Background and purpose
The pharmacologic effects of pioglitazone on the incidence of Parkinson disease (PD) are not clear. No study has examined the interaction between pioglitazone and statin ...treatment on prevention of PD. This study analyzed the associations between pioglitazone, statins, and the incidence of PD in patients with diabetes mellitus (DM) in Taiwan.
Methods
We used the National Health Insurance database from 1996 to 2013. DM and PD were diagnosed according to the International Classification of Diseases, Ninth Revision, Clinical Modification codes. We used the propensity score‐matching method to match the study groups. Cox regression analyses were employed to calculate the relative risk of the incidence of PD.
Results
There were 48 828 patients matched and categorized equally into the pioglitazone group and the non‐pioglitazone group. The number of PD patients in the pioglitazone group and the non‐pioglitazone group was 275 (1.1%) and 417 (1.7%), respectively. The pioglitazone group had a lower incidence of PD, with an adjusted hazard ratio (aHR) of 0.66 95% confidence interval (CI): 0.57–0.78, and this benefit was dose‐dependent. Of note, as compared with either pioglitazone or statin treatment, our results first showed that the combination of pioglitazone and statins further lowered the risk of PD, with an aHR of 0.78 (95% CI: 0.64–0.94; P = 0.010).
Conclusions
Our study results suggested that pioglitazone could be a promising agent for reducing the incidence of PD in patients with DM, and works synergistically with statins.
Pioglitazone and statins may lower the indidence of Parkinsion disease independently and synergistically in patients with diabetes mellitus.
Background and purpose
Restless legs syndrome (RLS) is an underestimated movement disorder in patients with end‐stage renal disease (ESRD). Several clinical and laboratory factors were inconsistently ...reported to associate with RLS. We aim to perform a large‐scale multicenter study to investigate the possible associated risk factors of RLS in patients with ESRD in Taiwan, a country with the highest incidence of uremia in the world.
Methods
From October 2009 to October 2011, we constitutively recruited 1130 patients with ESRD from 17 hemodialysis centers. Demographic, laboratory data, presence and severity of RLS were collected. Odds ratios (ORs) were estimated by logistic regression models.
Results
We found the prevalence of RLS to be 25.3% in patients with ESRD. Having type 2 diabetes OR = 3.61 (2.27–5.77), P < 0.01, low serum transferrin saturation OR = 1.42 (1.01–2.03), P < 0.05 and duration of dialysis OR = 1.09 (1.03–1.14), P < 0.01 were associated with RLS. In contrast, high serum hemoglobin level was inversely associated with RLS OR = 0.61 (0.40–0.89), P < 0.05. RLS has a significant impact on sleep quality in dialysis patients. Among patients with RLS, history of type 2 diabetes OR = 4.04 (1.65–10.79), P < 0.05, low serum hemoglobin level OR = 5.41 (2.43–13.12), P < 0.01 and duration of dialysis OR = 1.01 (1.01–1.02), P < 0.01 were associated with increased severity of RLS.
Conclusions
Our findings demonstrated that RLS is common in Taiwanese dialysis patients. Clinicians should have a high suspicion for the presence of RLS symptoms in patients with ESRD, especially those with type 2 diabetes, anemia, low serum iron status and long duration of dialysis.
The AIM-II Trial included patients with nondysplastic Barrett's esophagus (NDBE) treated with radiofrequency ablation (RFA). Complete eradication of NDBE (complete response-intestinal metaplasia ...CR-IM) was achieved in 98.4 % of patients at 2.5 years. We report the proportion of patients demonstrating CR-IM at 5-year follow-up.
Prospective, multicenter US trial (NCT00489268). After endoscopic RFA of NDBE up to 6 cm, patients with CR-IM at 2.5 years were eligible for longer-term follow-up. At 5 years, we obtained four-quadrant biopsies from every 1 cm of the original extent of Barrett's esophagus. All specimens were reviewed by one expert gastrointestinal pathologist, followed by focal RFA and repeat biopsy if NDBE was identified. Primary outcomes were (i) proportion of patients demonstrating CR-IM at 5-year biopsy, and (ii) proportion of patients demonstrating CR-IM at 5-year biopsy or after the single-session focal RFA.
Of 60 eligible patients, 50 consented to participate. Of 1473 esophageal specimens obtained at 5 years 85 % contained lamina propria or deeper tissue (per patient, mean 30 , standard deviation SD 13). CR-IM was demonstrated in 92 % (46 / 50) of patients, while 8 % (4 / 50) had focal NDBE; focal RFA converted all these to CR-IM. There were no buried glands, dysplasia, strictures, or serious adverse events. Kaplan-Meier CR-IM survival analysis showed probability of maintaining CR-IM for at least 4 years after first durable CR-IM was 0.91 (95 % confidence interval CI 0.77 - 0.97) and mean duration of CR-IM was 4.22 years (standard error SE 0.12).
In patients with NDBE treated with RFA, CR-IM was demonstrated in the majority of patients (92 %) at 5-year follow-up, biopsy depth was adequate to detect recurrence, and all failures (4 / 4, 100 %) were converted to CR-IM with single-session focal RFA.
Homologous recombination repair deficiency (HRD) is a frequent feature of high-grade serous ovarian, fallopian tube and peritoneal carcinoma (HGSC) and is associated with sensitivity to PARP ...inhibitor (PARPi) therapy. HRD testing provides an opportunity to optimise PARPi use in HGSC but methodologies are diverse and clinical application remains controversial.
To define best practice for HRD testing in HGSC the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project that incorporated a systematic review approach. The main aims were to (i) define the term ‘HRD test’; (ii) provide an overview of the biological rationale and the level of evidence supporting currently available HRD tests; (iii) provide recommendations on the clinical utility of HRD tests in clinical management of HGSC.
A broad range of repair genes, genomic scars, mutational signatures and functional assays are associated with a history of HRD. Currently, the clinical validity of HRD tests in ovarian cancer is best assessed, not in terms of biological HRD status per se, but in terms of PARPi benefit. Clinical trials evidence supports the use of BRCA mutation testing and two commercially available assays that also incorporate genomic instability for identifying subgroups of HGSCs that derive different magnitudes of benefit from PARPi therapy, albeit with some variation by clinical scenario. These tests can be used to inform treatment selection and scheduling but their use is limited by a failure to consistently identify a subgroup of patients who derive no benefit from PARPis in most studies. Existing tests lack negative predictive value and inadequately address the complex and dynamic nature of the HRD phenotype.
Currently available HRD tests are useful for predicting likely magnitude of benefit from PARPis but better biomarkers are urgently needed to better identify current homologous recombination proficiency status and stratify HGSC management.
•Homologous recombination repair deficiency (HRD) is a common feature of high-grade serous gynaecological cancers (HGSC).•Currently, the clinical validity of HRD tests in ovarian cancer is best assessed in terms of PARPi benefit.•Germline and somatic BRCA mutation and genomic instability tests help to predict likely magnitude of benefit from a PARPi.•Existing HRD tests fail to consistently identify a subgroup of patients who derive no benefit from PARPis in most studies.•HRD is a dynamic entity and better biomarkers that capture current homologous recombination proficiency status are needed.
Stereotactic radiosurgery (RS) is a promising treatment for intractable medial temporal lobe epilepsy (MTLE). However, the basis of its efficacy is not well understood.
Thirty patients with MTLE were ...prospectively randomized to receive 20 or 24 Gy 50% isodose RS centered at the amygdala, 2 cm of the anterior hippocampus, and the parahippocampal gyrus. Posttreatment MRI was evaluated quantitatively for abnormal T2 hyperintensity and contrast enhancement, mass effect, and qualitatively for spectroscopic and diffusion changes. MRI findings were analyzed for potential association with radiation dose and seizure remission (Engel Ib or better outcome).
Despite highly standardized dose targeting, RS produced variable MRI alterations. In patients with multiple serial imaging, the appearance of vasogenic edema occurred approximately 9-12 months after RS and correlated with onset of seizure remission. Diffusion and spectroscopy-detected alterations were consistent with a mechanism of temporal lobe radiation injury mediated by local vascular insult and neuronal loss. The degree of these early alterations at the peak of radiographic response was dose-dependent and predicted long-term seizure remission in the third year of follow-up. Radiographic changes were not associated with neurocognitive impairments.
Temporal lobe stereotactic radiosurgery resulted in significant seizure reduction in a delayed fashion which appeared to be well-correlated with structural and biochemical alterations observed on neuroimaging. Early detected changes may offer prognostic information for guiding management.
The emergency use authorization of two mRNA vaccines in less than a year from the emergence of SARS-CoV-2 represents a landmark in vaccinology
. Yet, how mRNA vaccines stimulate the immune system to ...elicit protective immune responses is unknown. Here we used a systems vaccinology approach to comprehensively profile the innate and adaptive immune responses of 56 healthy volunteers who were vaccinated with the Pfizer-BioNTech mRNA vaccine (BNT162b2). Vaccination resulted in the robust production of neutralizing antibodies against the wild-type SARS-CoV-2 (derived from 2019-nCOV/USA_WA1/2020) and, to a lesser extent, the B.1.351 strain, as well as significant increases in antigen-specific polyfunctional CD4 and CD8 T cells after the second dose. Booster vaccination stimulated a notably enhanced innate immune response as compared to primary vaccination, evidenced by (1) a greater frequency of CD14
CD16
inflammatory monocytes; (2) a higher concentration of plasma IFNγ; and (3) a transcriptional signature of innate antiviral immunity. Consistent with these observations, our single-cell transcriptomics analysis demonstrated an approximately 100-fold increase in the frequency of a myeloid cell cluster enriched in interferon-response transcription factors and reduced in AP-1 transcription factors, after secondary immunization. Finally, we identified distinct innate pathways associated with CD8 T cell and neutralizing antibody responses, and show that a monocyte-related signature correlates with the neutralizing antibody response against the B.1.351 variant. Collectively, these data provide insights into the immune responses induced by mRNA vaccination and demonstrate its capacity to prime the innate immune system to mount a more potent response after booster immunization.
Myc oncoproteins are commonly upregulated in human cancers of different organ origins, stabilized by Aurora A, degraded through ubiquitin-proteasome pathway-mediated proteolysis, and exert oncogenic ...effects by modulating gene and protein expression. Histone deacetylases are emerging as targets for cancer therapy. Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. Affymetrix gene array studies revealed that the gene most significantly repressed by SIRT2 was the ubiquitin-protein ligase NEDD4. Consistent with this finding, SIRT2 repressed NEDD4 gene expression by directly binding to the NEDD4 gene core promoter and deacetylating histone H4 lysine 16. Importantly, NEDD4 directly bound to Myc oncoproteins and targeted Myc oncoproteins for ubiquitination and degradation, and small-molecule SIRT2 inhibitors reactivated NEDD4 gene expression, reduced N-Myc and c-Myc protein expression, and suppressed neuroblastoma and pancreatic cancer cell proliferation. Additionally, SIRT2 upregulated and small-molecule SIRT2 inhibitors decreased Aurora A expression. Our data reveal a novel pathway critical for Myc oncoprotein stability, and provide important evidences for potential application of SIRT2 inhibitors for the prevention and therapy of Myc-induced malignancies.
Current staging methods for pancreatic cancer (PC) are inadequate, and biomarkers to aid clinical decision making are lacking. Despite the availability of the serum marker carbohydrate antigen 19.9 ...(CA19.9) for over two decades, its precise role in the management of PC is yet to be defined, and as a consequence, it is not widely used.
We assessed the relationship between perioperative serum CA19.9 levels, survival and adjuvant chemotherapeutic responsiveness in a cohort of 260 patients who underwent operative resection for PC.
By specifically assessing the subgroup of patients with detectable CA19.9, we identified potential utility at key clinical decision points. Low postoperative CA19.9 at 3 months (median survival 25.6 vs 14.8 months, P = 0.0052) and before adjuvant chemotherapy were independent prognostic factors. Patients with postoperative CA 19.9 levels >90 U/ml did not benefit from adjuvant chemotherapy (P = 0.7194) compared with those with a CA19.9 of ≤90 U/ml (median 26.0 vs 16.7 months, P = 0.0108). Normalization of CA19.9 within 6 months of resection was also an independent favorable prognostic factor (median 29.9 vs 14.8 months, P = 0.0004) and normal perioperative CA19.9 levels identified a good prognostic group, which was associated with a 5-year survival of 42%.
Perioperative serum CA19.9 measurements are informative in patients with detectable CA19.9 (defined by serum levels of >5 U/ml) and have potential clinical utility in predicting outcome and response to adjuvant chemotherapy. Future clinical trials should prioritize incorporation of CA19.9 measurement at key decision points to prospectively validate these findings and facilitate implementation.
Summary
Background
Basal cell carcinomas (BCCs) exhibit aberrant activation of the hedgehog pathway. Sonidegib is a hedgehog pathway inhibitor approved for the treatment of locally advanced BCC ...(laBCC) and metastatic BCC (mBCC) based on primary results of the BOLT study Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment.
Objectives
This is the final 42‐month analysis of the BOLT study, evaluating the efficacy and safety of sonidegib.
Methods
Adults with no prior hedgehog pathway inhibitor therapy were randomized in a 1 : 2 ratio to sonidegib 200 mg or 800 mg once daily. Treatment continued for up to 42 months or until disease progression, unacceptable toxicity, death, study termination or withdrawal of consent. The primary efficacy end point was the objective response rate (ORR) by central review, assessed at baseline; weeks 5, 9 and 17; then subsequently every 8 or 12 weeks during years 1 or 2, respectively. Safety end points included adverse event monitoring and reporting.
Results
The study enrolled 230 patients, 79 and 151 in the 200‐mg and 800‐mg groups, respectively, of whom 8% and 3.3% remained on treatment by the 42‐month cutoff, respectively. The ORRs by central review were 56% 95% confidence interval (CI) 43–68 for laBCC and 8% (95% CI 0·2–36) for mBCC in the 200‐mg group and 46·1% (95% CI 37·2–55·1) for laBCC and 17% (95% CI 5–39) for mBCC in the 800‐mg group. No new safety concerns emerged.
Conclusions
Sonidegib demonstrated sustained efficacy and a manageable safety profile. The final BOLT results support sonidegib as a viable treatment option for laBCC and mBCC.
What's already known about this topic?
Basal cell carcinoma (BCC) is usually treatable with surgery or radiation therapy, but there are limited treatment options for patients with advanced BCC.
Sonidegib, a hedgehog pathway inhibitor approved for the treatment of advanced BCC, demonstrated clinically relevant efficacy and manageable safety in prior analyses of the phase II randomized, double‐blind BOLT study Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment.
What does this study add?
This final 42‐month analysis of BOLT is the longest follow‐up available for a hedgehog pathway inhibitor.
Clinically relevant efficacy results were sustained from prior analyses, with objective response rates by central review of the approved 200‐mg daily dose of 56% in locally advanced BCC and 8% in metastatic BCC.
No new safety concerns were raised.
The results confirmed sonidegib as a viable long‐term treatment option for patients with advanced BCC.
Linked Comment: Fife. Br J Dermatol 2020; 182:1322–1323.
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