Special populations in metastatic renal cell carcinoma.

PURPOSE OF REVIEW: This review focuses on special populations poorly represented in current evidence-based practice for metastatic renal cell carcinoma (mRCC). This includes the elderly and frail, patients on immunosuppression or with autoimmune diseases, patients with brain, liver, and/or bone metastases, and RCC with sarcomatoid features. RECENT FINDINGS: Certain populations are poorly represented in current trials for mRCC. Patients with central nervous system (CNS) metastases are often excluded from first-line therapy trials. Modern doublet systemic therapy appears to benefit patients with bone or liver metastases, but data supporting this conclusion is not robust. Post-hoc analyses on patients with sarcomatoid differentiation have shown improved response to modern doublet therapy over historical treatments. The elderly are underrepresented in current clinical trials, and most trials exclude all but high-performing (nonfrail) patients, though true frailty is likely poorly captured using the current widely adopted indices. It is difficult to make conclusions about the efficacy of modern therapy in these populations from subgroup analyses. Data from trials on other malignancies in patients with autoimmune diseases or solid organ transplant recipients on immunosuppression suggest that immune checkpoint inhibitors (ICIs) may still have benefit, though at the risk of disease flare or organ rejection. The efficacy of ICIs has not been demonstrated specifically for RCC in this group of patients. SUMMARY: The elderly, frail, and immunosuppressed, those with tumors having aggressive histologic features, and patients with brain, bone, and/or liver metastases represent the populations least understood in the modern era of RCC treatment.

Safe Use of POEM in a Patient With Decompensated Cirrhosis and Severe Achalasia.

Patients with both achalasia and decompensated cirrhosis can often present a therapeutic challenge because portal hypertension has generally been considered a contraindication to definitive therapies for achalasia. This case report depicts a patient who presented with progressive dysphagia, weight loss, and large-volume ascites; was diagnosed with type II achalasia and decompensated cirrhosis without esophageal varices; and underwent peroral endoscopic myotomy after preprocedural transjugular intrahepatic portosystemic shunt placement. Our case highlights the importance of multidisciplinary care and need for definitive therapies for these complex patients at high risk of malnutrition and sarcopenia.

Oral and cutaneous pemphigus vulgaris: an atypical clinical presentation.

Pemphigus vulgaris (PV) is a rare painful and blistering autoimmune mucocutaneous disorder that appears in middle-aged adults. Oral lesions typically precede cutaneous involvement and tend to be more recalcitrant to therapy. The objective of this article is to present a case of oral and cutaneous PV in an atypical patient, a 23-year-old woman. The case was distinguished by the patient's age, which was 2 to 3 decades younger than the reported mean age of onset, and its coincidence with celiac disease, an immunopathologic process rarely seen in association with PV. Intravenous administration of the monoclonal antibody rituximab provided rapid clinical improvement in the cutaneous lesions and gradual improvement in the oral lesions after 2 infusions. Dental practitioners should remain vigilant for oral manifestations of dermatologic disease and refer affected patients to appropriate healthcare providers for long-term management.

Pharmacologic Therapies for Non-Muscle Invasive Bladder Cancer: Current and Future Treatments.

Bladder cancer is the sixth most common malignancy in the United States and 70% of cases are non-muscle invasive at the time of diagnosis. Effective treatment is crucial to prevent progression, which occurs in about 30% of patients. The American Urological Association (AUA) guidelines recommend treatment of non-muscle invasive bladder cancer (NMIBC) with intravesical Bacille Calmette-Guerin (BCG) and chemotherapy. However, ongoing shortages and high rates of BCG unresponsiveness creates a major need for novel therapies. In this narrative review, we discuss the evolving landscape of therapeutic options for NMIBC. Pembrolizumab, an anti-programmed cell death (PD)-1 antibody, was the first systemic therapy to be FDA-approved for BCG-unresponsive, high-risk disease. Promising new agents under investigation include various other checkpoint inhibitors and adenovirus-based therapies including CG0070 and nadofaragene firadenovec (rAd-IFNa/Syn3). Finally, new mechanisms of drug delivery are under investigation, including delivery with the GemRIS (TAR-200) device and delivery of intravesical chemotherapy at higher temperatures. With the promise of novel therapies on the horizon, we can expect the role of urologists in the management of NMIBC to evolve and expand.

Impact of inflammatory bowel disease on radical prostatectomy outcomes and costs of care.

BACKGROUND: Recent studies suggest an association between prostate cancer and inflammatory bowel disease (IBD). Our objectives were to investigate clinical and financial impacts of IBD on radical prostatectomy (RP) and to determine the impact of surgical approach on our findings. METHODS: The Premier Hospital Database was queried for patients who underwent RP from 2003 to 2017. Multivariable logistic regression models were used to determine the independent impact of IBD on complications and readmission rates. We determined 90-day readmissions and examined 90-day hospital costs adjusted to 2019 US dollars with multivariable quantile regression models. RESULTS: Our study population included 262,189 men with prostate cancer, including 3,408 (1.3%) with IBD. There were higher odds for any complication for IBD patients compared with non-IBD controls for RP (15.64% vs. 10.66%). Patients with IBD had overall complication rates of 14.1% (P < 0.05) for open surgery and 17.2% for minimally invasive surgery (MIS) (P < 0.01). Between 2013 and 2017, the IBD cohort had significantly more complications (odds ratios (ORs): 2; 95% confidence interval (CI): 1.5 to 2.67; P < 0.0001), was more likely to have surgical costs in the top quartile (OR: 1.6; 95% CI: 1.23 to 2.1; P < 0.01), and had higher readmission rates (OR: 1.51; 95% CI: 1.1 to 2.06; P = 0.01). CONCLUSIONS: The IBD cohort who underwent MIS had the highest complication rates. Hospital readmissions and surgical costs were significantly higher for the IBD cohort who underwent RP between 2013 and 2017, when a minimally invasive approach was more prevalent than an open approach. These findings may be important when deciding which surgical approach to take when performing RP on men with IBD.

Ion Mobility Spectrometry - High Resolution LTQ-Orbitrap Mass Spectrometry for Analysis of Homemade Explosives.

The detailed chemical characterization of homemade explosives (HMEs) and other chemicals that can mimic or mask the presence of explosives is important for understanding and improving the performance of commercial instrumentation used for explosive detection. To that end, an atmospheric-pressure drift tube ion mobility spectrometry (IMS) instrument has been successfully coupled to a commercial tandem mass spectrometry (MS) system. The tandem MS system is comprised of a linear ion trap and a high resolution Orbitrap analyzer. This IMS-MS combination allows extensive characterization of threat chemical compounds, including HMEs, and complex real-world background chemicals that can interfere with detection. Here, the composition of ion species originating from a specific HME, erythritol tetranitrate, has been elucidated using accurate mass measurements, isotopic ratios, and tandem MS. Gated IMS-MS and high-resolution MS have been used to identify minor impurities that can be indicative of the HME source and/or synthesis route. Comparison between data obtained on the IMS/MS system and on commercial stand-alone IMS instruments used as explosive trace detectors (ETDs) has also been performed. Such analysis allows better signature assignments of threat compounds, modified detection algorithms, and improved overall ETD performance. Graphical Abstract ᅟ.

Surface effects on the crystallization of cyclo-1,3,5-trimethylene-2,4,6-trinitramine (RDX) and the consequences for its N K X-ray emission spectrum.

Recent studies of the crystallization of cyclotrimethylene-trinitramine (RDX) have shown that the presence of the α- and ß-phases of the compound is sensitive to the substrate when using drop cast crystallization methods. The specific phase has potential consequences for measurements of the nitrogen K X-ray emission spectrum (XES) that were recently reported for this compound using samples crystallized on In metal substrates. We have determined that the crystallization of RDX on a clean In metal substrate starts out completely as the ß-phase but progressively incorporates the α-phase as the film thickens. In addition, we have carried out additional molecular orbital calculations of the N 1s X-ray fluorescence from the valence band, comparing the results expected from the α-and ß- phases. The differences due to the presence of the ß-phase instead of, or in addition to, the α-phase appear to be minimal.

Evidence of the participation of remote residues in the catalytic activity of Co-type nitrile hydratase from Pseudomonas putida.

Active sites may be regarded as layers of residues, whereby the residues that interact directly with substrate also interact with residues in a second shell and these in turn interact with residues in a third shell. These residues in the second and third layers may have distinct roles in maintaining the essential chemical properties of the first-shell catalytic residues, particularly their spatial arrangement relative to the substrate binding pocket, and their electrostatic and dynamic properties. The extent to which these remote residues participate in catalysis and precisely how they affect first-shell residues remains unexplored. To improve our understanding of the roles of second- and third-shell residues in catalysis, we used THEMATICS to identify residues in the second and third shells of the Co-type nitrile hydratase from Pseudomonas putida (ppNHase) that may be important for catalysis. Five of these predicted residues, and three additional, conserved residues that were not predicted, have been conservatively mutated, and their effects have been studied both kinetically and structurally. The eight residues have no direct contact with the active site metal ion or bound substrate. These results demonstrate that three of the predicted second-shell residues (α-Asp164, ß-Glu56, and ß-His147) and one predicted third-shell residue (ß-His71) have significant effects on the catalytic efficiency of the enzyme. One of the predicted residues (α-Glu168) and the three residues not predicted (α-Arg170, α-Tyr171, and ß-Tyr215) do not have any significant effects on the catalytic efficiency of the enzyme.

Disruption of the hexagonal networks of trimesic acid (benzene-1,3,5-tricarboxylic acid, TMA) by acetic acid.

The single crystal X-ray structure of the acetic acid solvate of trimesic acid shows the complete disruption of the hydrogen-bonded hexagonal networks of TMA by bonding to an acetic acid molecule.

cGMP-independent nitric oxide signaling and regulation of the cell cycle.

BACKGROUND: Regulatory functions of nitric oxide (NO*) that bypass the second messenger cGMP are incompletely understood. Here, cGMP-independent effects of NO* on gene expression were globally examined in U937 cells, a human monoblastoid line that constitutively lacks soluble guanylate cyclase. Differentiated U937 cells (>80% in G0/G1) were exposed to S-nitrosoglutathione, a NO* donor, or glutathione alone (control) for 6 h without or with dibutyryl-cAMP (Bt2cAMP), and then harvested to extract total RNA for microarray analysis. Bt2cAMP was used to block signaling attributable to NO*-induced decreases in cAMP. RESULTS: NO* regulated 110 transcripts that annotated disproportionately to the cell cycle and cell proliferation (47/110, 43%) and more frequently than expected contained AU-rich, post-transcriptional regulatory elements (ARE). Bt2cAMP regulated 106 genes; cell cycle gene enrichment did not reach significance. Like NO*, Bt2cAMP was associated with ARE-containing transcripts. A comparison of NO* and Bt2cAMP effects showed that NO* regulation of cell cycle genes was independent of its ability to interfere with cAMP signaling. Cell cycle genes induced by NO* annotated to G1/S (7/8) and included E2F1 and p21/Waf1/Cip1; 6 of these 7 were E2F target genes involved in G1/S transition. Repressed genes were G2/M associated (24/27); 8 of 27 were known targets of p21. E2F1 mRNA and protein were increased by NO*, as was E2F1 binding to E2F promoter elements. NO* activated p38 MAPK, stabilizing p21 mRNA (an ARE-containing transcript) and increasing p21 protein; this increased protein binding to CDE/CHR promoter sites of p21 target genes, repressing key G2/M phase genes, and increasing the proportion of cells in G2/M. CONCLUSION: NO* coordinates a highly integrated program of cell cycle arrest that regulates a large number of genes, but does not require signaling through cGMP. In humans, antiproliferative effects of NO* may rely substantially on cGMP-independent mechanisms. Stress kinase signaling and alterations in mRNA stability appear to be major pathways by which NO* regulates the transcriptome.