Is serum C-terminal telopeptide cross-link of type 1 collagen a reliable parameter for predicting the risk of medication-related osteonecrosis of the jaws? A systematic review and meta-analysis of diagnostic test accuracy

Clinical Oral Investigations - To determine the usefulness of Serum C-terminal telopeptide cross-link of type 1 collagen (sCTX) as a preoperative marker for predicting the risk of developing...     

Immune-Related Adverse Events as Clinical Biomarkers in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors

Background

Immune checkpoint inhibitors (ICIs) are an important treatment for metastatic renal cell carcinoma (mRCC). These agents may cause immune-related adverse events (irAEs), and the relationship between irAEs and outcomes is poorly understood. We investigated the association between irAEs and clinical outcomes in patients with mRCC treated with ICIs.

Methods

We performed a retrospective study of 200 patients with mRCC treated with ICIs at Winship Cancer Institute from 2015 to 2020. Data on irAEs were collected from clinic notes and laboratory values and grades were determined using Common Terminology Criteria in Adverse Events version 5.0. The association with overall survival (OS) and progression-free survival (PFS) was modeled by Cox proportional hazards model. Logistic regression models were used to define odds ratios (ORs) for clinical benefit (CB). Landmark analysis and extended Cox models were used to mitigate lead-time bias by treating irAEs as a time-varying covariate.

Results

Most patients (71.0%) were male, and one-third of patients (33.0%) experienced at least one irAE, most commonly involving the endocrine glands (13.0%), gastrointestinal tract (10.5%), or skin (10.0%). Patients who experienced irAEs had significantly longer OS (hazard ratio [HR], 0.52; p = .013), higher chance of CB (OR, 2.10; p = .023) and showed a trend toward longer PFS (HR, 0.71; p = .065) in multivariate analysis. Patients who had endocrine irAEs, particularly thyroid irAEs, had significantly longer OS and PFS and higher chance of CB. In a 14-week landmark analysis, irAEs were significantly associated with prolonged OS (p = .045). Patients who experienced irAEs had significantly longer median OS (44.5 vs. 18.2 months, p = .005) and PFS (7.5 vs. 3.6 months, p = .003) without landmark compared with patients who did not.

Conclusion

We found that patients with mRCC treated with ICIs who experienced irAEs, particularly thyroid irAEs, had significantly improved clinical outcomes compared with patients who did not have irAEs. This suggests that irAEs may be effective clinical biomarkers in patients with mRCC treated with ICIs. Future prospective studies are warranted to validate these findings.

Implications for Practice

This study found that early onset immune-related adverse events (irAEs) are associated with significantly improved clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICIs). In this site-specific irAE analysis, endocrine irAEs, particularly thyroid irAEs, were significantly associated with improved clinical outcomes. These results have implications for practicing medical oncologists given the increasing use of ICIs for the treatment of mRCC. Importantly, these results suggest that early irAEs and thyroid irAEs at any time on treatment with ICIs may be clinical biomarkers of clinical outcomes in patients with mRCC treated with ICIs.

     

Effect of body mass index on the outcomes of patients with upper and lower urinary tract cancers treated by radical surgery: Results from a Canadian multicenter collaboration

ObjectiveTo evaluate the effect of body mass index (BMI) on the outcomes of patients with urinary tract carcinoma treated with radical surgery.Materials and methodsData were collected from 10 Canadian centers on patients who underwent radical cystectomy (RC) (1998–2008) or radical nephroureterectomy (RNU) (1990–2010). Various parameters among subsets of patients (BMI<25, 25≤BMI<30, and BMI≥30 kg/m²) were analyzed. Kaplan-Meier and multivariate analyses were performed to assess the effect of BMI on overall survival, disease-specific survival, and recurrence-free survival (RFS).ResultsAmong the 847 RC and 664 RNU patients, there was no difference in histology, stage, grade, and margin status among the 3 patient subsets undergoing either surgery. However, RC patients with lower BMIs (<25 kg/m²) were significantly older (P = 0.004), had more nodal metastasis (P = 0.03), and trended toward higher stage (P = 0.052). RNU patients with lower BMIs (<25 kg/m²) were significantly older (P = 0.0004) and fewer received adjuvant chemotherapy (P = 0.04) compared with those with BMI≥30 kg/m²; however, there was no difference in tumor location (P = 0.20), stage (P = 0.48), and management of distal ureter among the groups (P = 0.30). On multivariate analysis, BMI was not prognostic for overall survival, disease-specific survival, and RFS in the RC group. However, BMI≥30 kg/m² was associated with more bladder cancer recurrences and worse RFS in the RNU group (HR = 1.588; 95% CI: 1.148–2.196; P = 0.0052).ConclusionsIncreased BMI did not influence survival among RC patients. BMI≥30 kg/m² is associated with worse bladder cancer recurrences among RNU patients; whether this is related to difficulty in obtaining adequate bladder cuff in patients with obesity requires further evaluation.     

Resting state functional connectivity of the hippocampus associated with neurocognitive function in left temporal lobe epilepsy

The majority of patients with temporal lobe epilepsy (TLE) experience disturbances of episodic memory from structural damage or dysfunction of the hippocampus. The objective of this study was to use functional Magnetic Resonance Imaging (fMRI) to identify regions where resting state connectivity to the left hippocampus (LH) is correlated with neuropsychological measures of verbal memory retention in TLE patients. Eleven left TLE (LTLE) patients and 15 control subjects participated in resting state fMRI scans. All LTLE patients underwent neuropsychological testing. Resting state functional connectivity maps to the LH were calculated for each patient, and subsequently used in a multiple regression analysis with verbal memory retention scores as a covariate. The analysis identified brain regions whose connectivity to the LH was linearly related to memory retention scores across the group of patients. In LTLE patients, right sided (contralateral) clusters in the precuneus and inferior parietal lobule (IPL) exhibited increased connectivity to the LH with increased memory retention score; left sided (ipsilateral) regions in the precuneus and IPL showed increased connectivity to the LH with decreased retention score. Patients with high memory retention scores had greater connectivity between the LH–right parietal clusters than between the LH–left parietal clusters; in contrast, control subjects had significantly and consistently greater LH–left hemisphere than LH–right hemisphere connectivity. Our results suggest that increased connectivity in contralateral hippocampal functional pathways within the episodic verbal memory network represents a strengthening of alternative pathways in LTLE patients with strong verbal memory retention abilities. Hum Brain Mapp 35:735–744, 2014. © 2012 Wiley Periodicals, Inc.     

Considering Efficacy and Cost,Where Does Ramucirumab Fit in the Management of Metastatic Colorectal Cancer?

Health care institutions, physicians, and patients can—and should—be more involved in evaluating the role of new therapies such as ramucirumab in metastatic colorectal cancer based on their value. This is especially true in the case of a treatment that adds no additional benefit in terms of efficacy or toxicity compared with the current standard of care and has a higher cost.Ramucirumab, a monoclonal antibody against vascular endothelial growth factor receptor 2 (VEGFR2) recently gained approval by the U.S. Food and Drug Administration (FDA) for use in gastric and lung cancer [1–3]. Based on safety and efficacy, it was subsequently approved in April 2015 by the FDA for use in metastatic colorectal cancer.The RAISE trial, a randomized phase III trial, confirmed the benefit from ramucirumab in colorectal cancer after progression on bevacizumab, oxaliplatin, and a fluoropyrimidine [4]. A total of 1,072 patients with metastatic colorectal cancer who had progressed on FOLFOX plus bevacizumab were randomized to receive either FOLFIRI plus ramucirumab or FOLFIRI plus placebo. The trial demonstrated a median overall survival (OS) benefit of 1.6 months (hazard ratio [HR]: 0.84) with the use of ramucirumab.The control arm of the study (FOLFIRI) is not the current standard of care in the U.S. The ML18147 trial previously demonstrated a median OS benefit of 1.4 months (HR: 0.81) when bevacizumab was continued beyond progression in combination with second-line 5-fluorouracil-based chemotherapy [5]. The VELOUR study previously demonstrated a median OS benefit of 1.4 months (HR: 0.82) when ziv-aflibercept was added to second-line FOLFIRI [6]. In addition to the antiangiogenic therapeutic options, patients whose tumors are RAS wild type are also eligible for EGFR-targeted therapy in combination with standard chemotherapy in this setting [7–12].Oncologists now have three options for antiangiogenic agents that can be added to the chemotherapy backbone in patients with colorectal cancer refractory to FOLFOX plus bevacizumab. Although all three agents have not been compared in a head-to-head trial, they appear to have similar efficacy and toxicity profiles in randomized trials. If cost is incorporated into the decision-making process, there are major differences. We have made calculations of the monthly drug cost using a mean U.S. body weight of 82 kg [13]. We used the Medicare average sale price to calculate the monthly costs of each drug [14]. Open in a separate windowWe propose that there are two types of low-value cancer treatments. Type 1 is a new therapy that has a statistically significant but clinically modest benefit at a high cost. In this scenario, the precise value can be formally determined by a cost-effectiveness analysis. If the incremental cost-effectiveness ratio is above a certain threshold, the treatment can be described as a low-value treatment. Type 2 is a treatment that adds no additional benefit in terms of efficacy or toxicity compared with the current standard of care options and has a higher cost. In this situation, a formal cost-effectiveness analysis is not required. A perfect example is ziv-aflibercept in the second-line setting of metastatic colorectal cancer. In 2012, ziv-aflibercept was approved by the FDA, and the drug price was significantly higher than bevacizumab. At that time, there was a public protest by physicians at Memorial Sloan Kettering Cancer Center [15], and the price was subsequently decreased by the manufacturer. Ramucirumab in metastatic colorectal cancer falls into the second category of a low-value treatment.Health care cost is a huge social and economic challenge in the U.S. Drug costs represent a sizable portion of health care costs. Unfortunately, at this time, there is no formal process to regulate the cost of new therapeutic agents and to ensure that the cost justifies the added benefit of new therapies. The FDA evaluates clinical trial data regarding safety and efficacy of a drug prior to granting approval. The FDA has no mandate to consider the cost of a drug prior to approval. Furthermore, Medicare is prevented from negotiating the cost of a drug with pharmaceutical companies as a result of the Medicare Modernization Act of 2003. Both policy makers and physicians in the U.S. usually are not willing to deny a particular treatment in the case of a type 1 low-value treatment. Policy makers are reluctant to address this issue to avoid criticism relating to rationing of care. Physicians consider their prime objective to be bringing the best possible care to their patients regardless of cost. In the case of a type 2 low-value treatment, however, both policy makers and physicians should be willing to deny such a therapy, given the presence of comparable and cheaper alternatives. At our institution, ramucirumab is currently on the formulary for use in advanced gastric cancer. The gastrointestinal oncology group has decided not to use ramucirumab for colorectal cancer at the current price. In our opinion, health care institutions, physicians, and patients can—and should—be more involved in evaluating the role of new therapies based on their value, especially in the case of a type 2 low-value treatment.