BACKGROUND: Papillary renal cell carcinoma (PRCC) has a relatively poor prognosis in the metastatic setting. In contrast to clear cell kidney cancer, there are limited treatment options specifically ...tested in PRCC. Alterations in the MET pathway are common in PRCC and may play a pivotal role in promoting tumor growth and the development of resistance to systemic therapy. OBJECTIVE: Current data on the efficacy of MET inhibitors over standard of care in PRCC is immature and evolving. The purpose of this systematic review is to assess and summarize the results and limitations of landmark trials of MET inhibitors for PRCC as well as to discuss barriers faced by trials of these drugs. METHODS: Manuscripts and abstracts were collected from PubMed, the American Society of Clinical Oncology (ASCO) historical abstracts and European Society for Medical Oncology (ESMO) historical abstracts. Included studies must have been either a clinical trial, systematic review or narrative review and included PRCC patients. Patients must have been treated with a selective or non-selective MET inhibitor. After the final application of criteria, 30 studies were included. RESULTS/CONCLUSIONS: Cabozantinib has the best evidence for use showing improved outcomes in PRCC. Other MET inhibitors, including savolitinib, crizotinib, and foretinib have shown possible benefit in patients with MET-positive disease, but the inconsistent definition of MET status and a low patient accrual rate prevented further extrapolation of the individual trial results. Future trials of single agent savolitinib, as well as combination MET inhibitor/ immuno-oncology (IO) therapies, have the potential to change the therapeutic landscape of using MET inhibitors for PRCC.
Key message
Exploring large genomic data sets based on the latest reference genome assembly identifies the rice ortholog APO1 as a key candidate gene for number of rachis nodes per spike in wheat.
...Increasing grain yield in wheat is a key breeding objective worldwide. Several component traits contribute to grain yield with spike attributes being among the most important. In this study, we performed a genome-wide association analysis for 12 grain yield and component traits measured in field trials with contrasting agrochemical input levels in a panel of 220 hexaploid winter wheats. A highly significant, environmentally consistent QTL was detected for number of rachis nodes per rachis (NRN) on chromosome 7AL. The five most significant SNPs formed a strong linkage disequilibrium (LD) block and tagged a 2.23 Mb region. Using pairwise LD for exome SNPs located across this interval in a large worldwide hexaploid wheat collection, we reduced the genomic region for NRN to a 258 Kb interval containing four of the original SNP and six high-confidence genes. The ortholog of one (TraesCS7A01G481600) of these genes in rice was
ABBERANT PANICLE ORGANIZATION1
(
APO1
), which is known to have significant effects on panicle attributes. The
APO1
ortholog was the best candidate for NRN and was associated with a 115 bp promoter deletion and two amino acid (C47F and D384 N) changes. Using a large worldwide collection of tetraploid and hexaploid wheat, we found 12 haplotypes for the NRN QTL and evidence for positive enrichment of two haplotypes in modern germplasm. Comparison of five QTL haplotypes in Australian yield trials revealed their relative, context-dependent contribution to grain yield. Our study provides diagnostic SNPs and value propositions to support deployment of the NRN trait in wheat breeding.
COVID-19 vaccination is one of the pivotal key tools against the ongoing pandemic, but its acceptance relies on efficacy and safety data among various populations, including patients with cancers. ...However, there is limited data on seroconversion rates, efficacy, and safety of the COVID-19 vaccine in patients with cancer. Breakthrough infections after vaccination have also been reported, which could further strengthen the refusal behavior of specific populations to be immunized. Our objective was to investigate the efficacy and safety of COVID-19 vaccination in real-world patients with advanced genitourinary cancers.
A retrospective study of the 738 patients with advanced metastatic genitourinary malignancy was conducted at our genitourinary oncology clinic from October 2020 to September 2021, out of which 462 patients (62.6%) were vaccinated. During the study period, two vaccinated, and six unvaccinated patients tested positive for SARS-CoV-2 (breakthrough infection rate: 0.4% vs. 2.2%, p = 0.027). Vaccine protection against infection was 81.8% (95% CI: 0.04–0.98). One vaccinated and 4 unvaccinated patients were hospitalized due to COVID-19 (0.2% vs. 1.4%, p = 0.048). Vaccine effectiveness in preventing hospitalization was 85.7% (95% CI: 0.02–1.33). Within one month of vaccination, 1.5% of patients (n = 7) had emergency visits, 0.8% (n = 4) were hospitalized for any reason, and of these, 3 (0.6%) experienced a delay in the receipt of their cancer therapy.
In our hypothesis-generating data among patients with advanced genitourinary cancers, COVID-19 vaccination was efficacious and safe and was rarely associated with treatment disruptions. These data should help improve the acceptance of the COVID-19 vaccine in the general population and patients with cancer. The vaccine effectiveness in our patients is comparable with existing published data without cancer.
COVID-19; Vaccination; Cancer; Prostate cancer; Kidney cancer; Bladder cancer.
Poly (ADP-ribose) polymerase (PARP) inhibitors are approved for patients with metastatic castration-resistant prostate cancer harboring deleterious or suspected deleterious
and/or
mutations. ...Identifying patients with prostate cancer harboring these mutations may be challenging. Circulating cell-free DNA (cfDNA) provides an avenue for an easier detection of these mutations. Herein, we aimed to evaluate the concordance of
mutations in the tumor tissue and cfDNA in patients with metastatic prostate cancer in the real-world setting.
Somatic genomic profiling results were obtained from a clinical cohort of patients at our institution who had at least two samples tested. One of the samples needed to be from either primary or metastatic tissue. Concordance was adjusted to not include mutation types that the cfDNA platforms were not designed to detect.
The presence or absence of mutations in the
gene was assessed in a total of 589 samples, including 327 cfDNA samples, from 260 patients with metastatic prostate cancer. The median time between the first test and any subsequent test was 22.8 (0.0-232) months.
mutation was present in the patient's original prostate tissue in 23 samples (3.9%) of patients. The adjusted concordance between prostate tumor tissue and cfDNA was 97.9% 95% CI, 95.3-99.1%. The adjusted concordance between metastatic samples and cfDNA was 93.5% 95% CI, 86.4-97.3%. Of the patients who had a
mutation detected in their prostate tissue, there was a 70% probability of detecting a
mutation in the patient's cfDNA as well. For patients who did not have a detectable
mutation in their primary prostate tissue, the probability of detecting a subsequent one later in the disease course was less than 0.9%.
There is a high level of concordance between tissue and blood for
mutations. Testing cfDNA can provide reliable information on
mutational status and is a viable alternative to solid tissue sequencing when unavailable. The development of a new
mutation later in the disease course is a rare event.
Recent technological developments allow us to measure the status of dozens of proteins in individual cells. This opens the way to understand the heterogeneity of complex multi‐signaling networks ...across cells and cell types, with important implications to understand and treat diseases such as cancer. These technologies are, however, limited to proteins for which antibodies are available and are fairly costly, making predictions of new markers and of existing markers under new conditions a valuable alternative. To assess our capacity to make such predictions and boost further methodological development, we organized the Single Cell Signaling in Breast Cancer DREAM challenge. We used a mass cytometry dataset, covering 36 markers in over 4,000 conditions totaling 80 million single cells across 67 breast cancer cell lines. Through four increasingly difficult subchallenges, the participants predicted missing markers, new conditions, and the time‐course response of single cells to stimuli in the presence and absence of kinase inhibitors. The challenge results show that despite the stochastic nature of signal transduction in single cells, the signaling events are tightly controlled and machine learning methods can accurately predict new experimental data.
SYNOPSIS
This study presents the results and conclusions of the ‘Single Cell Signaling in Breast Cancer DREAM challenge’, where teams were challenged to use state‐of‐the‐art methods for predicting single‐cell signaling from single‐cell and bulk proteomics, transcriptomics and genomics data.
Over 80 million single‐cell multiplexed measurements across 67 cell lines, 54 conditions and 10 time points are used to benchmark predictive models of single‐cell signaling.
73 approaches are used by 27 teams for predicting responses to kinase inhibitors on single cell level, and dynamic responses from unperturbed basal omics data.
Top models of whole signaling response models perform almost as well as a biological replicate.
Cell‐line specific variation in dynamics can be partially predicted from basal omics.
This study presents the results and conclusions of the ‘Single Cell Signaling in Breast Cancer DREAM challenge’, where teams were challenged to use state‐of‐the‐art methods for predicting single‐cell signaling from single‐cell and bulk proteomics, transcriptomics and genomics data.
PDF
