Driven by access to better drugs, on average, newly diagnosed multiple myeloma patients have over 10 years overall survival. Using modern combination therapies – with or without the addition of high-dose melphalan and autologous stem cell transplantation – up to 80% of patients reach a complete response. As a logical and necessary step forward, clinical studies have explored strategies to detect minimal residual disease (MRD) and its correlation with clinical outcomes. In this context, MRD has been proposed as a regulatory endpoint for drug approval in newly diagnosed multiple myeloma. To better define the role of MRD negativity in relation to clinical outcomes, we undertook a meta-analysis including published clinical trials of newly diagnosed multiple myeloma patients. We applied a random effects model which weighted studies using the inverse-variance method. Studies were combined on the scale of the logarithm of the hazard ratio (HR) and the corresponding standard error. We found that remaining MRD positive was associated with worse progression-free survival (HR=2.85; 95% confidence interval (CI) 2.17–3.74; P<0.001) and overall survival (HR=2.08; 95% CI 1.44–3.01; P<0.001). Our results show that MRD negativity is a strong predictor of clinical outcomes, supportive of MRD becoming a regulatory endpoint for drug approval in newly diagnosed multiple myeloma.
NUTM1-rearranged tumors are defined by the presence of a gene fusion between NUTM1 and various gene partners and typically follow a clinically aggressive disease course with poor outcomes despite conventional multimodality therapy. NUTM1-rearranged tumors display histologic features of a poorly differentiated carcinoma with areas of focal squamous differentiation and typically express the BRD4–NUTM1 fusion gene defining a distinct clinicopathologic entity—NUT carcinoma (NC). NCs with mesenchymal differentiation have rarely been described in the literature. In this report, we describe the characterization of two cases of high-grade spindle cell sarcoma harboring a novel MGA–NUTM1 fusion. Whole-genome sequencing identified the presence of complex rearrangements resulting in a MGA–NUTM1 fusion gene in the absence of other significant somatic mutations. Genetic rearrangement was confirmed by fluorescence in situ hybridization, and expression of the fusion gene product was confirmed by transcriptomic analysis. The fusion protein was predicted to retain nearly the entire protein sequence of both MGA (exons 1–22) and NUTM1 (exons 3–8). Histopathologically, both cases were high-grade spindle cell sarcomas without specific differentiation markers. In contrast to typical cases of NC, these cases were successfully treated with aggressive local control measures (surgery and radiation) and both patients remain alive without disease. These cases describe a new subtype of NUTM1-rearranged tumors warranting expansion of diagnostic testing to evaluate for the presence of MGA–NUTM1 or alternative NUTM1 gene fusions in the diagnostic workup of high-grade spindle cell sarcomas or small round blue cell tumors of ambiguous lineage.
Human aging is an inevitable and complex phenomenon characterized by a progressive, gradual degradation of physiological and cellular processes that leads from vulnerability to death. Mammalian somatic cells display limited proliferative properties in vitro that results in a process of permanent cell cycle arrest commonly known as senescence. Events leading to cellular senescence are complex but may be due to the increase in tumor suppressor genes, caused by lifetime somatic mutations. Cumulative mutation leaves an imprint on the genome of the cell, an important risk factor for the occurrence of cancer. Adults over the age of 65+ are vulnerable to age related diseases such as cancers but such changes may begin at middle age. MicroRNAs (miRNAs), which are small non-coding RNA, can regulate cancer progression, recurrence and metastasis. This chapter discusses the role of miRNA in tumor microenvironment, consequent to aging.
Background: Fatal opioid overdose deaths involving illicitly manufactured fentanyl continue to escalate in the U.S. Drug checking services, as a harm reduction intervention for people who use drugs, has gained support as an effective strategy to reduce fatal overdoses. We examined implementation of drug checking services using portable devices in a syringe services program in the Northeastern U.S. Methods: Trained staff collected trace drug specimens from used paraphernalia provided by participants who requested drug checking services. All the specimens were tested using a portable mass spectrometer and sub-samples were tested for the detection of fentanyl using fentanyl testing strips. We assessed characteristics of participants who used drug checking services, self-reported types of trace specimens of substances that participants reported providing for testing, the actual mass spectrometer test results of these specimens, and agreement of the mass spectrometer and fentanyl testing strips results in detection of fentanyl and fentanyl analogues. Results: Of 155 unique participants who provided demographic information, 59% identified as male and 74.1% as White, with a mean age of 37.7 years. Based on analysis of 396 specimens tested with the portable mass spectrometer, the most common single substance detected was fentanyl (37.7%), without a trace of heroin or other adulterants, followed by methamphetamine (18.2%), and cocaine (13.6%). Fentanyl and fentanyl analogues were detected in specimens provided by participants that were reported as heroin (60.8%), cocaine (11.1%), and methamphetamine (6.7%). We found modest agreement of testing results between the mass spectrometer and fentanyl testing strips. Conclusions: Use of drug checking services within syringe services programs is in its initial test stages. Knowledge about the contents of substances purchased, and conversations between syringe services program participants and staff, have the potential to facilitate informed decisions to decrease overdose risks through engagement in harm reduction strategies. Through analysis of newly implemented drug checking services, we noted participant characteristics and dissonance between participants’ reports of the trace drug specimens submitted for testing and the actual drugs and adulterants detected by mass spectrometer results, which has implications for overdose risk, highlighting opportunities for harm reduction responses.
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