culturing. For a subset of tumors, clear changes towards a more aggressive phenotype were visible over time, indicating that the culture method induced dedifferentiation of meningioma cells. To assess PRRT efficacy, we demonstrated specific uptake of 177Lu-DOTA-TATE via somatostatin receptor subtype 2 (SSTR2), which was highly overexpressed in the majority of tumor samples. PRRT induced DNA damage which was detectable for an extended timeframe as compared to EBRT. Interestingly, levels of DNA damage in spheroids after PRRT correlated with SSTR2-expression levels of parental tumors. Our patient-derived meningioma culture model can be used to assess the short-term response to PRRT and EBRT in radiobiological studies. Further improvement of this model should pave the way towards the development of a relevant culture model for assessment of the long-term response to radiation and, potentially, individual patient responses to PRRT and EBRT.

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Background: Peptide receptor radionuclide therapy (PRRT) increases progression-free survival and quality of life of neuroendocrine tumor (NET) patients, however complete cures are rare and dose-limiting toxicity has been reported. PRRT induces DNA damage of which DNA double strand breaks (DSBs) are the most cytotoxic. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key player in DSB repair and its inhibition therefore is a potential way to enhance PRRT efficacy without increasing the dosage. Methods: We analyzed effects of combining PRRT and DNA-PKcs inhibitor AZD7648 on viability, cell death and clonogenic survival on SSTR2-expressing cell lines BON1-SSTR2, GOT1 and NCI-H69. Therapy-induced DNA damage response was assessed by analyzing DSB foci levels and cell cycle distributions. In vivo efficacy was investigated in BON1-SSTR2 and NCI-H69 xenografted mice and hematologic and renal toxicity were monitored by blood counts, creatinine levels and analyzing renal morphology. Results: Combining PRRT and AZD7648 significantly decreased viability of BON1-SSTR2, GOT1 and NCI-H69 cells and induced cell death in GOT1 and BON1-SSTR2 cells. A strong effect of AZD7648 on PRRT-induced DSB repair was found. In GOT1 cells, this was accompanied by induction of cell cycle blocks. However, BON1-SSTR2 cells were unable to fully arrest their cell cycle and polyploid cells with high DNA damage levels were detected. In vivo, AZD7648 significantly sensitized BON1-SSTR2 and NCI-H69 xenograft models to PRRT. In addition, combination therapy did not induce significant changes in body weight, blood composition, plasma creatinine levels and renal morphology, indicating the absence of severe acute hematologic and renal toxicity. Conclusion: These results highlight that the potentiation of the therapeutic effect of PRRT by DNA-PKcs inhibition is a highly effective and well-tolerated therapeutic strategy. Based on our findings, we recommend initiation of phase I/II studies in patients to find a safe and effective combination regimen.

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Peptide receptor radionuclide therapy (PRRT), a form of internal targeted radiation treatment using [177Lu]Lu [DOTA0-Tyr3]octreotate, is used to treat patients with metastasized neuroendocrine tumors (NETs). Even though PRRT is now the second line of treatment for patients with metastasized NETs, the majority of patients will not be cured by the treatment. PRRT functions by inducing DNA damage upon radioactive decay and inhibition of DNA damage repair proteins could therefore be used as a strategy to potentiate PRRT. Previous work has shown promising results on the combination of PRRT with the PARP inhibitor olaparib in cell lines and mice and we have been taken the next step for further in vivo validation using two different xenografted mouse models. We observed that this combination therapy resulted in increased therapeutic efficacy only in one model and not the other. Overall, our findings indicate a tumor-type dependent anti-tumor response to the combination of PRRT and olaparib. These data emphasize the unmet need for the molecular stratification of tumors to predetermine the potential clinical value of combining PARP inhibition with PRRT.

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BACKGROUND: Radiopharmaceuticals are considered as regular medicinal products and therefore the same regulations as for non-radioactive medicinal products apply. However, specific aspects should be considered due to the radiochemical properties. Radiopharmaceutical dedicated monographs are developed in the European Pharmacopoeia to address this. Currently, different quality control methods for non-registered radiopharmaceuticals are utilized, often focusing on radio-TLC only, which has its limitations. When the radiochemical yield (RCY) is measured by radio-TLC analysis, degradation products caused by radiolysis are frequently not detected. In contrast, HPLC analysis defines the radiochemical purity (RCP), allowing for detection of peak formation related to radiolysis. During the introduction and optimization phase of therapeutic radiopharmaceuticals, significant percentages of impurities, like radiolysed construct formation, may have consequential impact on patient treatment. Since more hospitals and institutes are offering radiopharmaceutical therapies, such as [177Lu]Lu-PSMA with an in-house production, the demand for adequate quality control is increasing. Here we show the optimization and implementation of a therapeutic radiopharmaceutical, including the comparison of ITLC and HPLC quality control. RESULTS: Downscaled conditions (74 MBq/µg) were in concordance to clinical conditions (18 GBq/250 µg, 5 mL syringe/100 mL flacon); all results were consistent with an > 98% RCY (radio-TLC) and stability of > 95% RCP (HPLC). Radio-TLC did not identify radiolysis peaks, while clear identification was performed by HPLC analysis. Decreasing the RCP with 50%, reduced the cell-binding capacity with 27%. CONCLUSION: This research underlines the importance of the radiolabeling and optimization including clinical implementation and clarifies the need for cross-validation of the RCY and RCP for quality control measurements. Only HPLC analysis is suitable for identification of radiolysis. Here we have proven that radiolysed [177Lu]Lu-PSMA has less binding affinity and thus likely will influence treatment efficacy. HPLC analysis is therefore essential to include in at least the validation phase of radiopharmaceutical implementation to ensure clinical treatment quality.

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DNA damage-inducing therapies are of tremendous value for cancer treatment and function by the direct or indirect formation of DNA lesions and subsequent inhibition of cellular proliferation. Of central importance in the cellular response to therapy-induced DNA damage is the DNA damage response (DDR), a protein network guiding both DNA damage repair and the induction of cancer-eradicating mechanisms such as apoptosis. A detailed understanding of DNA damage induction and the DDR has greatly improved our knowledge of the classical DNA damage-inducing therapies, radiotherapy and cytotoxic chemotherapy, and has paved the way for rational improvement of these treatments. Moreover, compounds targeting specific DDR proteins, selectively impairing DNA damage repair in cancer cells, form a promising novel therapy class that is now entering the clinic. In this review, we give an overview of the current state and ongoing developments, and discuss potential avenues for improvement for DNA damage-inducing therapies, with a central focus on the role of the DDR in therapy response, toxicity and resistance. Furthermore, we describe the relevance of using combination regimens containing DNA damage-inducing therapies and how they can be utilized to potentiate other anticancer strategies such as immunotherapy.

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Background and Aim. The optimum management of Bowen's Disease (BD) is undefined. A review of current practice is required to allow the development of best practice guidelines. Methods. All BD cases, diagnosed in one UK centre and one Australian centre over a year (1 July 2012-30 June 2013), were analysed retrospectively. Patients with BD were identified from histopathology reports and their medical records were analysed to collect demographic data, site of lesion, and treatment used. Results. The treatment of 155 lesions from the UK centre and 151 lesions from the Australian centre was analysed. At both centres BD was most frequently observed on the face: UK had 70 (45%) lesions and Australia had 83 (55%) lesions (P = 0.08). The greatest number of lesions was managed by the plastic surgery department in the UK centre, 72 (46%), and the dermatology department in the Australian centre, 121 (80%). The most common therapy was surgical excision at both centres. Conclusions. In both UK and Australia, BD arises on sun-exposed sites and was most commonly treated with surgical excision despite a lack of robust evidence-based guidelines.

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OBJECTIVE: An unmet need is represented in angioplasty catheters that permit the predilation stage of treating complex coronary anatomy oftentimes not amenable to conventional device therapies. BACKGROUND: Lesion preparation with balloon angioplasty prior to stent placement remains the most common method of percutaneous coronary revascularization. METHODS: Clinical and angiographic outcomes were evaluated following a treatment strategy of coronary artery disease that included predilation with a low-profile, 1.25-mm angioplasty catheter prior to stent placement. The study primary end point of procedural success was defined as successful device delivery and lesion treatment, including the absence of clinically significant perforation, arrhythmia, flow-limiting dissection, or reduction in baseline Thrombolysis In Myocardial Infarction (TIMI) grade with final achievement of TIMI 3 flow. RESULTS: Among 51 patients (54 lesions), predilation using a 1.25 mm angioplasty catheter was associated with procedural and device-related success rates of 100%. In-hospital target lesion failure occurred in one patient (2.0%) related to postprocedural myocardial infarction. Patient and angiographic characteristics included diabetes, 43.1%; lesion length ≥ 20 mm, 20.4%; bifurcation lesion, 31.5%; lesion classification B2/C, 74.1%; and baseline TIMI 0/1 flow, 13.0%. No subsequent in-hospital adverse events occurred. CONCLUSIONS: Percutaneous coronary revascularization involving a predilation strategy with a low profile, 1.25-mm angioplasty catheter is associated with favorable procedural safety and efficacy and may represent an effective initial treatment for complex coronary anatomy.

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Ultrafiltration enhances volume removal and weight reduction vs diuretics. However, their differential impact on total body sodium, potassium, and magnesium has not been described. Fifteen patients with congestion despite diuretic therapy had urine electrolytes measured after a diuretic dose. Ultrafiltration was initiated and ultrafiltrate electrolytes were measured. The urine sodium after diuretics (60+/-47 mmol/L) was less than in the ultrafiltrate (134+/-8.0 mmol/L) (P=.000025). The urine potassium level after diuretics (41+/-23 mmol/L) was greater than in the ultrafiltrate (3.7+/-0.6 mmol/L) (P=.000017). The urine magnesium level after diuretics (5.2+/-3.1 mg/dL) was greater than in the ultrafiltrate (2.9+/-0.7 mg/dL) (P=.017). In acute decompensated heart failure patients with congestion despite diuretic therapy, diuretics are poor natriuretics and cause significant potassium and magnesium loss. Ultrafiltration extracts more sodium while sparing potassium and magnesium. The sustained clinical benefits of ultrafiltration compared with diuretics may be partly related to their disparate effects on total body sodium, potassium, and magnesium, in addition to their differential efficacy of volume removal.

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