Systemic therapies and primary tumour downsizing in renal cell carcinoma: a real-world comparison of anti-angiogenic and immune checkpoint inhibition regimens.

PURPOSE: To investigate responses in the primary tumour to different systemic treatment regimens in patients with metastatic renal cell carcinoma (mRCC). METHODS: A single-centre retrospective analysis of treatment-naive mRCC patients without prior nephrectomy receiving VEGF tyrosine kinase inhibitors (VEGF only), immune checkpoint inhibitors (IO only), or combinations thereof (IO + VEGF). The primary outcome was the rate of partial response in the primary tumour (primary tumour PR, ≥ 30% diameter reduction). Secondary outcomes were time to best primary tumour diameter change, overall survival (OS) and progression-free survival (PFS) by Kaplan-Meier analysis. Predictors of survival outcomes were explored by Cox proportional hazards regression analysis. RESULTS: The rate of primary tumour PR was 14% for VEGF only (4/28 patients), 22% for IO only (5/23) and 50% for IO + VEGF (7/14), with median best primary tumour diameter change of - 8.0%, + 5.1%, and - 31.1% respectively, and median time to best primary tumour diameter change of 3.2, 3.0 and 6.9 months respectively. Median OS was significantly greater with IO + VEGF compared to VEGF only (HR 0.45, p = 0.04) and non-significantly greater compared to IO only (HR 0.46, p = 0.06). In multivariable analysis, primary tumour PR was the only response variable significantly associated with both OS (adjusted HR 0.32, p = 0.01) and PFS (adjusted HR 0.29, p < 0.01). CONCLUSION: mRCC patients without prior nephrectomy receiving first-line IO + VEGF regimens showed the greatest primary tumour responses, suggesting further prospective evaluation of this combination in the neoadjuvant and deferred cytoreductive nephrectomy settings.

A Case of Delayed Diagnosis of Idiopathic Infantile Hypercalcemia Due to CYP24A1 Mutation: A 10-Year Journey.

The parathyroid gland is responsible for the synthesis and secretion of parathyroid hormone, which is synthesized and released at an inverse relationship to the level of ionized calcium in the blood. Primary hyperparathyroidism affects women more than men. There are various causes for hyperparathyroidism-induced hypercalcemia and the most common cause is parathyroid adenoma. A less common cause of vitamin D-mediated parathyroid hormone-independent hypercalcemia is the loss of function mutation of the CYP24A1 gene. The CYP24A1 gene encodes the vitamin D 24-hydroxylase enzyme, responsible for hydroxylating the active form of vitamin D into an inactive form, and mutations in the CY24A1 gene can lead to elevated active vitamin D metabolite levels. It can result in hypercalcemia and hypercalciuria-related complications. We present a case of a 72-year-old male patient referred to the endocrine clinic, who had repeated treatments for hypercalcemia and recurrent renal calculi. He underwent ultrasound, computerized tomography, and sestamibi scans, all reported as normal. Following this, the patient underwent a positron emission tomography (PET) scan, which was also normal. He then finally underwent genetic testing and tested positive for the CYP24A1 gene. He was started on fluconazole 50mg once a day and cinacalcet 30mg twice with normalization of calcium level. Three of his family members also tested positive for the condition.

Consenting surgical patients for the risk of contracting COVID-19 during the hospital stay.

BACKGROUND/AIMS: Postoperative pulmonary complications occur in half of patients with perioperative COVID-19 and are associated with high mortality. The Royal College of Surgeons of England published guidance on recovery of surgical services during and after the COVID-19 pandemic. One part of this toolkit looked at unique considerations during the COVID-19 pandemic, in particular the risk of contracting COVID-19 while in the hospital. This quality improvement project sought to assess consent forms from the authors' surgical department to see if patients were being consented for the risks associated with COVID-19 during their stay in the hospital. METHODS: Over an 8-week period in October and November 2020, consent forms for patients under the general surgery department were audited four times against the Royal College of Surgeons of England's standards. Patients were included in the study if they were deemed to have capacity to consent to a procedure. Posters in the hospital, generic emails and teaching sessions were used as the interventions after each cycle of the audit. RESULTS: Baseline measurement showed that fewer than 37% of patients were consented for the risk of contracting COVID-19; this rose to almost 61%, 71% and 85% in the second, third and fourth parts of the project respectively. Year 1 and 2 core surgical trainees and clinical fellows below registrar level showed the greatest improvement, from consenting only 8% of patients up to 100% of patients, while specialty registrars showed improvement in consenting from 52% to 73%. The change was sustained 2 years after the initial interventions, with almost 60% of patients consented for the risk associated with in-hospital COVID-19 infection in March 2023. CONCLUSIONS: Errors or omission of important elements in documentation of patient consent can delay operations, expose hospital trusts to medicolegal risk and ultimately may represent a failure to fully respect patient autonomy. This project sought to evaluate consenting practice during the presence of COVID-19 in society. While the teaching session showed some improvement in the consenting for the risk of COVID-19, emails and visual posters increased the consent rates further.

Baseline and Dynamic Changes in Hemoglobin Levels Predict Treatment Response and Prognosis in Metastatic Renal Cell Carcinoma: A Multicenter Retrospective Study.

INTRODUCTION: Clinical markers of response in metastatic renal cell carcinoma (mRCC) are lacking. Low hemoglobin (Hb) is associated with poor outcomes in the IMDC risk score. This study evaluates the role of Hb as a marker of treatment outcomes in mRCC. PATIENTS AND METHODS: This multicenter retrospective study evaluated 276 patients with mRCC treated with frontline immune checkpoint inhibitor (ICI) therapy, ICI and vascular endothelial growth factor (VEGF) inhibitor (VEGFI) combinations (ICI/VEGFI), or VEGFI monotherapy between 2014 and 2021. Hb levels at baseline, week 6 and 12 and at disease progression or death were recorded. Patients were categorized as responders (CR+PR) or nonresponders (SD+PD) using cross-sectional imaging at week 12. The association between baseline and dynamic changes in Hb and oncological outcomes was assessed. RESULTS: Thirty-seven percent, 40% and 22% of patients received ICIs, ICI/VEGFI and VEGFI respectively. In patients receiving ICIs, there was a significant increase in Hb amongst responders from baseline to week 12 (P= .02). Amongst patients receiving ICI/VEGFI, there was an increase in Hb from baseline to week 12 which was greater in responders (P< .001). In patients receiving VEGFI monotherapy, responders had a higher Hb at baseline (P= .01), week 6 (P= .04), and week 12 (P= .003). An increase in Hb was a significant independent predictor of progression-free survival amongst patients receiving ICIs (HR 0.40, 95%CI, 0.19-0.83, P= .009). CONCLUSION: Baseline and dynamic changes in Hb are associated with first-line treatment outcomes in patients with mRCC and represent a pragmatic early serological marker.

Avelumab in locally advanced or metastatic urothelial carcinoma.

INTRODUCTION: Outcomes for patients with advanced or metastatic urothelial carcinoma (UC) remain poor. Targeting the programmed death ligand-1 (PD-(L)1) immune checkpoint pathway has emerged as a useful target in patients with UC. Avelumab is a PD-L1 inhibitor, resulting in restoration of a cytotoxic, antitumor T cell response. Results from the JAVELIN bladder 100 trial has resulted in a new standard of care of platinum-based chemotherapy sequenced by maintenance avelumab in advanced or metastatic UC. AREAS COVERED: This review covers the clinical evidence for avelumab in UC. This includes the maintenance approach with avelumab, which has become the standard of care, following platinum-based chemotherapy. EXPERT OPINION: Immune checkpoint inhibitor treatment in metastatic UC holds much promise, but has not been optimized. First-line maintenance avelumab is an attractive option for these patients. Future research will significantly change the landscape of treatment in the near future.

SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4.

We recently identified the splicing kinase gene SRPK1 as a genetic vulnerability of acute myeloid leukemia (AML). Here, we show that genetic or pharmacological inhibition of SRPK1 leads to cell cycle arrest, leukemic cell differentiation and prolonged survival of mice transplanted with MLL-rearranged AML. RNA-seq analysis demonstrates that SRPK1 inhibition leads to altered isoform levels of many genes including several with established roles in leukemogenesis such as MYB, BRD4 and MED24. We focus on BRD4 as its main isoforms have distinct molecular properties and find that SRPK1 inhibition produces a significant switch from the short to the long isoform at the mRNA and protein levels. This was associated with BRD4 eviction from genomic loci involved in leukemogenesis including BCL2 and MYC. We go on to show that this switch mediates at least part of the anti-leukemic effects of SRPK1 inhibition. Our findings reveal that SRPK1 represents a plausible new therapeutic target against AML.