Evaluating requests for physician-assisted suicide. A survey among German oncologists.

BACKGROUND: Cancer patients form a notable proportion of requestors for physician-assisted suicide (PAS). This manuscript provides data on German oncologists' views concerning due criteria for the assessment of requests for PAS and quality assurance. METHODS: The German Society of Haematology and Medical Oncology (DGHO) has conducted a survey among its members to elicit data about practices and views on regulating PAS in March 2021. Descriptive analysis and bivariate logistic regression of quantitative data on socio-demographic and other determinants possibly associated with respondents' views on PAS as well as content analysis of qualitative data were performed. RESULTS: About 57.1% (n = 425) of respondents (n = 745) indicated that they had been asked for information about PAS by patients. Information about palliative (92.7%; n = 651) and psychological care options (85.6%; n = 598) was deemed most important in cases of requests for PAS. More than half of the respondents (57.6%; n = 429) were in favour of a formal expert assessment of decisional capacity and about 33.4% (n = 249) favoured a time span of 14 days between the counselling and prescription of a lethal drug. There was no association between participants who received more requests and a preference for disclosing publicly their willingness to assist with suicide. A majority of respondents requested measures of quality assurance (71.3%; n = 531). CONCLUSION: According to respondents' views, the regulation of PAS will require diligent procedures regarding the assessment of decisional capacity and counselling. The findings suggest that the development of adequate and feasible criteria to assess the quality of practices is an important task.

Bevacizumab-based treatment as salvage therapy in patients with recurrent symptomatic brain metastases.

BACKGROUND: Salvage treatment for recurrent brain metastases (BM) of solid cancers is challenging due to the high symptomatic burden and the limited local treatment options. METHODS: Patients with recurrent BM with no option for further local therapies were retrospectively identified from BM databases. Bevacizumab-based treatment was initiated as a salvage treatment. Radiological imaging before and after bevacizumab-based treatment was reevaluated for treatment response using the Response Assessment in Neuro-Oncology (RANO) BM criteria. RESULTS: Twenty-two patients (36.4% male) with recurrent BM from breast cancer (40.9%), colorectal cancer (31.8%), or lung cancer (27.3%) were identified. Previous BM-directed therapies were radiosurgery in 16/22 (72.7%) patients, whole-brain radiotherapy in 8/22 (36.4%), and neurosurgical resection in 11/22 (50.0%). Time since BM diagnosis to initiation of bevacizumab treatment was 16.5 months. Of 22 patients 14 (63.6%) received concurrent systemic therapies. Neurological symptom improvement could be achieved in 14/22 (63.6%) and stabilization in 6/22 (27.3%) patients, resulting in a clinical benefit in 20/22 (90.9%) patients. Steroids could be reduced or stopped in 15/22 (68.2%) patients. Rate of improvement on T1-weighted imaging was 15/19 (78.9%; median reduction: -26.0% ± 32.9) and 19/20 (95%; median reduction: -36.2% ± 22.2) on T2-weighted FLAIR imaging. According to RANO-BM best response was partial response in 7/19 (36.8%), stable disease in 9/19 (47.3%), and progressive disease in 3/19 (15.7%) patients. Median CNS-specific progression-free survival was 8 months and median overall survival after initiation of bevacizumab treatment was 17 months. CONCLUSIONS: Bevacizumab-based treatment had clinically relevant intracranial activity in the vast majority of patients suffering from recurrent, symptomatic BM. The data supports a prospective clinical trial of bevacizumab as a salvage treatment in BM.

Targeted delivery of siRNA using transferrin-coupled lipoplexes specifically sensitizes CD71 high expressing malignant cells to antibody-mediated complement attack.

The overexpression of membrane-bound complement regulatory proteins (mCRP; CD46, CD55, CD59) preventing opsonization and complement-dependent cytotoxicity (CDC) is considered a major barrier for successful antibody-based cancer immunotherapy. To avoid a potential deleterious effect of mCRP neutralization on normal tissue cells, complement regulation has to be selectively targeted to the malignant cells. In this study, anti-mCRP small interfering RNAs (siRNAs) were encapsulated in transferrin-coupled lipoplexes for the specific delivery to transferrin receptor CD71(high) expressing BT474, DU145, and SW480 as well as corresponding CD71-knockdown (CD71(low)) tumor cells. Targeted delivery with transferrin-siRNA-lipoplexes became possible by charge neutralization and resulted in efficient silencing of all three mCRPs up to 90%, which is dependent on their CD71 expression. The mCRP knockdown led to a significant increase of CDC on CD71(high) tumor cells by 68% in BT474, 58% in DU145, and 40% in SW480 cells but only slightly increased on CD71(low) cells. Downregulation of CD46 and CD55 significantly increased C3 opsonization only on CD71(high) tumor cells. Our results demonstrate for the first time that by specific delivery of anti-mCRP siRNA through transferrin receptor, complement regulation can be selectively neutralized, allowing specific antibody-mediated killing of tumor cells without affecting healthy bystander cells, which appears to be a suited strategy to improve antibody-based cancer immunotherapy.

Lipoplex mediated silencing of membrane regulators (CD46, CD55 and CD59) enhances complement-dependent anti-tumor activity of trastuzumab and pertuzumab.

The therapeutic potential of anticancer antibodies is limited by the resistance of tumor cells to complement-mediated attack, primarily through the over-expression of membrane complement regulatory proteins (mCRPs: CD46, CD55 and CD59). Trastuzumab, an anti- HER2 monoclonal antibody, approved for the treatment of HER2-positive breast and gastric cancers, exerts only minor complement-mediated cytotoxicity (CDC). Pertuzumab is a novel anti-HER2 monoclonal antibody, which blocks HER2 dimerization with other ligand-activated HER family members. Here, we explored the complement-mediated anti-tumor effects of trastuzumab and pertuzumab on HER2-positive tumor cells of various histological origins. Delivery of chemically stabilized anti-mCRP siRNAs using cationic lipoplexes, AtuPLEXes, to HER2-over-expressing BT474, SK-BR-3 (breast), SKOV3 (ovarian) and Calu-3 (lung) cancer cells reduced mCRPs expression by 85-95%. Knockdown of individual complement regulators variably led to increased CDC only upon combined treatment with trastuzumab and pertuzumab. The combined down-regulation of all the three regulators augmented CDC by 48% in BT474, 46% in SK-BR-3 cells, 78% in SKOV3 cells and by 30% in Calu-3 cells and also increased complement-induced apoptosis and caspase activity on mCRP neutralized tumor cells. In addition, antibody-induced C3 opsonization of tumor cells was significantly enhanced after mCRP silencing and further augmented tumor cell killing by macrophages. Our findings suggest that siRNA-induced inhibition of complement regulator expression clearly enhances complement- and macrophage-mediated anti-tumor activity of trastuzumab and pertuzumab on HER2-positive tumor cells. Thus - if selectively targeted to the tumor - siRNA-induced inhibition of complement regulation may serve as an innovative strategy to potentiate the efficacy of antibody-based immunotherapy.