Face masks and personal respirators are used to curb the transmission of SARS-CoV-2 in respiratory droplets; filters embedded in some personal protective equipment could be used as a non-invasive ...sample source for applications, including at-home testing, but information is needed about whether filters are suited to capture viral particles for SARS-CoV-2 detection. In this study, we generated inactivated virus-laden aerosols of 0.3-2 microns in diameter (0.9 µm mean diameter by mass) and dispersed the aerosolized viral particles onto electrostatic face mask filters. The limit of detection for inactivated coronaviruses SARS-CoV-2 and HCoV-NL63 extracted from filters was between 10 to 100 copies/filter for both viruses. Testing for SARS-CoV-2, using face mask filters and nasopharyngeal swabs collected from hospitalized COVID-19-patients, showed that filter samples offered reduced sensitivity (8.5% compared to nasopharyngeal swabs). The low concordance of SARS-CoV-2 detection between filters and nasopharyngeal swabs indicated that number of viral particles collected on the face mask filter was below the limit of detection for all patients but those with the highest viral loads. This indicated face masks are unsuitable to replace diagnostic nasopharyngeal swabs in COVID-19 diagnosis. The ability to detect nucleic acids on face mask filters may, however, find other uses worth future investigation.
Neoadjuvant immunotherapies hold promise in muscle-invasive bladder cancer (MIBC).
To report on 2-yr disease-free (DFS) and overall (OS) survival including novel tissue-based biomarkers and ...circulating tumor DNA (ctDNA) in the ABACUS trial.
ABACUS was a multicenter, single-arm, neoadjuvant, phase 2 trial, including patients with MIBC (T2-4aN0M0) who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy.
Two cycles of atezolizumab were given prior to radical cystectomy. Serial tissue and blood samples were collected.
The primary endpoints of pathological complete response (pCR) rate and dynamic changes to T-cell biomarkers were published previously. Secondary outcomes were 2-yr DFS and OS. A biomarker analysis correlated with relapse-free survival (RFS) was performed, which includes FOXP3, major histocompatibility complex class I, CD8/CD39, and sequential ctDNA measurements.
The median follow-up time was 25 mo (95% confidence interval CI 25-26). Ninety-five patients received at least one cycle of atezolizumab. Eight patients did not undergo cystectomy (only one due to disease progression). The pCR rate was 31% (27/88; 95% CI 21-41). Two-year DFS and OS were 68% (95% CI 58-76) and 77% (95% CI 68-85), respectively. Two-year DFS in patients achieving a pCR was 85% (95% CI 65-94). Baseline PD-L1 and tumor mutational burden did not correlate with RFS (hazard ratio HR 0.60 95% CI 0.24-1.5, p = 0.26, and 0.72 95% CI 0.31-1.7, p = 0.46, respectively). RFS correlated with high baseline stromal CD8+ (HR 0.25 95% CI 0.09-0.68, p = 0.007) and high post-treatment fibroblast activation protein (HR 4.1 95% CI 1.3-13, p = 0.01). Circulating tumor DNA positivity values at baseline, after neoadjuvant therapy, and after surgery were 63% (25/40), 47% (14/30), and 14% (five/36), respectively. The ctDNA status was highly prognostic at all time points. No relapses were observed in ctDNA-negative patients at baseline and after neoadjuvant therapy. The lack of randomization and exploratory nature of the biomarker analysis are limitations of this work.
Neoadjuvant atezolizumab in MIBC is associated with clinical responses and high DFS. CD8+ expression and serial ctDNA levels correlated with outcomes, and may contribute to personalized therapy in the future.
We showed that bladder cancer patients receiving immunotherapy followed by cystectomy have good long-term outcomes. Furthermore, we found that certain biological features can predict patients who might have particular benefit from this therapy.
Autologous stem cell transplant (ASCT) is the current standard of care for eligible patients with multiple myeloma (MM). The UK national trial CARDAMON investigated whether, following carfilzomib, ...cyclophosphamide, and dexamethasone (KCD) induction, ASCT was of benefit compared with further cycles of KCD as consolidation. All patients received carfilzomib maintenance. KCD consolidation did not show non-inferiority, but the difference was marginal, and we previously concluded “that further studies are warranted to explore deferred autologous HSCT in some subgroups.” Whilst some of the benefit of ASCT derives from the myeloablative effect of melphalan, there is evidence that immune reprogramming has an important role. It has also been reported that neoantigen burden has prognostic significance in MM, with patients with a high neoantigen load having worse outcomes. Taken together, we hypothesized that patients with higher neoantigen load would gain most benefit from ASCT, due to immune reprogramming. We therefore developed a pipeline to predict neoantigen load in myeloma patients ( Fig. 1A) and explored whether this had prognostic significance in the context of consolidation or ASCT in patients enrolled in CARDAMON. We collected paired tumour and germline whole exome sequencing and RNA-Seq data. We called nonsynonymous and frame-shift mutations using MuTECT2 and calculated RNA-Seq expression using Salmon. We used ARCAS-HLA for HLA genotyping. We translated high-confidence mutations within a sliding window and predicted HLA allele binding using NETMHCpan-4.0, predicting binding when the IC50 was less than 200nM, per the standard definition of a strong binding peptide. We removed any neoantigens that were not expressed, using the RNA-Seq data. Neoantigen load for an individual patient was taken as the number of predicted expressed neoantigens. We chose a neoantigen cut-off based on mutation rates distinguishing immunologically “cold” or “hot” tumours. Consequently, patients with <= 130 neoantigens were defined as low antigen load, and those with >130 were defined as high neoantigen load. We observed a total of 15,162 high affinity neoantigens across 58 patients, with a median of 200 neoantigens per patient (range 34 - 653). Forty-six neoantigens were shared across patients, mostly NRAS, KRAS, and BRAF. We first compared patients by randomization group. For patients who received consolidation, there was no significant difference in progression-free survival (PFS) between high and low antigen loads (p=0.32). For patients in the ASCT arm, a high antigen load was associated with a longer PFS (p=0.013). This was surprising, as high antigen load has previously been shown to be a poor prognostic factor, although our numbers were small and confirmation in independent data is ongoing. We then considered patients split by antigen load. For those with low antigen load, we saw no difference in PFS between those who received ASCT and those who received consolidation. However, for patients with a high antigen load, there was a marked improvement in PFS for those undergoing ASCT ( Fig. 1B Upper; median PFS not reached vs. 25 months; hazard ratio 0.50, 95% confidence interval 0.20-0.65; p=0.0039). This difference translated to overall survival ( Fig. 1B Lower; median OS not reached in either group; hazard ratio 0.12, 95% confidence interval 0.014-0.50; p=0.028). The marked benefit of ASCT over consolidation in this subgroup analysis is in contrast to the marginal difference between the two therapies for allcomers in the CARDAMON trial. Whilst upfront ASCT remains the treatment of choice for eligible patients, the risk/benefit ratio may be less clear in the more frail and in the context of deep response to induction. In summary: We have developed a bioinformatic pipeline to predict neoantigen burden in newly diagnosed myeloma, which suggests higher neoantigen load is associated with a major benefit from ASCT. This approach provides novel insight into the biology of ASCT and could be used to stratify patient need for ASCT in the future, although the immunological mechanisms implicated in these findings remain to be identified. Neoantigen subtype effect (frameshift vs SNV) and validation in a larger cohort is ongoing.
The FFHS Phyto-Finders collect phytoplankton off the coast of North Carolina as part of the NOAA Phytoplankton Monitoring Network. In the past, we submitted paper forms to NOAA, which were ...electronically archived. Unfortunately, that database crashed and all our historical data were lost. This prompted us to create our own database, both to take control of storage and to enhance our search and analysis capabilities. This paper describes the design process, the initial construction and use, and planned future developments of this database.
Abstract only
4511
Background: Savolitinib is a potent and selective MET inhibitor with activity in MET-driven papillary renal cancer (PRC). Durvalumab is a PD-L1 inhibitor which has been tested in ...combination with savolitinib in metastatic PRC with response rates of 29% (12/41). Here we describe the efficacy of this combination in MET-driven metastatic PRC. Methods: This single arm phase I/II trial explored durvalumab (1500mg Q4W) and savolitinib (600mg OD) together in metastatic PRC, with a 4wk savolitinib run in. Biomarker analysis results were compared with responses to treatment as planned in the protocol. The analysis presented here focuses on those patients with MET DNA alterations (central analysis:chromosome 7 gain/MET or HGF amplification/MET kinase domain mutations). Confirmed response rate (RR) (RECIST v1.1), progression-free survival (PFS), tolerability (CTCAE v4.03) and overall survival (OS) were analysed. Results: 42 patients were enrolled in the metastatic papillary cohort, of which 41 patients received treatment. The median follow up was 26.8 months. The confirmed RR was 29% (12/41) and median PFS was 4.9 months (95% CI 2.5-10.0). 14/41 (34%) of these patients had MET-driven disease. 71% (10/14) of MET-driven patients had not previously received systemic therapy and 7% (1/14) were PD-L1 positive. IMDC good, intermediate, and poor risk disease occurred in 36% (5/14), 57% (8/14), and 7% (1/14) of MET-driven patients respectively. Confirmed RR in MET-driven patients was 57% (8/14) with duration of response at 9.4 months (95% CI 3.9-Not reached NR). Median PFS and OS in MET-driven patients were 10.5 months (95% CI 2.9-15.7) and 27.4 months (95% CI 7.3-NR) respectively. No new safety signals were seen. Conclusions: The combination of savolitinib and durvalumab has clinical activity in MET-driven PRC. A randomised phase III study is planned based upon these data. Clinical trial information: NCT02819596.
Risk-reducing salpingo-oophorectomy is the 'gold standard' for preventing tubo-ovarian cancer in women at increased risk. However, when performed in pre-menopausal women, it results in premature ...menopause and associated detrimental health consequences. This, together with acceptance of the central role of the fallopian tube in etiopathogenesis of high-grade serous carcinoma, by far the most common type of tubo-ovarian cancer, has led to risk-reducing early salpingectomy with delayed oophorectomy being proposed as a two-step surgical alternative for pre-menopausal women declining/delaying oophorectomy.
To evaluate the impact on sexual function of risk-reducing early salpingectomy, within a two-step, risk-reducing, early salpingectomy with delayed oophorectomy tubo-ovarian cancer prevention strategy in pre-menopausal women at increased risk of tubo-ovarian cancer.
Risk-reducing early salpingectomy is non-inferior for sexual and endocrine function compared with controls; risk-reducing early salpingectomy is superior for sexual/endocrine function, non-inferior for quality-of-life, and equivalent in satisfaction to the standard risk-reducing salpingo-oophorectomy.
Multi-center, observational cohort trial with three arms: risk-reducing early salpingectomy with delayed oophorectomy; risk-reducing salpingo-oophorectomy; controls (no surgery). Consenting individuals undergo an ultrasound, serum CA125, and follicle-stimulating hormone measurements and provide information on medical history, family history, quality-of-life, sexual function, cancer worry, psychological well-being, and satisfaction/regret. Follow-up by questionnaire takes place annually for 3 years. Women receiving risk-reducing early salpingectomy can undergo delayed oophorectomy at a later date of their choosing, or definitely by the menopause.
Inclusion criteria: pre-menopausal; aged >30 years; at increased risk of tubo-ovarian cancer (mutation carriers or on the basis of a strong family history); completed their family (for surgical arms).
post-menopausal; previous bilateral salpingectomy or bilateral oophorectomy; pregnancy; previous tubal/ovarian/peritoneal malignancy; <12 months after cancer treatment; clinical suspicion of tubal/ovarian cancer at baseline.
Sexual function measured by validated questionnaires.
1000 (333 per arm).
It is estimated recruitment will be completed by 2023 and results published by 2027.
ISRCTN registry: 25 173 360 (https://doi.org/10.1186/ISRCTN25173360).
Acceptance of the role of the fallopian tube in 'ovarian' carcinogenesis and the detrimental sequelae of surgical menopause in premenopausal women following risk-reducing salpingo-oophorectomy (RRSO) ...has resulted in risk-reducing early-salpingectomy with delayed oophorectomy (RRESDO) being proposed as an attractive alternative risk-reducing strategy in women who decline/delay oophorectomy. We present the results of a qualitative study evaluating the decision-making process among
carriers considering prophylactic surgeries (RRSO/RRESDO) as part of the multicentre PROTECTOR trial (ISRCTN:25173360).
In-depth semistructured 1:1 interviews conducted using a predeveloped topic-guide (development informed by literature review and expert consultation) until informational saturation reached. Wording and sequencing of questions were left open with probes used to elicit additional information. All interviews were audio-recorded, transcribed verbatim, transcripts analysed using an inductive theoretical framework and data managed using NVIVO-v12.
Informational saturation was reached following 24 interviews. Seven interconnected themes integral to surgical decision making were identified: fertility/menopause/cancer risk reduction/surgical choices/surgical complications/sequence of ovarian-and-breast prophylactic surgeries/support/satisfaction. Women for whom maximising ovarian cancer risk reduction was relatively more important than early menopause/quality-of-life preferred RRSO, whereas those more concerned about detrimental impact of menopause chose RRESDO. Women managed in specialist familial cancer clinic settings compared with non-specialist settings felt they received better quality care, improved hormone replacement therapy access and were more satisfied.
Multiple contextual factors (medical, physical, psychological, social) influence timing of risk-reducing surgeries. RRESDO offers women delaying/declining premenopausal oophorectomy, particularly those concerned about menopausal effects, a degree of ovarian cancer risk reduction while avoiding early menopause. Care of high-risk women should be centralised to centres with specialist familial gynaecological cancer risk management services to provide a better-quality, streamlined, holistic multidisciplinary approach.
Abstract only
619
Background: There is a strong rationale for investigating MET and PD-L1 inhibition in metastatic papillary renal cancer (PRC). We previously reported response rates (RR) and ...progression free survival (PFS) for savolitinib (MET inhibitor) and durvalumab (PD-L1 inhibitor) together. Here we report overall survival (OS) data available 12 months after the last patient was enrolled. Methods: This single arm phase I/II trial explores durvalumab (1500mg Q4W) and savolitinib (600mg OD) together in PRC, with a 4wk savolitinib run in. Treatment naïve or previously treated patients with metastatic PRC were included. Confirmed RR (RECIST v1.1), PFS, tolerability (CTCAE v4.03) and overall survival (OS) were analysed. MET and PD-L1 biomarkers were explored (NCT02819596). Results: 42 patients were enrolled with 41 receiving at least one dose of study treatment. Safety and efficacy analyses were performed on these 41 patients. The median follow up was 14.3 months. IMDC good, intermediate and poor risk disease occurred in 29%, 63%, and 7% of patients respectively. Overall confirmed RR was 27% while median PFS was 4.9 months (95% CI: 2.5 – 12.0 months). Median OS was 12.3 months (95% CI: 5.8 – 21.3 months). Confirmed RR and median OS in the previously untreated cohort (N=27) were 33% and 12.3 months (95% CI: 4.7 – not reached (NR) months) respectively. Treatment related Grade 3/4 toxicity occurred in 34% of patients. No new safety signals were seen. PD-L1 and MET expression were not associated with higher RR (25% and 40% respectively) or longer OS. Conclusions: The combination of savolitinib and durvalumab has clinical activity in PRC and outcomes were not enhanced in biomarker positive cancers. Clinical trial information: NCT02819596.
There are limited data on toxicity and surgical safety associated with neoadjuvant programmed death ligand 1 (PD-L1) inhibitors prior to radical cystectomy (RC) in patients with muscle-invasive ...bladder cancer (MIBC).
To present a comprehensive safety analysis of the largest neoadjuvant series, with focus on timing and severity of toxicity and surgical complications occurring after neoadjuvant atezolizumab in patients with MIBC enrolled in the ABACUS trial.
ABACUS (NCT02662309) is an open-label, multicenter, phase II trial for patients with histologically confirmed (T2-T4aN0M0) MIBC, awaiting RC. Patients either were ineligible or refused cisplatin-based neoadjuvant chemotherapy.
Two cycles of neoadjuvant atezolizumab (1200 mg, every 3 wk) followed by RC.
Description of atezolizumab toxicity profile in the neoadjuvant setting, impact on surgery, and delayed immune-mediated adverse events (AEs) were assessed.
Ninety-five patients received treatment. Of them, 44% (42/95) had atezolizumab-related AEs during the neoadjuvant period (fatigue 20%, decreased appetite 6%, and transaminases increased 6%). Treatment-related grade 3–5 AEs occurred in 11% (10/95) of patients during the study. Of the patients, 21% (20/95) received only one cycle of atezolizumab due to AEs; 92% (87/95) underwent RC. No surgery was delayed due to atezolizumab-related toxicities. Surgical complications occurred in 62% (54/87) of patients. Of these patients, 43% (37/87) and 20% (17/87) had minor (grade 1–2) and major (grade 3–5) complications, respectively. Thirteen of 87 (15%) patients had post-RC atezolizumab-related AEs, including adrenal insufficiency and transaminases increased. Three deaths occurred during the period of study-related interventions (one non–treatment-related aspiration pneumonia, one immune-related myocardial infarction, and one cardiogenic shock after RC). Not all surgical safety parameters were available.
Two cycles of neoadjuvant atezolizumab are well tolerated and do not seem to impact surgical complication rates. Owing to the long half-life, AEs may occur in the postoperative period, including endocrine abnormalities requiring attention and intervention.
Here, we report a comprehensive dataset of patients receiving neoadjuvant immune checkpoint inhibitors before radical cystectomy. Treatment with neoadjuvant atezolizumab is safe and does not seem to complicate surgery significantly.
Neoadjuvant treatment with atezolizumab followed by radical cystectomy is associated with fewer adverse events and low surgical complication rates. Long-term side effects can occur due the long half-life of atezolizumab.
PDF
