Determinants of Response and Intrinsic Resistance to PD-1 Blockade in Microsatellite Instability-High Gastric Cancer [Research Article]

xloma.fota13 shared this article with you from Inoreader Determinants of Response and Intrinsic Resistance to PD-1 Blockade in Microsatellite Instability-High Gastric Cancer [Research Article] Via Cancer Discovery Online First Articles Sequence alterations in microsatellites and an elevated mutational burden are observed in 20% of gastric cancers (GC) and associated with clinical response to anti-programmed death (PD)-1 antibodies. However, 50% of microsatellite instability-high (MSI-H) cancers are intrinsically resistant to PD-1 therapies. We conducted a phase II trial of pembrolizumab in advanced MSI-H GC patients and included serial and multi-region tissue samples in addition to serial peripheral blood analyses. The number of whole-exome sequencing (WES)-derived nonsynonymous mutations correlated with anti-tumor activity and prolonged progression-free survival (PFS). Coupling WES to single-cell RNA sequencing, we identified dynamic tumor evolution with greater on treatment collapse of mutational architecture in responders. Diverse T-cell receptor repertoire was associated with longer PFS to pembrolizumab. Additionally, increase in PD-1+ CD8+ T cells correlated with durable clinical bene fit. Our findings highlight the genomic, immunologic, and clinical outcome heterogeneity within MSI-H GC and may inform development of strategies to enhance responsiveness. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

MAP3K7 loss drives enhanced androgen signaling and independently confers risk of recurrence in prostate cancer with joint loss of CHD1

xloma.fota13 shared this article with you from Inoreader MAP3K7 loss drives enhanced androgen signaling and independently confers risk of recurrence in prostate cancer with joint loss of CHD1 Via Molecular Cancer Research Online First Articles Abstract: Prostate cancer (PCa) genomic subtypes that stratify aggressive disease and inform treatment decisions at the primary stage are currently limited. Previously, we functionally validated an aggressive subtype present in 15% of PCa characterized by dual deletion of MAP3K7 and CHD1. Recent studies in the field have focused on deletion of CHD1 and its role in androgen receptor (AR) chromatin distribution and resistance to AR-targeted therapy, however, CHD1 is rarely lost without co-deletion of MAP3K7. Here we show that in the clinically relevant context of co-loss of MAP3K7 and CHD1 there are significant, collective changes to aspects of AR signaling. While CHD1 loss mainly impacts the expansion of the AR cistrome, loss of MAP3K7 drives increased AR target gene expression. PCa cell line models engineered to co-suppress MAP3K7 and CHD1 also demonstrated increased AR-v7 expression and resistance to the AR-targeting drug enzalutamide. Furthermore, we dete rmined that low protein expression of both genes is significantly associated with biochemical recurrence (BCR) in a clinical cohort of radical prostatectomy specimens. Low MAP3K7 expression, however, was the strongest independent predictor for risk of BCR over all other tested clinicopathologic factors including CHD1 expression. Collectively, these findings illustrate the importance of MAP3K7 loss in a molecular subtype of PCa that poses challenges to conventional therapeutic approaches. Implications: These findings strongly implicate MAP3K7 loss as a biomarker for aggressive prostate cancer with significant risk for recurrence that poses challenges for conventional androgen receptor-targeted therapies. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

FDA Approval Summary: Pembrolizumab for the first-line treatment of patients with MSI-H/dMMR advanced unresectable or metastatic colorectal carcinoma

xloma.fota13 shared this article with you from Inoreader FDA Approval Summary: Pembrolizumab for the first-line treatment of patients with MSI-H/dMMR advanced unresectable or metastatic colorectal carcinoma Via Clinical Cancer Research Online First Articles The Food and Drug Administration (FDA) approved pembrolizumab on June 29, 2020, for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) colorectal cancer (CRC) with no prior systemic treatment for advanced disease. The approval was based on data from Study Keynote-177, which randomly allocated patients to receive either pembrolizumab or standard of care (SOC) with chemotherapy. Overall survival (OS) and independently-assessed progression free survival (PFS) were the primary endpoints. At the time of the final PFS analysis and second pre-specified interim OS analysis, the estimated median PFS was 16.5 months (95% CI: 5.4, 32.4) vs. 8.2 months (95% CI: 6.1, 10.2) in the pembrolizumab and SOC arms, respectively (Hazard Ratio [HR]: 0.60 (95% CI: 0.45, 0.80; two-sided p-value= 0.0004)). FDA assessed unblinded OS data during the review of the application and identified no safety concerns that would preclude approval of this supplement. Adverse reactions occurring in >30% of patients receiving pembrolizumab were diarrhea, fatigue/asthenia, and nausea. Adverse reactions occurring in >30% of patients receiving SOC were diarrhea, nausea, fatigue/asthenia, neutropenia, decreased appetite, peripheral neuropathy (high-level term), vomiting, abdominal pain, constipation, and stomatitis. Duration of treatment in the pembrolizumab arm was almost double (median 11.1 months, range 0-30.6 months) than the duration of treatment in patients receiving SOC (median 5.7 months). Approval of pembrolizumab is likely to change the treatment paradigm for 1st line treatment with MSI-H advanced CRC given the study results and different safety profile. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Resolvin D1 reduces cancer growth stimulating a protective neutrophil-dependent recruitment of anti-tumor monocytes

xloma.fota13 shared this article with you from Inoreader Resolvin D1 reduces cancer growth stimulating a protective neutrophil-dependent recruitment of anti-tumor monocytes Via Journal of Experimental & Clinical Cancer Research - Latest Articles Innovative therapies to target tumor-associated neutrophils (PMN) are of clinical interest, since these cells are centrally involved in cancer inflammation and tumor progression. Resolvin D1 (RvD1) is a lipid ... View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Disputed rpoB mutations in Mycobacterium tuberculosis and tuberculosis treatment outcomes [Susceptibility]

xloma.fota13 shared this article with you from Inoreader Disputed rpoB mutations in Mycobacterium tuberculosis and tuberculosis treatment outcomes [Susceptibility] Via AAC Accepts: Articles Published Ahead of Print Discordant results for Mycobacterium tuberculosis isolates with disputed mutations between genotypic drug susceptibility testing (DST) (gDST) and phenotypic DST (pDST) impact RIF-resistant (RR) and multidrug-resistant (MDR) tuberculosis (TB) treatments due to a lack of practical clinical guidelines. To investigate the role of disputed rpoB mutations in M. tuberculosis and TB treatment outcomes, initial isolates of 837 clinical RR or MDR-TB cases confirmed during 2014-2018 were retested us ing agar-based RIF pDST and rpoB gene sequencing. Minimum inhibitory concentrations (MICs) were determined for isolates with disputed rpoB mutations. Disputed rpoB mutations were identified in 77 (9.2%) M. tuberculosis isolates, including 50 (64.9%) and 14 (18.2%) phenotypic RIF- and rifabutin (RFB)-resistant isolates, respectively. The predominant single mutations were L533P (44.2%) and L511P (20.8%). Most of the isolates harboring L511P (87.5%), H526N (100%), D516Y (70.0%) and L533P (63.6%) mutations had MICs ≤1 mg/L, whereas isolates harboring H526L (75%) had MICs > 1 mg/L. Of the 63 cases with treatment outcomes, 11 (17.5%) cases died, 1 (1.6%) case transferred out and 51 (81%) cases had favorable outcomes, including 8 and 20 cases treated with standard-dose RIF- and RFB-containing regimens, respectively. Excluding cases transferred out, received no or 1-day treatment, we observed statistically significant differences between active and inactive fluoroquinolones (FQs) [P =0.004, Odds ratio =0.05 (95% confidence intervals, 0.01-0.38)] in 57 cases. We concluded that disputed rpoB mutations are not rare. Depending on resources, sequencing and/or MIC testing is recommended for better management of RR and MDR-TB cases. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

E. coli GyrA Tower Domain Interacts with QnrB1 Loop B and Plays an Important Role in QnrB1 Protection from Quinolone Inhibition [Mechanisms of Resistance]

xloma.fota13 shared this article with you from Inoreader E. coli GyrA Tower Domain Interacts with QnrB1 Loop B and Plays an Important Role in QnrB1 Protection from Quinolone Inhibition [Mechanisms of Resistance] Via AAC Accepts: Articles Published Ahead of Print The Qnr pentapeptide repeat proteins interact with DNA gyrase and protect it from quinolone inhibition. The two external loops, particularly the larger loop B, of Qnr proteins are essential for quinolone protection of DNA gyrase. The specific QnrB1 interaction sites on DNA gyrase are not known. In this study, we investigated the interaction between GyrA and QnrB1 using site-specific photo crosslinking of QnrB1 loop B combined with mass spectrometry. We found that amino acid residues 286-298 on the Tower domai n of GyrA interact with QnrB1 and play a key role in QnrB1 protection of gyrase from quinolone inhibition. Alanine replacement of arginine at residue 293 and a small deletion of amino acids 286-289 of GyrA resulted in a decrease in the QnrB1-mediated increase in quinolone MICs and also abolished the QnrB1 protection of purified DNA gyrase from ciprofloxacin inhibition. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Experience with Liposomal Amphotericin B in Outpatient Parenteral Antimicrobial Therapy (OPAT) [Clinical Therapeutics]

xloma.fota13 shared this article with you from Inoreader Experience with Liposomal Amphotericin B in Outpatient Parenteral Antimicrobial Therapy (OPAT) [Clinical Therapeutics] Via AAC Accepts: Articles Published Ahead of Print Background: Outpatient parenteral antimicrobial therapy (OPAT) is a safe, effective, and convenient treatment strategy for patients receiving intravenous antimicrobials in the outpatient setting; however, data is limited describing the use and safety of liposomal amphotericin B (L-AMB). Methods: Records of patients receiving L-AMB OPAT between 1/1/2015 and 7/31/2018 were retrospectively reviewed. The primary objective was to describe the OPAT patient population discharged on L-AMB and evaluate factors a ssociated with readmission and adverse events (AE). Analysis was performed to evaluate for predictors of worse outcomes. Results: Forty-two patients (67% male, median age 50 years) were identified, most commonly treated for histoplasmosis. The most common doses of L-AMB were 3 mg/kg (n=16, 38%) or 5 mg/kg (n=14, 33%) based on actual body weight. Twenty-six (62%) patients completed their anticipated course of L-AMB. Twenty-two (52%) patients were readmitted within 30 days of discharge, median time to readmission was 11 days (Interquartile range [IQR] 5-18). While hypokalemia and acute kidney injury (AKI) were common, occurring in 26 (62%) and 20 (48%), respectively, only 5 (12%) were readmitted to the hospital due L-AMB-associated AE. Ninety percent of patients achieved at least partial renal recovery within 30 days after L-AMB discontinuation. Factors significantly associated with AKI include higher L-AMB dose, lower serum potassium levels after therapy initiation, and receipt of potassium supplementation at discharge. Conclusion: L-AMB is associated with significant AEs; however, these results suggest treatment is feasible in the outpatient setting with close monitoring, as the majority of AEs were managed effectively as an outpatient without long-term sequelae. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Comparison of In Vitro Susceptibility of Delafloxacin with Ciprofloxacin, Moxifloxacin, and other Comparator Antimicrobials Against Isolates of Nontuberculous Mycobacteria [Susceptibility]

xloma.fota13 shared this article with you from Inoreader Comparison of In Vitro Susceptibility of Delafloxacin with Ciprofloxacin, Moxifloxacin, and other Comparator Antimicrobials Against Isolates of Nontuberculous Mycobacteria [Susceptibility] Via AAC Accepts: Articles Published Ahead of Print Nontuberculous mycobacteria (NTM) infections are increasing globally. Mycobacterium avium complex (MAC) and M. abscessus complex are the most commonly reported NTM. Oral treatment options are limited, especially for the M. abscessus. We tested delafloxacin, a new oral fluoroquinolone, against 131 isolates of NTM. Delafloxacin microdilution MICs were performed as recommended by the Clinical and Laboratory Standards Institute using cation adjusted Mueller Hinton broth. The rapidly growing m ycobacteria tested included: M. abscessus subsp. abscessus (16) and subsp. massiliense (5), M. chelonae (11), M. immunogenum (5), M. fortuitum group (13), M. porcinum (7), M. senegalense (7), M. mucogenicum group (5), and M. goodii (1). For the slowly growing NTM (SGM), M. avium (16), M. intracellulare (13), M. chimaera (9), M. arupense (5), M. simiae (5), M. lentiflavum (4), M. kansasii (6), and M. marinum (3) were tested. Delafloxacin was most active in vitro against M. fortuitum and M. mucogenicum groups and M. kansasii with MIC50 values of 0.12-0.5 μg/mL (MIC range 0.001-4 μg/mL) compared to ≤0.06->4 μg/mL for ciprofloxacin and ≤0.06->8 μg/mL for moxifloxacin. For other SGM (including MAC), and the M. abscessus/chelonae, the delafloxacin MIC range was 8->16 μg/mL compared to ciprofloxacin and moxifloxacin of 0.5->4 μg/mL and ≤0.06-8 μg/mL, respectively. To our knowledge, this is the first MIC study with delafloxacin to use Clinical and Laboratory Standards Institute (CLSI) recommended methods. This study illustrates the potential utility of delafloxacin in treatment of infections due to some NTM. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

In Vitro and In Vivo Antifungal Activity of AmBisome Compared to Conventional Amphotericin B and Fluconazole against Candida auris [Susceptibility]

xloma.fota13 shared this article with you from Inoreader In Vitro and In Vivo Antifungal Activity of AmBisome Compared to Conventional Amphotericin B and Fluconazole against Candida auris [Susceptibility] Via AAC Accepts: Articles Published Ahead of Print Antifungal activity of AmBisome against Candida auris was determined in vitro and in vivo. AmBisome showed MIC50 and MIC90 values of 1 and 2 μg/mL, respectively. Unlike conventional amphotericin B, significant in vivo efficacy was observed in the AmBisome 7.5 mg/kg -treated group in survival and reduction of kidney tissue fungal burden compared to the untreated group. Our data shows that AmBisome shows significant antifungal activity against C. auris < i>in vitro as well as in vivo. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Falls Predict Acute Hospitalization in Parkinson's Disease

xloma.fota13 shared this article with you from Inoreader Falls Predict Acute Hospitalization in Parkinson's Disease Via pubmed: dysphagia J Parkinsons Dis. 2021 Apr 7. doi: 10.3233/JPD-212539. Online ahead of print. ABSTRACT BACKGROUND: There is a need for identifying risk factors for hospitalization in Parkinson's disease (PD) and also interventions to reduce acute hospital admission. OBJECTIVE: To analyze the frequency, causes, and predictors of acute hospitalization (AH) in PD patients from a Spanish cohort. METHODS: PD patients recruited from 35 centers of Spain from the COPPADIS-2015 (COhort of Patients with PArkinson's DIsease in Spain, 2015) cohort from January 2016 to November 2017, were included in the study. In order to identify predictors of AH, Kaplan-Meier estimates of factors considered as potential predictors were obtained and Cox regression performed on time to hospital encounter 1-year after the baseline visit. RESULTS: Thirty-five out of 605 (5.8%) PD patients (62.5±8.9 years old; 59.8% males) presented an AH during the 1-year follow-up afte r the baseline visit. Traumatic falls represented the most frequent cause of admission, being 23.7% of all acute hospitalizations. To suffer from motor fluctuations (HR [hazard ratio] 2.461; 95% CI, 1.065-5.678; p = 0.035), a very severe non-motor symptoms burden (HR [hazard ratio] 2.828; 95% CI, 1.319-6.063; p = 0.008), falls (HR 3.966; 95% CI 1.757-8.470; p = 0.001), and dysphagia (HR 2.356; 95% CI 1.124-4.941; p = 0.023) was associated with AH after adjustment to age, gender, disease duration, levodopa equivalent daily dose, total number of non-antiparkinsonian drugs, and UPDRS-IIIOFF. Of the previous variables, only falls (HR 2.998; 95% CI 1.080-8.322; p = 0.035) was an independent predictor of AH. CONCLUSION: Falls is an independent predictor of AH in PD patients. PMID:33843696 | DOI:10.3233/JPD-212539 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Outcomes after cervical vertebral interbody fusion using an interbody fusion device and polyaxial pedicle screw and rod construct in 10 horses (2015-2019)

xloma.fota13 shared this article with you from Inoreader Outcomes after cervical vertebral interbody fusion using an interbody fusion device and polyaxial pedicle screw and rod construct in 10 horses (2015-2019) Via pubmed: dysphagia Equine Vet J. 2021 Apr 12. doi: 10.1111/evj.13449. Online ahead of print. ABSTRACT BACKGROUND: Further development of surgical techniques for equine cervical stabilisation is necessary to make the procedure less technically demanding, reduce complications, and improve outcomes. OBJECTIVE: To describe clinical outcomes and owner reports in horses undergoing placement of an interbody fusion device and polyaxial pedicle screw and rod construct for cervical vertebral fusion in horses with cervical vertebral compressive myelopathy. STUDY DESIGN: Retrospective case series. METHODS: Data were retrieved from medical records of 10 horses undergoing cervical vertebral fusion (2015-2019). Records were evaluated for signalment, duration of clinical signs, number and location of compression sites, grade of ataxia, duration of hospitalisation, and complications. Long-term follow-up was obtained through clinical re-evaluation, postoperativ e radiographs, and owner contact. RESULTS: Breeds were mixed. Median age was 24 (range 12-168) months. There were 2/10 mares, 4/10 geldings, and 4/10 stallions. Preoperative grade of ataxia ranged from 1-3/5. Fusion was performed at one (n=3) or two (n=7) sites. Two horses were euthanised within the first year. In 6 out of 8 horses with ≥1-year follow-up, ataxia improved by 1 - 3 grades, with an average improvement of 1.25 grades. In four horses, ataxia improved to grade 0-1. In two horses the gait was unaffected, but neck comfort improved. Complications included seroma formation (n=9), pain (n=5), fever (n=4), upper respiratory tract obstruction (n=2), azotemia (n=2), screw breakage (n=2), progression of neurological signs (n=1), Horner's Syndrome (n=1), dysphagia (n=1), hives (n=1), implant infection (n=1), and nondisplaced fracture (n=1). MAIN LIMITATIONS: Small case series, heterogeneous patient population. CONCLUSIONS: This technique resulted in ≥1 grade g ait improvement in 6/10 cases operated and 6/8 cases for which ≥1-year follow-up was available, similar to other methods. Fatal complications related to implant placement did not occur. This technique may represent a safer alternative to current techniques of ventral interbody fusion with similar outcomes. PMID:33844334 | DOI:10.1111/evj.13449 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.