Deep PSA response and extended time-to-nadir as robust predictors of survival in Asian patients with de novo metastatic hormone-sensitive prostate cancer receiving upfront intensified treatment.

INTRODUCTION: In de novo metastatic hormone-sensitive prostate cancer (mHSPC) treated with upfront intensification using androgen receptor signaling inhibitor or chemotherapy (Docetaxel), achieving a PSA nadir less than 0.2 ng/mL, indicative of superior survival in trials, may often be unattainable in real-world settings. We explored the predictive value of the degree of PSA decline and time to PSA nadir (TTPN) on oncological outcomes. METHODS: A prospectively maintained database of consecutive prostate cancer cases in Hong Kong was accessed. Patients diagnosed with de novo mHSPC from 2016 to 2022 and treated with upfront intensification were included in this analysis. Landmark analysis on PSA kinetics at 6-months following treatment intensification was performed. They were classified based on 1) TTPN (≥6 months vs. <6 months), and 2) a combined response (deep responders achieving both ≥95% PSA decline and TTPN ≥ 6 months vs. shallow responders). Multivariable regression analysis was employed to identify the effects of confounders. FINDINGS: A total of 131 patients were included in this analysis. Classifying patients by combined response best predicted survival outcomes. Deep responders had better progression-free survival (HR = 0.56; 95%CI = 0.34-0.91; p = 0.019), overall survival (HR = 0.50; 95%CI = 0.26-0.97; p = 0.036), and cancer-specific survival (HR = 0.43; 95%CI = 0.19-0.99; p = 0.042). Difference in overall survival remained significant after adjustment in multivariable regression analysis. CONCLUSION: Our analysis demonstrates that alternative PSA targets can predict treatment response and survival outcomes in de novo mHSPC patients in a real-world setting, providing valuable information for patient counselling and potentially guiding future trial design.

Adjuvant treatment for renal cell carcinoma: current status and future.

PURPOSE OF REVIEW: Renal cell carcinoma (RCC) is resistant to chemotherapy. Adjuvant interferon and tyrosine kinase inhibitors were ineffective. Immune checkpoint inhibitors (ICIs), however, have shed new hope in this setting. In the current review, updated evidence of adjuvant therapy in RCC is summarized. RECENT FINDINGS: KEYNOTE-564 demonstrated survival benefits of adjuvant Pembrolizumab in RCC. EAU guidelines now recommend adjuvant pembrolizumab to ccRCC patients at an increased risk of recurrence, as defined in the study. At a median follow-up of 24 months, the disease-free survival (DFS) was significantly longer for the Pembrolizumab group than placebo group [DFS 77.3 vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% confidence interval (95% CI), 0.53-0.87; P = 0.002]. From its updated analysis, at median follow up of 57.2 months, overall survival (OS) benefit of Pembrolizumab was demonstrated (hazard ratio for death, 0.62; 95% CI, 0.44-0.87; P = 0.005). A number of other adjuvant ICI trials have though been negative. SUMMARY: Pembrolizumab is currently the only adjuvant therapy for RCC showing survival benefits, amid a number of negative trials on adjuvant immunotherapy. Currently, there is no role for adjuvant tyrosine-kinase inhibitors and radiotherapy for RCC. Meanwhile, a multidisciplinary approach and shared decision-making should be adopted.

The Role of Surgery in Metastatic Renal Cell Carcinoma in 2024.

Renal cell carcinoma (RCC) is the most common solid tumour of the kidney and accounts for 3% of all cancers. While immune checkpoint inhibitor (ICI)-based combination therapies have emerged as the first-line treatment for metastatic renal cell carcinoma (mRCC), the role of surgery has become more controversial. This review summarizes the evidence, current role and future directions for surgery in mRCC management. The survival benefits of cytoreductive nephrectomy (CN) shown in the interferon era have encountered increasing disputes in the tyrosine-kinase inhibitor (TKI) and ICI eras. Undoubtedly, several systematic reviews based on retrospective data have supported the survival benefits of CN. Nevertheless, 2 prospective trials, CARMENA and SURTIME, proved that sunitinib as the upfront therapy resulted in noninferior survival outcomes compared with immediate CN. The safety of CN does have solid ground in the current literature. Several studies suggested that preoperative systemic therapy did not seem to aggravate perioperative complications or mortality rates, in experienced centres. Meticulous patient selection is the rule of thumb in the modern management of mRCC patients. The limitations of the existing prognostication models, however, must be acknowledged. Clinicians should adopt a multidisciplinary and holistic approach and contemplate all patient, disease, surgeon and socio-economical factors, before deciding who should go for surgery. The advent of metastasis-directed therapy (MDT) and survival benefits of adjuvant pembrolizumab shown in the oligometastatic subgroup, where complete metastasectomy could be achieved (M1 NED), calls for more comparative studies against upfront ICI combinations. In summary, CN brings survival benefits to well-selected good-to-intermediate-risk mRCC patients. Individualized and multidisciplinary care is pivotal.

Relationship between IDDSI Flow Test and Consistometric Measures for Consistency Classification - An Examination of Thickened Liquids Prepared Using Starch-Based and Xanthan Gum-Based Thickening Agents.

INTRODUCTION: Consistency of liquid food plays an important role in managing patients with dysphagia, which can be objectively evaluated by using IDDSI Flow Test and consistometry. The present study established the relationship between IDDSI Flow Test and consistometric measures, and examined the measurement limitations of each test associated with thickened liquids prepared using starch-based and xanthan gum-based thickening agents. METHODS: Thirteen thickened liquid samples of consistency ranging from IDDSI Level 1 (mildly thick) to Level 3 (moderately thick) were prepared using starch-based and xanthan gum-based thickeners. IDDSI Flow Test and consistometric measures were obtained and analyzed using correlation and regression. RESULTS: A strong correlation was observed between both tests. Regression analyses revealed a linear and a quadratic relationship between IDDSI Flow Test and consistometric measurements, respectively. CONCLUSION: Starch-based and xanthan gum-based thickeners exhibited different relationships between IDDSI Flow Test and consistometric measurements. Findings allow easy conversion and adaptation of consistometric measures to the IDDSI framework, which renders the use of consistometry in the clinical settings as a complementary quantitative measurement of liquid consistency to IDDSI Flow Test.

Association of insomnia with incident chronic cognitive impairment in older adults with type 2 diabetes mellitus: A prospective study of the Hong Kong Diabetes Register.

AIMS: To examine the risk association of insomnia with incident chronic cognitive impairment in older adults with type 2 diabetes mellitus (T2D). METHODS: Between July 2010 and June 2015, patients with T2D aged ≥60 years enrolled in the Hong Kong Diabetes Register completed the Insomnia Severity Index (ISI) questionnaire. Patients were considered having insomnia if they had ISI score > 14. We prospectively followed up the cohort and censored outcome through reviewing diagnoses and clinical notes entered by attending physicians in electronic medical record to identify incident cases of mild cognitive impairment and dementia. RESULTS: After excluding shift workers and those with established chronic cognitive impairment at baseline, we included 986 patients with T2D in this study (58.3 % men, mean age ± standard deviation: 62.5 ± 2.6 years, disease duration of diabetes: 10.7 ± 8.2 years, HbA1c: 7.4 ± 1.3 %, insulin users: 28.7 %, insomnia: 9.1 %). After a median follow-up of 7.6 (interquartile range = 2.0) years, 41 (4.2 %) developed chronic cognitive impairment. Using Cox regression analysis, insomnia (hazard ratio, HR 2.909, p = 0.012) and HbA1c ≥ 7 % (HR 2.300, p = 0.038) were positively associated with incident chronic cognitive impairment while insulin use (HR 0.309, p = 0.028) showed negative association. CONCLUSIONS: Insomnia, suboptimal glycemic control and non-insulin use are independent risk factors for incident chronic cognitive impairment in older adults with T2D.

Applicability of the Global Lung Function Initiative prediction equations in Hong Kong Chinese children.

BACKGROUND AND OBJECTIVE: This study aimed to assess the applicability of the Global Lung Function Initiative (GLI) prediction equations for spirometry in Hong Kong children and to develop prediction equations based on the Generalized Additive Models for Location, Scale, and Shape (GAMLSS) modeling. METHODS: Healthy Chinese children and adolescents aged 6-17 years old were recruited from randomly selected schools to undergo spirometry. The measurements were transformed to z-score according to the GLI-2012 equations for South East (SE) Asians and the GLI-2022 global race-neutral equations. Prediction equations for spirometric indices were developed with GAMLSS modeling to identify predictors. RESULTS: A total of 886 children (477 boys) with a mean age of 12.5 years (standard deviation [SD] 3.3 years) were included. By the GLI-2012 SE Asian equations, positive mean z-scores were observed in forced expiratory volume in 1 s (FEV1 ) (boys: 0.138 ± SD 0.828; girls: 0.206 ± 0.823) and forced vital capacity (FVC) (boys: 0.160 ± 0.930; girls: 0.310 ± 0.895) in both sexes. Negative mean z-scores were observed in FEV1 /FVC ratio (boys: -0.018 ± 0.998; girls: -0.223 ± 0.897). In contrast, negative mean z-scores in FEV1 and FVC, and positive mean z-scores in FEV1 /FVC were observed when adopting the GLI-2022 race-neutral equations. The mean z-scores were all within the range of ±0.5. By GAMLSS models, age and height were significant predictors for all four spirometric indices, while weight was an additional predictor for FVC and FEV1 . CONCLUSION: Our study provided data supporting the applicability of the GLI prediction equations in Hong Kong Chinese children. The GLI-2012 equations may underestimate FEV1 and FVC, while the GLI-2022 equations may overestimate the parameters, but the differences lie within the physiological limits. By GAMLSS modeling, weight was an additional predictor for FVC and FEV1 .

Reduction in podocyte density as a pathologic feature in early diabetic nephropathy in rodents: prevention by lipoic acid treatment.

BACKGROUND: A reduction in the number of podocytes and podocyte density has been documented in the kidneys of patients with diabetes mellitus. Additional studies have shown that podocyte injury and loss occurs in both diabetic animals and humans. However, most studies in animals have examined relatively long-term changes in podocyte number and density and have not examined effects early after initiation of diabetes. We hypothesized that streptozotocin diabetes in rats and mice would result in an early reduction in podocyte density and that this reduction would be prevented by antioxidants. METHODS: The number of podocytes per glomerular section and the podocyte density in glomeruli from rats and mice with streptozotocin (STZ)-diabetes mellitus was determined at several time points based on detection of the glomerular podocyte specific antigens, WT-1 and GLEPP1. The effect of insulin administration or treatment with the antioxidant, alpha-lipoic acid, on podocyte number was assessed. RESULTS: Experimental diabetes resulted in a rapid decline in apparent podocyte number and podocyte density. A significant reduction in podocytes/glomerular cross-section was found in STZ diabetes in rats at 2 weeks (14%), 6 weeks (18%) and 8 weeks (34%) following STZ injection. Similar declines in apparent podocyte number were found in STZ diabetes in C57BL/6 mice at 2 weeks, but not at 3 days after injection. Treatment with alpha-lipoic acid substantially prevented podocyte loss in diabetic rats but treatment with insulin had only a modest effect. CONCLUSION: STZ diabetes results in reduction in apparent podocyte number and in podocyte density within 2 weeks after onset of hyperglycemia. Prevention of these effects with antioxidant therapy suggests that this early reduction in podocyte density is due in part to increased levels of reactive oxygen species as well as hyperglycemia.

Implications of glucose transporter protein type 1 (GLUT1)-haplodeficiency in embryonic stem cells for their survival in response to hypoxic stress.

Glucose transporter protein type 1 (GLUT1) is a major glucose transporter of the fertilized egg and preimplantation embryo. Haploinsufficiency for GLUT1 causes the GLUT1 deficiency syndrome in humans, however the embryo appears unaffected. Therefore, here we produced heterozygous GLUT1 knockout murine embryonic stem cells (GT1+/-) to study the role of GLUT1 deficiency in their growth, glucose metabolism, and survival in response to hypoxic stress. GT1(-/-) cells were determined to be nonviable. Both the GLUT1 and GLUT3 high-affinity, facilitative glucose transporters were expressed in GT1(+/+) and GT1(+/-) embryonic stem cells. GT1(+/-) demonstrated 49 +/- 4% reduction of GLUT1 mRNA. This induced a posttranscriptional, GLUT1 compensatory response resulting in 24 +/- 4% reduction of GLUT1 protein. GLUT3 was unchanged. GLUT8 and GLUT12 were also expressed and unchanged in GT1(+/-). Stimulation of glycolysis by azide inhibition of oxidative phosphorylation was impaired by 44% in GT1(+/-), with impaired up-regulation of GLUT1 protein. Hypoxia for up to 4 hours led to 201% more apoptosis in GT1(+/-) than in GT1(+/+) controls. Caspase-3 activity was 76% higher in GT1(+/-) versus GT1(+/+) at 2 hours. Heterozygous knockout of GLUT1 led to a partial GLUT1 compensatory response protecting nonstressed cells. However, inhibition of oxidative phosphorylation and hypoxia both exposed their increased susceptibility to these stresses.