Elevated glucose promotes MMP13 and ADAMTS5 production by osteoarthritic chondrocytes under oxygenated but not hypoxic conditions.

Type 2 diabetes is linked with increased incidence and severity of osteoarthritis. The purpose of this study was to determine the effect of extracellular glucose within the normal blood glucose and hyperglycemic range on catabolic enzyme production by chondrocytes isolated from osteoarthritic (OA) and macroscopically normal (MN) human cartilage under oxygenated (18.9% oxygen) and hypoxic (1% oxygen) conditions. OA and MN chondrocytes were maintained in 4, 6, 8, or 10 mM glucose for 24 h. Glucose consumption, GLUT1 glucose transporter levels, MMP13 and ADAMTS5 production, and levels of RUNX2, a transcriptional regulator of MMP13, ADAMTS5, and GLUT1, were assessed by enzyme-linked assays, RT-qPCR and/or western blot. Under oxygenated conditions, glucose consumption and GLUT1 protein levels were higher in OA but not MN chondrocytes in 10 mM glucose compared to 4 mM. Both RNA and protein levels of MMP13 and ADAMTS5 were also higher in OA but not MN chondrocytes in 10 mM compared to 4 mM glucose under oxygenated conditions. Expression of RUNX2 was overall lower in MN than OA chondrocytes and there was no consistent effect of extracellular glucose concentration on RUNX2 levels in MN chondrocytes. However, protein (but not RNA) levels of RUNX2 were elevated in OA chondrocytes maintained in 10 mM versus 4 mM glucose under oxygenated conditions. In contrast, neither RUNX2 levels or MMP13 or ADAMTS5 expression were increased in OA chondrocytes maintained in 10 mM compared to 4 mM glucose in hypoxia. Elevated extracellular glucose leads to increased glucose consumption and increased RUNX2 protein levels, promoting production of MMP13 and ADAMTS5 by OA chondrocytes in oxygenated but not hypoxic conditions. These findings suggest that hyperglycaemia may exacerbate chondrocyte-mediated cartilage catabolism in the oxygenated superficial zone of cartilage in vivo in patients with undertreated type 2 diabetes, contributing to increased OA severity.

Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial.

BACKGROUND: Anterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability. METHODS: We did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score-4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367. FINDINGS: Between Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5-13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications. INTERPRETATION: Surgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management. FUNDING: The UK National Institute for Health Research Health Technology Assessment Programme.

The evolution of robotic systems for total knee arthroplasty, each system must be assessed for its own value: a systematic review of clinical evidence and meta-analysis.

INTRODUCTION: Robotic systems have been introduced to improve the precision of total knee arthroplasty. However, different robotic systems are available, each with unique features used to plan and execute the surgery. As such, due to this diversity, the clinical evaluation of each robotic platform should be separated. METHODS: An extensive literature search of PubMed, Medline, Embase and Web of Science was conducted with subsequent meta-analysis. Randomised controlled trials, comparative studies, and cohort studies were included regarding robot-assisted total knee arthroplasty. Evaluated outcomes included clinical results, surgical precision, ligament balance, surgical time, learning curve, complications and revision rates. These were split up based on the robot-specific brand: ROBODOC (T-SOLUTION ONE), OMNIBOT, MAKO, NAVIO (CORI) and ROSA. RESULTS: With a follow-up of more than 10 years, no improved clinical outcomes have been noted with the ROBODOC system compared to the conventional technique. If available, other platforms only present short-term clinical outcomes. Radiological outcomes are published for most robotic setups, demonstrating improved surgical precision compared to the conventional technique. Gap balance assessment is performed differently between all systems, leading to heterogeneous outcomes regarding its relationship on clinical outcomes. There is a similar learning curve based on operative time for all robotic platforms. In most studies, robot assistance requires longer operative time compared to the conventional technique. Complications and revision rates are published for ROBODOC and MAKO, without clear differences to conventional total knee arthroplasty. CONCLUSION: The main finding of this systematic review is that the current evidence regarding each robotic system is diverse in quantity and quality. Each system has its own specificities and must be assessed for its own value. Regarding scientific literature, the generic term of robotic should be banned from the general conclusion. LEVEL OF EVIDENCE: Systematic review level IV.

Calcitriol-mediated hypercalcemia as an immune-related adverse event in a patient receiving nivolumab and ipilimumab for metastatic renal cell carcinoma, case report.

BACKGROUND: Severe hypercalcemia is often associated with uncontrolled malignancy through several mechanisms. However, calcitriol-mediated hypercalcemia is a rare etiology for advanced solid tumors. CASE PRESENTATION: We report a case of calcitriol-mediated hypercalcemia secondary to immune checkpoint inhibition in a responder with metastatic clear cell renal cell carcinoma (ccRCC). In this case, a 68 year old male with metastatic ccRCC to the liver within 4 months of right radical nephrectomy went on to develop hypercalcemia (12.8 mg/dL) shortly following 2 cycles of nivolumab and ipilimumab. Additional testing showed an elevated calcitriol level (142 pg/mL), low parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) levels, and a normal 25-hydroxyvitamin D level. FDG-PET imaging showed hypermetabolic mediastinal, hilar, and intra-abdominal lymphadenopathy, however the subsequent lymph node biopsy only showed reactive lymphoid cells without malignancy or granuloma. The hypercalcemia was resistant to initial therapy with calcitonin, hydration, and zoledronic acid but quickly responded to high-dose prednisone (1 mg/kg), followed by normalization of calcitriol levels. The patient was rechallenged with nivolumab and ipilimumab which provided a partial response after 4 cycles. He was maintained on low dose prednisone (10 mg daily) leading to a sustained resolution of his hypercalcemia. CONCLUSION: This case suggests calcitriol-mediated hypercalcemia as a novel immune-related adverse event.

Prognostic Value of DNA Damage Response Genomic Alterations in Relapsed/Advanced Urothelial Cancer.

BACKGROUND: DNA damage response (DDR) genomic alterations may play an important role in clinical outcomes of patients with urothelial cancer (UC). However, data on the prognostic role of DDR gene alterations in patients with advanced UC remain unclear. MATERIALS AND METHODS: We retrospectively collected data of three independent patient cohorts with relapsed or advanced UC including 81 and 91 patients from four institutions who underwent FoundationOne genomic sequencing as well as 129 patients selected from The Cancer Genome Atlas bladder cohort. Fisher's exact test was used to determine differences of mutation frequency among the three cohorts. Logistic regression analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI). Overall survival (OS) was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% CI. RESULTS: DDR genomic alterations were present in 76.5% (62/81), 40.7% (37/91), and 51.2% (66/129) of the three cohorts. ATM alterations consistently correlated with significantly shorter OS, whereas other DDR alterations (excluding ATM) were associated with better prognosis. In 152 patients treated with platinum pooled from the three cohorts, the prognostic value of alterations in ATM as compared with other predefined DDR genes was substantially different (ATM: adjusted HR [HR], 2.03; 95% CI, 1.03-4; p = .04; other DDR: adjusted HR, 0.49; 95% CI, 0.31-0.8; p = .003). CONCLUSIONS: Genomic alterations in ATM and other DDR genes may have opposite prognostic value in relapsed and/or advanced UC. ATM may have a complex role in UC progression. IMPLICATIONS FOR PRACTICE: Somatic mutations of DNA damage response (DDR) genes are frequently found in urothelial cancer and appear to play an important role in tumorigenesis, progression, treatment response, and outcomes. In a set of DDR genes, ATM alterations were associated with worse survival, while other alterations were associated with better survival in advanced urothelial cancer. The results of this study suggest a complex role of ATM in tumor progression and call for further studies to determine the underlying mechanisms and biomarker clinical utility.

The use of accelerometer-based navigation for coronal TKA alignment: a prospective, single surgeon comparative study.

INTRODUCTION: There is the need for a device that can be used to accurately position components during total knee arthroplasty (TKA) with minimal impact on procedure time, workflow and cost. This study aimed to investigate the accuracy and time efficiency of a novel, accelerometer-based navigation system (ABN). METHODS: This prospective, single surgeon study of patients undergoing TKA for osteoarthritis over a 5 year period involved a total of 138 patients: 110 using the ABN system and 28 without. The ABN system consists of two coupled inertial pods that are secured to resection guides, providing a body-fixed 3D coordinate system for limb segments. Post-operative coronal alignment was measured from standardised long-leg AP radiographs. Deviation of the femur and tibia from the neutral coronal mechanical axis was recorded. Intra-observer repeatability was performed on three independent blinded data sets. The BMI and the surgical time (skin to skin) were recorded for all patients. RESULTS: The mean BMI was 34 in the ABN group and 33 in the control group (p = 0.92). The skin-to-skin time was also similar between the groups; 105 min in the navigation group and 100 min in the control group (p = 0.297). The use of navigation resulted in significantly fewer outliers as defined by < 3º deviation from the target angle. 3 of 110 navigated patients recorded an AP femur angle of more than 3º from the target of 90º, where 5 of 28 control patients fell outside of the ± 3º window (p = 0.009, Fig. 1). CONCLUSION: The use of the ABN system significantly improved accuracy of implant position and alignment without increasing surgical time.

Testicular Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Testicular cancer is relatively uncommon and accounts for <1% of all male tumors. However, it is the most common solid tumor in men between the ages of 20 and 34 years, and the global incidence has been steadily rising over the past several decades. Several risk factors for testicular cancer have been identified, including personal or family history of testicular cancer and cryptorchidism. Testicular germ cell tumors (GCTs) comprise 95% of malignant tumors arising in the testes and are categorized into 2 main histologic subtypes: seminoma and nonseminoma. Although nonseminoma is the more clinically aggressive tumor subtype, 5-year survival rates exceed 70% with current treatment options, even in patients with advanced or metastatic disease. Radical inguinal orchiectomy is the primary treatment for most patients with testicular GCTs. Postorchiectomy management is dictated by stage, histology, and risk classification; treatment options for nonseminoma include surveillance, systemic therapy, and nerve-sparing retroperitoneal lymph node dissection. Although rarely occurring, prognosis for patients with brain metastases remains poor, with >50% of patients dying within 1 year of diagnosis. This selection from the NCCN Guidelines for Testicular Cancer focuses on recommendations for the management of adult patients with nonseminomatous GCTs.

Phase II randomized, double-blind, placebo-controlled study of tivantinib in men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).

Background Tivantinib is a non-ATP competitive inhibitor of c-MET receptor tyrosine kinase that may have additional cytotoxic mechanisms including tubulin inhibition. Prostate cancer demonstrates higher c-MET expression as the disease progresses to more advanced stages and to a castration resistant state. Methods 80 patients (pts) with asymptomatic or minimally symptomatic mCRPC were assigned (2:1) to either tivantinib 360 mg PO BID or placebo (P). The primary endpoint was progression free survival (PFS). Results Of the 80 pts. enrolled, 78 (52 tivantinib, 26 P) received treatment and were evaluable. Median follow up is 8.9 months (range: 2.3 to 19.6 months). Patients treated with tivantinib had significantly better PFS vs. those treated with placebo (medians: 5.5 mo vs 3.7 mo, respectively; HR = 0.55, 95% CI: 0.33 to 0.90; p = 0.02). Grade 3 febrile neutropenia was seen in 1 patient on tivantinib while grade 3 and 4 neutropenia was recorded in 1 patient each on tivantinib and placebo. Grade 3 sinus bradycardia was recorded in two men on the tivantinib arm. Conclusions Tivantinib has mild toxicity and improved PFS in men with asymptomatic or minimally symptomatic mCRPC.

Medial opening wedge high tibial osteotomy for the treatment of medial unicompartmental knee osteoarthritis: A state-of-the-art review.

Medial unicompartmental knee osteoarthritis is a common condition that is frequently associated with significant pain and dysfunction. Medial opening wedge high tibial osteotomy (MOWHTO) offers a unique opportunity to preserve the knee joint and potentially alter the course of the degenerative process. Recent advances in this field of surgery have enabled surgeons to perform a MOWHTO in a safe, reliable and reproducible manner. This state-of-the-art review highlights the most important advances in the field of MOWHTO. Key concepts related to patient selection, pre-operative planning, surgical accuracy and patient outcome are considered. The importance of an individualized approach is emphasized and its influence on the future direction of the procedure is discussed.

Phase I Study of ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Progressing on Enzalutamide.

PURPOSE: Increased glucocorticoid receptor (GR) signaling is a proposed compensatory mechanism of resistance to androgen receptor (AR) inhibition in metastatic castration-resistant prostate cancer (mCRPC). ORIC-101 is a potent and selective orally-bioavailable GR antagonist. PATIENTS AND METHODS: Safety, pharmacokinetic/pharmacodynamic, and antitumor activity of ORIC-101 in combination with enzalutamide were studied in patients with mCRPC progressing on enzalutamide. ORIC-101 doses ranging from 80 to 240 mg once daily were tested in combination with enzalutamide 160 mg once daily. Pharmacokinetics/pharmacodynamics was assessed after a single dose and at steady state. Disease control rate (DCR) at 12 weeks was evaluated at the recommended phase 2 dose (RP2D). RESULTS: A total of 41 patients were enrolled. There were no dose-limiting toxicities and the RP2D was selected as 240 mg of ORIC-101 and 160 mg of enzalutamide daily. At the RP2D, the most common treatment-related adverse events were fatigue (38.7%), nausea (29.0%), decreased appetite (19.4%), and constipation (12.9%). Pharmacokinetic/pharmacodynamic data confirmed ORIC-101 achieved exposures necessary for GR target engagement. Overall, for 31 patients treated at the RP2D, there was insufficient clinical benefit based on DCR (25.8%; 80% confidence interval: 15.65-38.52) which did not meet the prespecified target rate, leading to termination of the study. Exploratory subgroup analyses based on baseline GR expression, presence of AR resistance variants, and molecular features of aggressive variant prostate cancer suggested possible benefit in patients with high GR expression and no other resistance markers, although this would require confirmation. CONCLUSIONS: Although the combination of ORIC-101 and enzalutamide demonstrated an acceptable tolerability profile, GR target inhibition with ORIC-101 did not produce clinical benefit in men with metastatic prostate cancer resistant to enzalutamide.

Comparison of surgical or non-surgical management for non-acute anterior cruciate ligament injury: the ACL SNNAP RCT.

Background: Anterior cruciate ligament injury of the knee is common and leads to decreased activity and risk of secondary osteoarthritis of the knee. Management of patients with a non-acute anterior cruciate ligament injury can be non-surgical (rehabilitation) or surgical (reconstruction). However, insufficient evidence exists to guide treatment. Objective(s): To determine in patients with non-acute anterior cruciate ligament injury and symptoms of instability whether a strategy of surgical management (reconstruction) without prior rehabilitation was more clinically and cost-effective than non-surgical management (rehabilitation). Design: A pragmatic, multicentre, superiority, randomised controlled trial with two-arm parallel groups and 1:1 allocation. Due to the nature of the interventions, no blinding could be carried out. Setting: Twenty-nine NHS orthopaedic units in the United Kingdom. Participants: Participants with a symptomatic (instability) non-acute anterior cruciate ligament-injured knee. Interventions: Patients in the surgical management arm underwent surgical anterior cruciate ligament reconstruction as soon as possible and without any further rehabilitation. Patients in the rehabilitation arm attended physiotherapy sessions and only were listed for reconstructive surgery on continued instability following rehabilitation. Surgery following initial rehabilitation was an expected outcome for many patients and within protocol. Main outcome measures: The primary outcome was the Knee Injury and Osteoarthritis Outcome Score 4 at 18 months post randomisation. Secondary outcomes included return to sport/activity, intervention-related complications, patient satisfaction, expectations of activity, generic health quality of life, knee-specific quality of life and resource usage. Results: Three hundred and sixteen participants were recruited between February 2017 and April 2020 with 156 randomised to surgical management and 160 to rehabilitation. Forty-one per cent (n = 65) of those allocated to rehabilitation underwent subsequent reconstruction within 18 months with 38% (n = 61) completing rehabilitation and not undergoing surgery. Seventy-two per cent (n = 113) of those allocated to surgery underwent reconstruction within 18 months. Follow-up at the primary outcome time point was 78% (n = 248; surgical, n = 128; rehabilitation, n = 120). Both groups improved over time. Adjusted mean Knee Injury and Osteoarthritis Outcome Score 4 scores at 18 months had increased to 73.0 in the surgical arm and to 64.6 in the rehabilitation arm. The adjusted mean difference was 7.9 (95% confidence interval 2.5 to 13.2; p = 0.005) in favour of surgical management. The per-protocol analyses supported the intention-to-treat results, with all treatment effects favouring surgical management at a level reaching statistical significance. There was a significant difference in Tegner Activity Score at 18 months. Sixty-eight per cent (n = 65) of surgery patients did not reach their expected activity level compared to 73% (n = 63) in the rehabilitation arm. There were no differences between groups in surgical complications (n = 1 surgery, n = 2 rehab) or clinical events (n = 11 surgery, n = 12 rehab). Of surgery patients, 82.9% were satisfied compared to 68.1% of rehabilitation patients. Health economic analysis found that surgical management led to improved health-related quality of life compared to non-surgical management (0.052 quality-adjusted life-years, p = 0.177), but with higher NHS healthcare costs (£1107, p < 0.001). The incremental cost-effectiveness ratio for the surgical management programme versus rehabilitation was £19,346 per quality-adjusted life-year gained. Using £20,000-30,000 per quality-adjusted life-year thresholds, surgical management is cost-effective in the UK setting with a probability of being the most cost-effective option at 51% and 72%, respectively. Limitations: Not all surgical patients underwent reconstruction, but this did not affect trial interpretation. The adherence to physiotherapy was patchy, but the trial was designed as pragmatic. Conclusions: Surgical management (reconstruction) for non-acute anterior cruciate ligament-injured patients was superior to non-surgical management (rehabilitation). Although physiotherapy can still provide benefit, later-presenting non-acute anterior cruciate ligament-injured patients benefit more from surgical reconstruction without delaying for a prior period of rehabilitation. Future work: Confirmatory studies and those to explore the influence of fidelity and compliance will be useful. Trial registration: This trial is registered as Current Controlled Trials ISRCTN10110685; ClinicalTrials.gov Identifier: NCT02980367. Funding: This award was funded by the National Institute of Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/140/63) and is published in full in Health Technology Assessment; Vol. 28, No. 27. See the NIHR Funding and Awards website for further award information.

The study aimed to find out whether it is better to offer surgical reconstruction or rehabilitation first to patients with a more long-standing injury of their anterior cruciate ligament in their knee. This injury causes physical giving way of the knee and/or sensations of it being wobbly (instability). The instability can affect daily activities, work, sport and can lead to arthritis. There are two main treatment options for this problem: non-surgical rehabilitation (prescribed exercises and advice from physiotherapists) or an operation by a surgeon to replace the damaged ligament (anterior cruciate ligament reconstruction). Although studies have highlighted the best option for a recently injured knee, the best management was not known for patients with a long-standing injury, perhaps occurring several months previously. Because the surgery is expensive to the NHS (around £100 million per year), it was also important to look at the costs involved. We carried out a study recruiting 316 non-acute anterior cruciate ligament-injured patients from 29 different hospitals and allocated each patient to either surgery or rehabilitation as their treatment option. We measured how well they did with special function and activity scores, patient satisfaction and costs of treatment. Patients in both groups improved substantially. It was expected that some patients in the rehabilitation group would want surgery if non-surgical management was unsuccessful. Forty-one per cent of patients who initially underwent rehabilitation subsequently elected to have reconstructive surgery. Overall, the patients allocated to the surgical reconstruction group had better results in terms of knee function and stability, activity level and satisfaction with treatment than patients allocated to the non-operative rehabilitation group. There were few problems or complications with either treatment option. Although the surgery was a more expensive treatment option, it was found to be cost-effective in the UK setting. The evidence can be discussed in shared decision-making with anterior cruciate ligament-injured patients. Both strategies of management led to improvement. Although a rehabilitation strategy can be beneficial, especially for recently injured patients, it is advised that later-presenting non-acute and more long-standing anterior cruciate ligament-injured patients undergo surgical reconstruction without necessarily delaying for a period of rehabilitation.

A phase I dose escalation and pharmacodynamic study of SU5416 (semaxanib) combined with weekly cisplatin and irinotecan in patients with advanced solid tumors.

BACKGROUND: This phase I study evaluated the safety of SU5416, a potent and selective inhibitor of the vascular endothelial growth factor (VEGF) receptor tyrosine kinase Flk-1, in combination with weekly cisplatin and irinotecan in patients with advanced solid tumors. METHODS: The patients received cisplatin 30 mg/m² and irinotecan 50 mg/m² weekly from week 1 to week 4, with SU5416 at either 65 mg/m² (dose level (DL)1) or 85 mg/m² (DL2) twice weekly for 6 weeks (1 cycle). Serial ¹8fluorodeoxyglucose-positron emission tomography (¹8FDG-PET) and ¹5O-H2O-PET scans were obtained. RESULTS: 13 patients were treated (7 on DL1, 6 on DL2); 7 patients completed at least 1 cycle of treatment. 3 patients experienced dose-limiting toxicity (DLT) at DL2 (grade 3 neutropenia and grade 3 thrombocytopenia causing treatment delay, grade 3 nausea/vomiting). No objective responses were observed at DL1, which was determined to be the maximum tolerated dose (MTD). 1 partial response (PR) was observed at DL2. ¹8FDG-PET responses were documented but did not predict response according to the Response Evaluation Criteria in Solid Tumors (RECIST). CONCLUSIONS: SU5416 at 65 mg/m² twice weekly combined with cisplatin and irinotecan weekly for 4 of 6 weeks is well tolerated but without evidence of clinical activity. ¹8FDG-PET may be a useful pharmacodynamic marker of SU5416 bioactivity but requires additional development.

Emerging Immunotherapy Approaches for Advanced Clear Cell Renal Cell Carcinoma.

The most common subtype of renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). While localized ccRCC can be cured with surgery, metastatic disease has a poor prognosis. Recently, immunotherapy has emerged as a promising approach for advanced ccRCC. This review provides a comprehensive overview of the evolving immunotherapeutic landscape for metastatic ccRCC. Immune checkpoint inhibitors (ICIs) like PD-1/PD-L1 and CTLA-4 inhibitors have demonstrated clinical efficacy as monotherapies and in combination regimens. Combination immunotherapies pairing ICIs with antiangiogenic agents, other immunomodulators, or novel therapeutic platforms such as bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapy are areas of active research. Beyond the checkpoint blockade, additional modalities including therapeutic vaccines, cytokines, and oncolytic viruses are also being explored for ccRCC. This review discusses the mechanisms, major clinical trials, challenges, and future directions for these emerging immunotherapies. While current strategies have shown promise in improving patient outcomes, continued research is critical for expanding and optimizing immunotherapy approaches for advanced ccRCC. Realizing the full potential of immunotherapy will require elucidating mechanisms of response and resistance, developing predictive biomarkers, and rationally designing combination therapeutic regimens tailored to individual patients. Advances in immunotherapy carry immense promise for transforming the management of metastatic ccRCC.

Randomized Trial of Olaparib With or Without Cediranib for Metastatic Castration-Resistant Prostate Cancer: The Results From National Cancer Institute 9984.

PURPOSE: Cediranib, a pan-vascular endothelial growth factor receptor inhibitor, suppresses expression of homologous recombination repair (HRR) genes and increases sensitivity to poly-(ADP-ribose) polymerase inhibition in preclinical models. We investigated whether cediranib combined with olaparib improves the clinical outcomes of patients with prostate cancer. METHODS: Patients with progressive metastatic castration-resistant prostate cancer (mCRPC) were randomly assigned 1:1 to arm A: cediranib 30 mg once daily plus olaparib 200 mg twice daily or arm B: olaparib 300 mg twice daily alone. The primary end point was radiographic progression-free survival (rPFS) in the intention-to-treat patients. The secondary end points were rPFS in patients with HRR-deficient and HRR-proficient mCRPC. RESULTS: In the intention-to-treat set of 90 patients, median rPFS was 8.5 (95% CI, 5.4 to 12.0) and 4.0 (95% CI, 3.2 to 8.5) months in arms A and B, respectively. Cediranib/olaparib significantly improved rPFS versus olaparib alone (hazard ratio [HR], 0.617; 95% CI, 0.392 to 0.969; P = .0359). Descriptive analyses showed a median rPFS of 10.6 (95% CI, 5.9 to not assessed [NA]) and 3.8 (95% CI, 2.33 to NA) months (HR, 0.64; 95% CI, 0.272 to 1.504) among patients with HRR-deficient mCRPC, and 13.8 (95% CI, 3.3 to NA) and 11.3 (95% CI, 3.8 to NA) months (HR, 0.98; 95% CI, 0.321 to 2.988) among patients with BRCA2-mutated mCRPC in arms A and B, respectively. The incidence of grades 3-4 adverse events was 61% and 18% in arms A and B, respectively. CONCLUSION: Cediranib combined with olaparib improved rPFS compared with olaparib alone in men with mCRPC. This combination was associated with an increased incidence of grades 3-4 adverse events. BRCA2-mutated subgroups treated with olaparib with or without cediranib were associated with a numerically longer median rPFS.

A multicenter study assessing survival in patients with metastatic renal cell carcinoma receiving immune checkpoint inhibitor therapy with and without cytoreductive nephrectomy.

BACKGROUND: Cytoreductive nephrectomy (CN) for the treatment of metastatic renal cell carcinoma (mRCC) was called into question following the publication of the CARMENA trial. While previous retrospective studies have supported CN alongside targeted therapies, there is minimal research establishing its role in conjunction with immune checkpoint inhibitor (ICI) therapy. OBJECTIVE: To evaluate the association between CN and oncological outcomes in patients with mRCC treated with immunotherapy. MATERIALS AND METHODS: A multicenter retrospective cohort study of patients diagnosed with mRCC between 2000 and 2020 who were treated at the Seattle Cancer Care Alliance and The Ohio State University and who were treated with ICI systemic therapy (ST) at any point in their disease course. Overall survival (OS) was estimated using Kaplan Meier analyses. Multivariable Cox proportional hazards models evaluated associations with mortality. RESULTS: The study cohort consisted of 367 patients (CN+ST n = 232, ST alone n = 135). Among patients undergoing CN, 30 were deferred. Median survivor follow-up was 28.4 months. ICI therapy was first-line in 28.1%, second-line in 17.4%, and third or subsequent line (3L+) in 54.5% of patients. Overall, patients who underwent CN+ST had longer median OS (56.3 months IQR 50.2-79.8) compared to the ST alone group (19.1 months IQR 12.8-23.8). Multivariable analyses demonstrated a 67% reduction in risk of all-cause mortality in patients who received CN+ST vs. ST alone (P < 0.0001). Similar results were noted when first-line ICI therapy recipients were examined as a subgroup. Upfront and deferred CN did not demonstrate significant differences in OS. CONCLUSIONS: CN was independently associated with longer OS in patients with mRCC treated with ICI in any line of therapy. Our data support consideration of CN in well selected patients with mRCC undergoing treatment with ICI.

Radiotherapy in Oligometastatic, Oligorecurrent and Oligoprogressive Prostate Cancer: A Mini-Review.

Globally, prostate cancer is one of the most common malignancies affecting men. With the advent of advanced molecular imaging, an increasing number of men are found to have oligometastatic disease (OD) either at primary diagnosis or at the time of biochemical failure. No strict definition exists for OD, with historical and ongoing studies utilizing diverse criteria. There is mounting evidence from many different malignancies that patients with OD have improved outcomes compared to their widely metastatic counterparts. As such, treatment intensification of those with OD or oligoprogressive disease has become an area of intense interest and study. This article will review the biology, evidence and controversy behind the treatment of de novo oligometastatic, oligorecurrent and oligoprogressive prostate cancer.

Clinical Efficacy of Enzalutamide vs Bicalutamide Combined With Androgen Deprivation Therapy in Men With Metastatic Hormone-Sensitive Prostate Cancer: A Randomized Clinical Trial.

Importance: Black patients have been underrepresented in prospective clinical trials of advanced prostate cancer. This study evaluated the efficacy of enzalutamide compared with bicalutamide, with planned subset analysis of Black patients with metastatic hormone-sensitive prostate cancer (mHSPC), which is a disease state responsive to androgen deprivation therapy (ADT). Objective: To compare the efficacy of enzalutamide vs bicalutamide in combination with ADT in men with mHSPC, with a subset analysis of Black patients. Design, Setting, and Participants: In this randomized clinical trial, a phase 2 screening design enabled a nondefinitive comparison of the primary outcome by treatment. Patients were stratified by race (Black or other) and bone pain (present or absent). Accrual of at least 30% Black patients was required. This multicenter trial was conducted at 4 centers in the US. Men with mHSPC with no history of seizures and adequate marrow, renal, and liver function were eligible. Data analysis was performed from February 2019 to March 2020. Interventions: Participants were randomized 1:1 to receive oral enzalutamide (160 mg daily) or bicalutamide (50 mg daily) in addition to ADT. Main Outcomes and Measures: The primary end point was the 7-month prostate-specific antigen (PSA) response (SMPR) rate, a previously accepted surrogate for overall survival (OS) outcome. Secondary end points included adverse reactions, time to PSA progression, and OS. Results: A total of 71 men (median [range] age, 65 [51-86] years) were enrolled; 29 (41%) were Black, 41 (58%) were White, and 1 (1%) was Asian. Thirty-six patients were randomized to receive enzalutamide, and 35 were randomized to receive bicalutamide. Twenty-six patients (37%) had bone pain and 37 patients (52%) had extensive disease. SMPR was achieved in 30 of 32 patients (94%; 95% CI, 80%-98%) taking enzalutamide and 17 of 26 patients (65%; 95% CI, 46%-81%) taking bicalutamide (P = .008) (difference, 29%; 95% CI, 5%-50%). Among Black patients, the SMPR was 93% (95% CI, 69%-99%) among those taking enzalutamide and 42% (95% CI, 19%-68%) among those taking bicalutamide (P = .009); among non-Black patients, the SMPR was 94% (95% CI, 74%-99%) among those taking enzalutamide and 86% (95% CI, 60%-96%) among those taking bicalutamide. The 12-month PSA response rates were 84% with enzalutamide and 34% with bicalutamide. Conclusions and Relevance: The findings of this randomized clinical trial comparing enzalutamide with bicalutamide suggest that enzalutamide is associated with improved outcomes compared with bicalutamide, in terms of the rate and duration of PSA response, in Black patients with mHSPC. Trial Registration: ClinicalTrials.gov Identifier: NCT02058706.

Risk Factors for Emergency Room and Hospital Care Among Patients With Solid Tumors on Immune Checkpoint Inhibitor Therapy.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) are being increasingly used across cancer types. Emergency room (ER) and inpatient (IP) care, common in patients with cancer, remain poorly defined in this specific population, and risk factors for such care are unknown. METHODS: We retrospectively reviewed charts for patients with solid tumors who received >1 ICI dose at 1 of 2 sites from January 1, 2011 to April 28, 2017. Demographics, medical history, cancer diagnosis/therapy/toxicity details, and outcomes were recorded. Descriptive data detailing ER/IP care at the 2 associated hospitals during ICI therapy (from first dose to 3 mo after last dose) were collected. The Fisher exact test and multivariate regression analysis was used to study differences between patients with versus without ER/IP care during ICI treatment. RESULTS: Among 345 patients studied, 50% had at least 1 ER visit during ICI treatment and 43% had at least 1 IP admission. Six percent of ER/IP visits eventually required intensive care. A total of 12% of ER/IP visits were associated with suspected or confirmed immune-related adverse events. Predictors of ER care were African-American race (odds ratio [OR]: 3.83, P=0.001), Hispanic ethnicity (OR: 3.12, P=0.007), and coronary artery disease (OR: 2.43, P=0.006). Predictors of IP care were African-American race (OR: 2.38, P=0.024), Hispanic ethnicity (OR: 2.29, P=0.045), chronic kidney disease (OR: 3.89, P=0.006), angiotensin converting enzyme inhibitor/angiotensin receptor blocker medication use (OR: 0.44, P=0.009), and liver metastasis (OR: 2.32, P=0.003). CONCLUSIONS: Understanding demographic and clinical risk factors for ER/IP care among patients on ICIs can help highlight disparities, prospectively identify high-risk patients, and inform preventive programs aimed at reducing such care.

A phase 1 trial of the histone deacetylase inhibitor AR-42 in patients with neurofibromatosis type 2-associated tumors and advanced solid malignancies.

PURPOSE: Given clinical activity of AR-42, an oral histone deacetylase inhibitor, in hematologic malignancies and preclinical activity in solid tumors, this phase 1 trial investigated the safety and tolerability of AR-42 in patients with advanced solid tumors, including neurofibromatosis type 2-associated meningiomas and schwannomas (NF2). The primary objective was to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary objectives included determining pharmacokinetics and clinical activity. METHODS: This phase I trial was an open-label, single-center, dose-escalation study of single-agent AR-42 in primary central nervous system and advanced solid tumors. The study followed a 3 + 3 design with an expansion cohort at the MTD. RESULTS: Seventeen patients were enrolled with NF2 (n = 5), urothelial carcinoma (n = 3), breast cancer (n = 2), non-NF2-related meningioma (n = 2), carcinoma of unknown primary (n = 2), small cell lung cancer (n = 1), Sertoli cell carcinoma (n = 1), and uveal melanoma (n = 1). The recommended phase II dose is 60 mg three times weekly, for 3 weeks of a 28-day cycle. DLTs included grade 3 thrombocytopenia and grade 4 psychosis. The most common treatment-related adverse events were cytopenias, fatigue, and nausea. The best response was stable disease in 53% of patients (95% CI 26.6-78.7). Median progression-free survival (PFS) was 3.6 months (95% CI 1.2-9.1). Among evaluable patients with NF2 or meningioma (n = 5), median PFS was 9.1 months (95% CI 1.9-not reached). CONCLUSION: Single-agent AR-42 is safe and well tolerated. Further studies may consider AR-42 in a larger cohort of patients with NF2 or in combination with other agents in advanced solid tumors. TRIAL REGISTRATION: NCT01129193, registered 5/24/2010.

IL-7 expands lymphocyte populations and enhances immune responses to sipuleucel-T in patients with metastatic castration-resistant prostate cancer (mCRPC).

BACKGROUND: Sipuleucel-T (sip-T) is a Food and Drug Administration (FDA)-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). We hypothesized that combining sip-T with interleukin (IL)-7, a homeostatic cytokine that enhances both B and T cell development and proliferation, would augment and prolong antigen-specific immune responses against both PA2024 (the immunogen for sip-T) and prostatic acid phosphatase (PAP). METHODS: Fifty-four patients with mCRPC treated with sip-T were subsequently enrolled and randomized 1:1 into observation (n=26) or IL-7 (n=28) arms of a phase II clinical trial (NCT01881867). Recombinant human (rh) IL-7 (CYT107) was given weekly×4. Immune responses were evaluated using flow cytometry, mass cytometry (CyTOF), interferon (IFN)-γ ELISpot, 3H-thymidine incorporation, and ELISA. RESULTS: Treatment with rhIL-7 was well tolerated. For the rhIL-7-treated, but not observation group, statistically significant lymphocyte subset expansion was found, with 2.3-2.6-fold increases in CD4+T, CD8+T, and CD56bright NK cells at week 6 compared with baseline. No significant differences in PA2024 or PAP-specific T cell responses measured by IFN-γ ELISpot assay were found between rhIL-7 and observation groups. However, antigen-specific T cell proliferative responses and humoral IgG and IgG/IgM responses significantly increased over time in the rhIL-7-treated group only. CyTOF analyses revealed pleiotropic effects of rhIL-7 on lymphocyte subsets, including increases in CD137 and intracellular IL-2 and IFN-γ expression. While not powered to detect clinical outcomes, we found that 31% of patients in the rhIL-7 group had prostate specific antigen (PSA) doubling times of >6 months, compared with 14% in the observation group. CONCLUSIONS: Treatment with rhIL-7 led to a significant expansion of CD4+ and CD8+ T cells, and CD56bright natural killer (NK) cells compared with observation after treatment with sip-T. The rhIL-7 treatment also led to improved antigen-specific humoral and T cell proliferative responses over time as well as to increased expression of activation markers and beneficial cytokines. This is the first study to evaluate the use of rhIL-7 after sip-T in patients with mCRPC and demonstrates encouraging results for combination approaches to augment beneficial immune responses.