Background
To formulate clinical pathways for identifying clinically significant prostate cancer (csPC) and avoiding insignificant prostate cancer (isPC) in those without suspicious regions of ...interest on multi‐parametric magnetic resonance imaging (mpMRI) of the prostate.
Methods
A retrospective review identified patients with negative mpMRI who underwent subsequent transperineal prostate biopsy across two centres. Patient characteristics and association with biopsy results were evaluated using univariate and multivariate regression analyses.
Results
A total of 144 patients were identified as having negative mpMRI and undergoing subsequent transperineal prostate biopsy; 18% (25/144) of the cohort were found to have csPC. Logistic regression analysis failed to identify statistically significant predictive factors. In this cohort, if all patients with prostate‐specific antigen > 3.0 were biopsied the least amount of csPC is missed, at 20% (5/25) however all isPC would be diagnosed. The least amount of isPC is diagnosed with a biopsy threshold of >15% from the European Randomized Study of Screening for Prostate Cancer calculator with 20% (5/25) of isPC diagnoses made however only 10.5% (2/19) csPC would be diagnosed. A biopsy threshold of >5% risk reduces the number of csPC missed to 37% (7/19) however increases isPC diagnoses to 54% (13/24) of the population.
Conclusion
False‐negative rates of prostate MRI for csPC are significant within our cohort at 18%. The decision to biopsy should be made in conjunction with a risk profile acceptable by the patient and clinician. The current study demonstrates that there is a need to balance the risk of missing csPC and harm of diagnosing isPC.
False‐negative rates of prostate magnetic resonance imaging are significant. This study presents several methods that can be used to mitigate the risk of false negatives depending on the patients' and doctors' risk profile.
A year into the coronavirus disease 2019 (COVID-19) pandemic there remains an urgent need to limit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread and to curb the pandemic in the ...US through nonpharmaceutical interventions. Clear evidence supports the effectiveness of simple strategies in identifying risks and mitigating the spread of infection, with much of this evidence coming from observational studies. Community risk factors for infection can be identified by comparing recent behaviors and exposures among people who have been infected with those who are not infected using a traditional case-control approach. High-risk environments identified from these investigations need to be clearly communicated to the public to support public health measures and motivate individual behavior change to reduce the risk of infection.
Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including patients ...with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring
, or
gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the recommended phase II dose. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with
-rearranged lung cancer.
Gene fusions of
, and
(encoding TRKA/B/C, ROS1, and ALK, respectively) lead to constitutive activation of oncogenic pathways. Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors, including in patients with primary or secondary CNS disease.
.
Summary Background Treatment options for patients with relapsed or refractory lymphoma and multiple myeloma are limited. CUDC-907 is an oral, first-in-class, small molecule that is designed to ...inhibit both histone deacetylase (HDAC) and PI3K enzymes, which are members of common oncogenic pathways in haematological malignancies. We aimed to assess overall safety and preliminary activity in this dose-escalation study of CUDC-907 monotherapy in patients with relapsed or refractory lymphoma and multiple myeloma. Methods This open-label, first-in-man, phase 1 trial recruited adult patients (aged ≥18 years) with lymphoma or multiple myeloma who were refractory to or had relapsed after two or more previous regimens, from four US cancer centres. CUDC-907 was orally administered in a standard 3 + 3 dose-escalation design at four different dosing schedules, to which participants were sequentially assigned as follows: once daily, intermittently (twice or three times weekly; simultaneous enrolment), and daily for 5 days followed by a 2-day break (5/2), in 21-day cycles. Dosing started at 30 mg for the once-daily schedule and 60 mg for other schedules, escalating in 30 mg increments. Patients continued to receive CUDC-907 until disease progression or until other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose, assessed in patients who received at least 66% of cycle 1 doses without modification and those who had a dose-limiting toxicity (DLT) in cycle 1 irrespective of dose modification. We assessed safety in all patients who received at least one dose of study drug. This ongoing trial is registered at ClinicalTrials.gov , number NCT01742988. Findings Between Jan 23, 2013, and July 27, 2015, we enrolled 44 patients, of whom ten were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to three-times-weekly (MTD 150 mg), and seven to the 5/2 dosing schedule (MTD 60 mg). 37 (84%) patients had discontinued study drug as a result of progressive disease or clinical signs of progressive disease at the data cutoff. Four DLTs occurred in three of 40 DLT-evaluable patients (diarrhoea and hyperglycaemia in one patient on 60 mg once daily, hyperglycaemia in one patient on 150 mg twice weekly, and diarrhoea in one patient on 150 mg three times weekly); no DLTs were reported in patients on the 5/2 schedule. Grade 3 or worse adverse events occurred in 19 (43%) of 44 patients, the most common of which were thrombocytopenia (in nine 20% of 44 patients), neutropenia (three 7%), and hyperglycaemia (three 7%). 11 (25%) of 44 patients had serious adverse events, three of which were regarded as treatment related (epistaxis and the DLTs of diarrhoea and hyperglycaemia). Adverse events led to dose reductions in six (14%) patients and treatment discontinuation in seven (16%). Five (14%) of 37 response-evaluable patients achieved an objective response (two complete responses and three partial responses). All five responses occurred in the subgroup of patients with diffuse large B-cell lymphoma (DLBCL; n=9), and three occurred in those with transformed follicular lymphoma DLBCL (n=5). 21 (57%) of 37 response-evaluable patients had stable disease, including those with DLBCL, Hodgkin's lymphoma, and multiple myeloma. On the basis of these findings, we selected CUDC-907 60 mg on the 5/2 dosing schedule as the recommended phase 2 dose. Interpretation The safety and tolerability profile of CUDC-907 and the promising preliminary evidence of response support continued development of CUDC-907 at the 60 mg 5/2 dosing schedule, alone and in combination with other therapies. A dose-expansion trial of this dose in patients with refractory and relapsed DLBCL in particular, is ongoing. Funding Curis, Inc, and the Leukemia and Lymphoma Society.
•Postharvest phenylalanine treatment of mango reduces chilling injury and decay.•Phenylalanine induces mango fruit response to chilling.•Phenylalanine activates phenylpropanoid pathway to induce ...chilling tolerance.•Higher antioxidant flavonoids and enzymes correlate to lower oxidation and lipid peroxidation.
Cold is the best means of prolonging fruit storage. However, tropical fruit are susceptible to cold storage. The mode of action of mango fruit tolerance to suboptimal cold temperature of 7 or 10 °C after postharvest application of 8 mM phenylalanine was investigated using transcriptomic and metabolomic analyses of mango fruit during suboptimal cold storage. Phenylalanine-treated fruit had less chilling injuries—black spot and pitting electrolyte leakage,—and reduced decay after suboptimal cold storage. Phenylalanine treatment induced genes related to plant–pathogen interactions, plant hormone signal transduction, and the phenylpropanoid pathway, increasing the levels of the flavonoids quercetin and kaempferol glycosides and anthocyanins, and antioxidant content. Reduced oxidation led to lower lipid peroxidation, and a reduction in fatty acid-degradation products, e.g., volatile aldehydes. Treatment with phenylalanine, therefore, enhances chilling tolerance of mango fruit through regulation of metabolic and defense-related pathways, maintaining high levels of flavonoids, and antioxidants enzyme activity, and reducing H2O2 content, lipid peroxidation, and volatile aldehydes.
The association between cutaneous melanoma and subsequent risk of prostate cancer (PC) was examined in a large population-based cohort study.
Male participants in the Sax Institute's 45 and Up Study ...(Australia) were recruited between 2006 and 2009. Questionnaire data and linked administrative health data from the Centre for Health Record Linkage and Services Australia identified melanomas diagnosed between 1/1/1994 and 12 months before Study recruitment (i.e., between 2005 and 2008), incident PCs, primary healthcare utilisation and prostate-specific antigen (PSA) tests. Men were excluded from the current analyses if they had a recorded PC or other cancer diagnosis other than melanoma and non-melanoma skin cancer prior to recruitment. Multivariable Cox regression was used to estimate hazard ratios (HRs) adjusting for PSA-testing frequency before PC diagnosis.
Of 96,548 eligible men, 1899 were diagnosed with melanoma during the melanoma diagnosis period and 3677 incident PC diagnosed during follow-up (latest date 31/12/2013). Men with melanoma diagnosis had increased risk of a subsequent PC diagnoses (vs. no melanoma; fully adjusted HR = 1.32; 95% CI: 1.09-1.60). There was weak evidence of higher risks of a subsequent PC diagnosis for men diagnosed with more than one melanoma compared to men diagnosed with only one melanoma (p = 0.077), and if first melanoma diagnosis was 10 to 15 years before Study recruitment (fully adjusted HR = 2.05; 95% CI 1.35, 3.12).
Melanoma diagnosis was associated with increased risk of subsequent PC diagnosis, after adjusting for PSA testing and primary healthcare utilisation. While our ability to adjust for PC screening reduced risk of detection bias, we acknowledge that residual confounding from increased medical surveillance after melanoma diagnoses cannot be entirely ruled out.
Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T ...lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAF
mutations
. BRAF/MEK-targeted therapies have effects on the tumor microenvironment that support their combination with PD-1/PD-L1 inhibitors
. This phase Ib study (ClinicalTrials.gov, number NCT01656642 ) evaluated the safety and anti-tumor activity of combining atezolizumab (anti-PD-L1) with vemurafenib (BRAF inhibitor), or cobimetinib (MEK inhibitor) + vemurafenib, in patients with BRAF
-mutated metastatic melanoma. Triple combination therapy with atezolizumab + cobimetinib + vemurafenib, after a 28-d run-in period with cobimetinib + vemurafenib, had substantial but manageable toxicity. Exploratory biomarker data show that the cobimetinib + vemurafenib run-in was associated with an increase in proliferating CD4
T-helper cells but not with an increase in T-regulatory cells, as observed in the vemurafenib-only run-in period. The confirmed objective response rate was 71.8% (95% confidence interval 55.1-85.0). The estimated median duration of response was 17.4 months (95% confidence interval 10.6-25.3) with ongoing response in 39.3% of patients after 29.9 months of follow-up. Further investigation in a phase III trial is underway.
Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function
. The interaction of menin with lysine methyltransferase 2A (KMT2A), an ...epigenetic regulator, is a dependence in acute leukaemia caused by either rearrangement of KMT2A or mutation of the nucleophosmin 1 gene (NPM1)
. KMT2A rearrangements occur in up to 10% of acute leukaemias and have an adverse prognosis, whereas NPM1 mutations occur in up to 30%, forming the most common genetic alteration in acute myeloid leukaemia
. Here, we describe the results of the first-in-human phase 1 clinical trial investigating revumenib (SNDX-5613), a potent and selective oral inhibitor of the menin-KMT2A interaction, in patients with relapsed or refractory acute leukaemia (ClinicalTrials.gov, NCT04065399). We show that therapy with revumenib was associated with a low frequency of grade 3 or higher treatment-related adverse events and a 30% rate of complete remission or complete remission with partial haematologic recovery (CR/CRh) in the efficacy analysis population. Asymptomatic prolongation of the QT interval on electrocardiography was identified as the only dose-limiting toxicity. Remissions occurred in leukaemias refractory to multiple previous lines of therapy. We demonstrate clearance of residual disease using sensitive clinical assays and identify hallmarks of differentiation into normal haematopoietic cells, including differentiation syndrome. These data establish menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes.
An efficient synthesis of imidazo1,2- a pyrimidine derivatives of pyrazole in excellent yield over a short reaction time based on a microwave-assisted, one-pot three-component condensation reaction ...of pyrazole aldehyde clubbed with imidazole 4 and triazole 5 nuclei, (substituted-phenyl/hetero-aryl)ethanones 6(a–g) , and 2-amino benzimidazole 7 in the presence of the strong base KOH is described. All the compounds were screened for their preliminary in vitro antimicrobial, antituberculosis and antimalarial activities against a panel of pathogenic strains. The majority of the compounds exhibited excellent inhibitory action against S. typhi , S. pneumoniae , B. subtilis , and C. tetani . Some of the compounds showed good antifungal activity and moderate antituberculosis activity as compared to first line drugs. Two of the compounds 8b and 9b exhibited excellent antimalarial activity against P. falciparum strains.
•D- and L-amino acids were degraded equally under simulated Mars conditions.•Smectites and sulfates preserved the highest amino acid proportions from degration.•Sulfates protect amino acids likely ...due to their opacity to UV radiation.•Minerals containing ferrous iron promote the destruction of amino acids.
The detection of organic molecules associated with life on Mars is one of the main goals of future life-searching missions such as the ESA-Roscosmos ExoMars and NASA 2020 mission. In this work we studied the preservation of 25 amino acids that were spiked onto the Mars-relevant minerals augite, enstatite, goethite, gypsum, hematite, jarosite, labradorite, montmorillonite, nontronite, olivine and saponite, and on basaltic lava under simulated Mars conditions. Simulations were performed using the Open University Mars Chamber, which mimicked the main aspects of the martian environment, such as temperature, UV radiation and atmospheric pressure. Quantification and enantiomeric separation of the amino acids were performed using gas-chromatography-mass spectrometry (GC–MS). Results show that no amino acids could be detected on the mineral samples spiked with 1 µM amino acid solution (0.1 µmol of amino acid per gram of mineral) subjected to simulation, possibly due to complete degradation of the amino acids and/or low extractability of the amino acids from the minerals. For higher amino acid concentrations, nontronite had the highest preservation rate in the experiments in which 50 µM spiking solution was used (5 µmol/g), while jarosite and gypsum had a higher preservation rate in the experiments in which 25 and 10 µM spiking solutions were used (2.5 and 1 µmol/g), respectively. Overall, the 3 smectite minerals (montmorillonite, saponite, nontronite) and the two sulfates (gypsum, jarosite) preserved the highest amino acid proportions. Our data suggest that clay minerals preserve amino acids due to their high surface areas and small pore sizes, whereas sulfates protect amino acids likely due to their opacity to UV radiation or by partial dissolution and crystallization and trapping of the amino acids. Minerals containing ferrous iron (such as augite, enstatite and basaltic lava) preserved the lowest amount of amino acids, which is explained by iron (II) catalyzed reactions with reactive oxygen species generated under Mars-like conditions. Olivine (forsterite) preserved more amino acids than the other non-clay silicates due to low or absent ferrous iron. Our results show that D- and L-amino acids are degraded at equal rates, and that there is a certain correlation between preservation/degradation of amino acids and their molecular structure: alkyl substitution in the α-carbon seem to contribute towards amino acid stability under UV radiation. These results contribute towards a better selection of sampling sites for the search of biomarkers on future life detection missions on the surface of Mars.
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