Implementation of Nurse Navigation Improves Rate of Molecular Tumor Testing for Ovarian Cancer in a Gynecologic Oncology Practice.

PURPOSE: The purpose of this study was to assess the impact of implementing a Nurse Navigator (NN) to improve the rate and timeliness of molecular tumor testing. METHODS: This is an evaluation of the impact of education sessions, consensus building, and NN implementation for molecular tumor testing in patients with epithelial ovarian cancer. The NNs' responsibilities included attending tumor boards and ensuring Next Generation Sequencing (NGS) is ordered, reviewed, and coordinated for appropriate patients. RESULTS: NNs significantly improved NGS testing rates from 35.29% to 77.27%, p = 0.002. Ordering a targeted panel test (TPT) was the most common reason for not ordering NGS in the pre-NN cohort (13/22, 59%). The total turnaround time for testing was reduced after the introduction of NNs from 145.2 days to 42.8 days, p < 0.0001. The post-NN group had a significantly higher rate of actionable mutations identified for the recurrent setting [67.6% versus 20.8% (p = 0.0005)] and a trend towards a higher rate of actionable mutations identified in the frontline setting [41.2% versus 33.3% (p = 0.41)]. CONCLUSION: NNs significantly improved somatic tumor testing rates and timeliness for patients with ovarian cancer. Discontinuing TPT in favor of NGS revealed a higher rate of actionable tumor mutations that would have been missed with TPT alone.

A Phase I Dose Escalation and Expansion Study of Epidiolex (Cannabidiol) in Patients with Biochemically Recurrent Prostate Cancer.

PURPOSE: Cannabinoids (CBD) have anti-tumor activity against prostate cancer (PCa). Preclinical studies have demonstrated a significant decrease in prostate specific antigen (PSA) protein expression and reduced tumor growth in xenografts of LNCaP and DU-145 cells in athymic mice when treated with CBD. Over-the-counter CBD products may vary in activity without clear standardization, and Epidiolex is a standardized FDA-approved oral CBD solution for treatment of certain types of seizures. We aimed to assess the safety and preliminary anti-tumor activity of Epidiolex in patients with biochemically recurrent (BCR) PCa. EXPERIMENTAL DESIGN: This was an open-label, single center, phase I dose escalation study followed by a dose expansion in BCR patients after primary definitive local therapy (prostatectomy +/- salvage radiotherapy or primary definitive radiotherapy). Eligible patients were screened for urine tetrahydrocannabinol prior to enrollment. The starting dose level of Epidiolex was 600 mg by mouth once daily and escalated to 800 mg daily with the use of a Bayesian optimal interval design. All patients were treated for 90 days followed by a 10-day taper. The primary endpoints were safety and tolerability. Changes in PSA, testosterone levels, and patient-reported health-related quality of life were studied as secondary endpoints. RESULTS: Seven patients were enrolled into the dose escalation cohort. There were no dose-limiting toxicities at the first two dose levels (600 mg and 800 mg). An additional 14 patients were enrolled at the 800 mg dose level into the dose expansion cohort. The most common adverse events were 55% diarrhea (grade 1-2), 25% nausea (grade 1-2), and 20% fatigue (grade 1-2). The mean PSA at baseline was 2.9 ng/mL. At the 12-week landmark time-point, 16 out of 18 (88%) had stable biochemical disease, one (5%) had partial biochemical response with the greatest measurable decline being 41%, and one (5%) had PSA progression. No statistically significant changes were observed in patient-reported outcomes (PROs), but PROs changed in the direction of supporting the tolerability of Epidiolex (e.g., emotional functioning improved). CONCLUSION: Epidiolex at a dose of 800 mg daily appears to be safe and tolerable in patients with BCR prostate cancer supporting a safe dose for future studies.

Performance status, comorbidities, and cycles of methotrexate exert the greatest influence on outcomes of primary and secondary CNS lymphomas: the Lexington experience.

Primary central nervous system lymphoma (PCNSL) occurs primarily in older patients and has a worse prognosis than other extranodal lymphomas. Contemporary treatment is based on high-dose methotrexate (HD-MTX), which crosses the blood-brain barrier. Secondary CNS lymphoma (SCNSL) can occur concomitantly with systemic lymphoma or later at relapse and generally has a dismal outcome. We reviewed disease characteristics and outcomes of 103 patients (44 PCNSL and 59 SCNSL) treated at our center between 2015 and 2020. Median ages at diagnosis were 64 and 62 years, respectively. In both groups, diffuse large B cell lymphoma (DLBCL) was the major histologic type; in SCNSL, other types were also seen. SCNSL, in contrast with PCNSL, manifested with smaller tumors or cerebrospinal fluid positivity. For SCNSL the mean interval to brain involvement was 18 months (0-138). The overall survival had a trend to worse in SCNSL; median survival 11 months versus 61 months in PCNSL (p = 0.089). Progression-free survival was similar in both groups. A significant proportion of SCNSL patients with poor performance status could not obtain CNS-directed treatments. The strongest predictor of poor outcome was ECOG performance status 2 + at diagnosis for both groups. Charlson comorbidity index was predictive only for the PCNSL cohort. Tumor size was not prognostic for survival. The number of HD-MTX cycles correlated with survival, whereas the regimen itself and average cumulative dose of methotrexate did not play a role. Our study is in line with the recent literature and confirms ongoing challenges. We discuss how the outcomes of CNS lymphomas can be improved.

A single arm phase II study of bone-targeted Sn-117 m-DTPA in symptomatic castration-resistant prostate cancer with skeletal metastases.

BACKGROUND: Several bone-seeking radionuclides have been developed for palliation of metastatic bone pain since 1956, however, so far radium-223 dichloride is the first and only Food and Drug Administration (FDA) approved targeted alpha therapy for metastatic castration-resistant prostate cancer (mCRPC) based on ALSYMPCA phase 3 study. While radium-223 does improve pain and overall survival outcomes, the improvement can come at the expense of side effects such as bone marrow toxicity. The development of new and better treatment with long-standing pain relief is clearly an unmet medical need. METHODS: The study is a non-randomized phase II study. The study population consists of 25 patients with CRPC who had progressed on any lines of prior therapies and whose serum testosterone level is less than 50 ng/dl and have metastatic lesions to at least two bone sites, with at least one site that has clinically meaningful pain at baseline (≥ 4 on an 11-point intensity scale). Eligible patients will be given two cycles of Sn-117 m-DTPA every 8 weeks or 56 days. Treatment will be administered by slow IV injection over 5-10 min. Retreatment after two cycles is allowed if patients meet the following retreatment criteria. The primary objective is to evaluate the efficacy of Sn-117 m-DTPA on sustained pain response in patients with CRPC metastatic to at least two bone sites and at least one with clinically meaningful pain at baseline (≥ 4 on an 11-point pain intensity scale). Sustained pain response is defined as: 1) achieving pain index ≤ 3 within a 12-week period and 2) maintaining pain index ≤ 3 over a 16-week period. The secondary objectives are: safety and tolerability, measurement of Sn-117 m-DTPA activity by gamma-camera dosimetry scans, therapeutic efficacy, time to the first symptomatic skeletal event, duration of pain response, changes in PSA and ALP levels, patient-reported outcomes and progression free survival and overall survival. DISCUSSION: Sn-117 m-DTPA is a unique bone-targeting theranostic radiopharmaceutical agent that selectively binds most heavily to bone metastases sites. This study will be the first prospective phase II trial to assess the pain efficacy and anti-tumor activity of Sn-117 m-DTPA in mCRPC with at least one clinically meaningful pain at baseline. TRIAL REGISTRATION: ClincialTrials.gov Identifier: NCT04616547.

Identification of prognostic genes in oral squamous cell carcinoma microenvironment.

BACKGROUND: Numerous studies reveal the clinical significance of tumor microenvironment (TME) in multiple cancers. The association between TME in oral squamous cell carcinoma (OSCC) and clinical outcomes remains unsolved. OBJECTIVE: This study aims to exhibit the TME of OSCC and identified the prognostic marker. METHODS: Gene expression profile and clinical data OSCC patients were from the TCGA database. The validated stage data was from the Gene Expression Omnibus (GSE65858). Immune/stromal scores of each patient were calculated by ESTIMATE algorithm. Biological functional prediction was conducted. Prognostic genes identified by survival analysis. Nomogram and Receiver operating characteristic curves were employed to test the predicting power. TIMER database was applied to evaluated the immune infiltrates. RESULTS: Lower immune scores were observed in male patients (P= 0.0107) and different primary tumor sites of oral cavity with different stromal scores (P= 0.0328). The Differentially expressed genes (DEGs) were involved in immune related pathways. HGF gene (hepatocyte growth factor) was prognostic related and with a better prognostic performance when combined with clinical features (AUC=TCGA 0.638, AUC=GEO 0.714). HGF was significantly related with B cell, CD4ï⁢»â¢T cell, CD8+T cell, macrophage, neutrophils, and dendritic cell infiltration. CONCLUSION: The current study analyzed the TME and presented immune related prognostic biomarkers for OSCC.

TERT Gene rs2736100 and rs2736098 Polymorphisms are Associated with Increased Cancer Risk: A Meta-Analysis.

Abnormal telomerase activity plays a key role in the development of carcinogenesis. The variants rs2736100 and rs2736098 of the telomerase reverse transcriptase (TERT) gene, which encodes the telomerase catalytic subunit, are associated with the risk of different types of cancers. However, the results remain controversy. We conducted a meta-analysis to more precisely assess this association. We comprehensively searched the PubMed and Web of Science databases up to June 1, 2020, and retrieved a total of 103 studies in 82 articles, including 89,320 cases and 121,654 controls. Among these studies, 69 published studies including 75,274 cases and 10,3248 controls were focused on rs2736100, and 34 published studies including 14,046 cases and 18,362 controls were focused on rs2736098. The results showed a strong association between variant rs2736100 and cancer risk in all populations. (G vs. T: OR 1.18, 95% CI 1.12-1.24; TG+GG vs. TT: OR 1.23, 95% CI 1.15-1.31; GG vs. TG+TT: OR 1.25, 95% CI 1.16-1.36); the variant rs2736098 was associated with cancer risk in all populations as well (A vs. G: OR 1.13, 95% CI 1.05-1.22; GA+AA vs. GG: OR 1.15, 95% CI 1.04-1.27; AA vs. GA+GG: OR 1.22, 95% CI 1.10-1.38). Stratified analysis based on the cancer type indicated that rs2736100 was associated with an increased risk of thyroid cancer, bladder cancer, lung cancer, glioma, and myeloproliferative neoplasms. rs2736098 only increased the risk of bladder cancer and lung cancer. Moreover, the TERT variants rs2736100 and rs2736098 were associated with a decreased risk of breast cancer and colorectal cancer. The variants rs2736098 and rs2736100 located in 5p15.33 around TERT were associated with increased cancer risk in all populations. These two variants had bidirectional effects in different tumors.

Nanopore sequencing of clonal IGH rearrangements in cell-free DNA as a biomarker for acute lymphoblastic leukemia.

Background: Acute Lymphoblastic Leukemia (ALL) is the most common pediatric cancer, and patients with relapsed ALL have a poor prognosis. Detection of ALL blasts remaining at the end of treatment, or minimal residual disease (MRD), and spread of ALL into the central nervous system (CNS) have prognostic importance in ALL. Current methods to detect MRD and CNS disease in ALL rely on the presence of ALL blasts in patient samples. Cell-free DNA, or small fragments of DNA released by cancer cells into patient biofluids, has emerged as a robust and sensitive biomarker to assess cancer burden, although cfDNA analysis has not previously been applied to ALL. Methods: We present a simple and rapid workflow based on NanoporeMinION sequencing of PCR amplified B cell-specific rearrangement of the (IGH) locus in cfDNA from B-ALL patient samples. A cohort of 5 pediatric B-ALL patient samples was chosen for the study based on the MRD and CNS disease status. Results: Quantitation of IGH-variable sequences in cfDNA allowed us to detect clonal heterogeneity and track the response of individual B-ALL clones throughout treatment. cfDNA was detected in patient biofluids with clinical diagnoses of MRD and CNS disease, and leukemic clones could be detected even when diagnostic cell-count thresholds for MRD were not met. These data suggest that cfDNA assays may be useful in detecting the presence of ALL in the patient, even when blasts are not physically present in the biofluid sample. Conclusions: The Nanopore IGH detection workflow to monitor cell-free DNA is a simple, rapid, and inexpensive assay that may ultimately serve as a valuable complement to traditional clinical diagnostic approaches for ALL.

Prognostic Impact of Cytoreductive Nephrectomy in Patients with Metastatic Renal Cell Carcinoma: Data from a Large Population-Based Database.

PURPOSE: Cytoreductive nephrectomy (CN) was considered a well-established treatment modality for patients with metastatic renal cell carcinoma (RCC) in the interferon era. However, its role after the introduction of multiple targeted therapies is less well established. Herein, We evaluated the effect of CN on overall survival (OS) on patients with RCC who were identified through the Surveillance, Epidemiology, and End Results database (SEER). MATERIALS AND METHODS: A total of 5,483 patients with metastatic RCC were identified from 2010 to 2016 using the SEER database. Factors pertaining to the following variables were collected: presence or absence of CN; age; gender; grade; status of metastasis to bone, liver, lung and brain; tumor stage; nodal status; histological subtypes; and chemotherapy status. Subjects who had CN were matched with those who did not in all previously mentioned covariates using inverse probability weighting. These weights were then used in adjusted Cox regression models to report doubly robust estimates. RESULTS: CN was associated with 67% reduction in the hazards of death. Advanced T-stage, N1 disease, advanced tumor grade, non-clear histology and metastasis to bone, liver, lung or brain are independent risk factors for death. Patients with T4 disease benefited less of CN compared to those with T1 disease, while higher number of metastatic sites didn't predict worse outcome among those who had CN. CONCLUSION: CN could provide a survival advantage in favorable risk patients with RCC in the era of targeted therapy.

Evaluation of Glutaminase Expression in Prostate Adenocarcinoma and Correlation with Clinicopathologic Parameters.

High Glutaminase (GLS1) expression may have prognostic implications in colorectal and breast cancers; however, high quality data for expression in prostate cancer (PCa) are lacking. The purpose of this study is to investigate the status of GLS1 expression in PCa and correlated expression levels with clinicopathologic parameters. This study was conducted in two phases: an exploratory cohort analyzing RNA-Seq data for GLS1 from The Cancer Genome Atlas (TCGA) data portal (246 PCa samples) and a GLS1 immunohistochemical protein expression cohort utilizing a tissue microarray (TMA) (154 PCa samples; 41 benign samples) for correlation with clinicopathologic parameters. In the TCGA cohort, GLS1 mRNA expression did not show a statistically significant difference in disease-free survival (DFS) but did show a small significant difference in overall survival (OS). In the TMA cohort, there was no correlation between GLS1 expression and stage, Gleason score, DFS and OS. GLS1 expression did not significantly correlate with the clinical outcomes measured; however, GLS1 expression was higher in PCa cells compared to benign epithelium. Future studies are warranted to evaluate expression levels in greater numbers of high-grade and advanced PCa samples to investigate whether there is a rational basis for GLS1 targeted therapy in a subset of patients with prostate cancer.

Evaluation of Fall and Fracture Risk Among Men With Prostate Cancer Treated With Androgen Receptor Inhibitors: A Systematic Review and Meta-analysis.

Importance: A high incidence of fall and fracture in a subset of patients treated with androgen receptor inhibitors (ARIs) has been reported, although the relative risk (RR) of fall and fracture for patients who receive ARI treatment is unknown. Objective: To evaluate whether treatment with ARIs is associated with an elevated relative risk for fall and fracture in patients with prostate cancer. Data Sources: Cochrane, Scopus, and MedlinePlus databases were searched from inception through August 2019. Study Selection: Randomized clinical trials comparing patients with prostate cancer treated with any ARI or placebo were included. Data Extraction and Synthesis: Two independent reviewers used a standardized data extraction and quality assessment form. A mixed effects model was used to estimate the effects of ARI on relative risk, with included studies treated as random effects and study groups treated as fixed effects in the pooled analysis. Sample size for each study was used to weight the mixed model. Statistical analysis was performed from August to October 2019. Main Outcomes and Measures: The primary outcome was RR of fall and fractures for patients receiving ARI treatment. Results: Eleven studies met this study's inclusion criteria. The total population was 11 382 men (median [range] age: 72 [43-97] years), with 6536 in the ARI group and 4846 in the control group. Participants in the ARI group could have received enzalutamide, apalutamide, or darolutamide in combination with androgen deprivation therapy or other enzalutamide combinations; patients in the control group could have received placebo, bicalutamide, or abiraterone. The reported incidence of fall was 525 falls (8%) in the ARI group and 221 falls (5%) in the control group. The incidence of fracture was 242 fractures (4%) in the ARI group and 107 fractures (2%) in the control group. Use of an ARI was associated with an increased risk of falls and fractures: all-grade falls (RR, 1.8; 95% CI, 1.42-2.24; P < .001); grade 3 or greater fall (RR, 1.6; 95% CI, 1.27-2.08; P < .001); all-grade fracture (RR, 1.59; 95% CI, 1.35-1.89; P < .001), and likely grade 3 or greater fracture (RR, 1.71; 95% CI, 1.12-2.63; P = .01). Conclusions and Relevance: Use of ARI was associated with an increase in falls and fractures in patients with prostate cancer as assessed by a retrospective systematic review and meta-analysis. Further studies are warranted to identify and understand potential mechanisms and develop strategies to decrease falls and fractures associated with ARI use.

The identification of autophagy-related genes in the prognosis of oral squamous cell carcinoma.

OBJECTIVES: The aim of this study was to identify prognostic autophagy-related genes and assess the ability of these genes to predict clinical outcomes in oral squamous cell carcinoma (OSCC). SUBJECTS AND METHODS: The details of the human autophagy-related genes were obtained from the Human Autophagy Database. The Cancer Genome Atlas database was used to obtain the gene expression profiles and clinical data of patients. Prediction of biological functions of differentially expressed genes was performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Prognosis-related genes were identified by Cox regression analysis, and the coefficient was applied to construct a prognostic risk score model. The median of the risk score was applied to distinguish between high- and low-risk groups. The Gene Expression Omnibus database, qRT-PCR and immunohistochemistry were used to validate the expression of key genes. RESULTS: KEGG analyses revealed that differentially expressed genes were mainly enriched in autophagy-related pathways and virus infection. BAK1, BID, NKX2-3 and SPHK1 were identified. The risk score model showed that the high-risk score had poorer overall survival (Kaplan-Meier analysis, p = 1.79 × 10-7 ). SPHK1 was upregulated in OSCC tissues and cells, and NXK2-3 was downregulated. CONCLUSIONS: Autophagy-related gene expression profiles may be a potential biomarker for OSCC prognosis.

Generalization of the time-to-event continual reassessment method to bivariate outcomes.

This article considers the problem of designing Phase I-II clinical trials with delayed toxicity and efficacy outcomes. The proposed design is motivated by a Phase I-II study evaluating all-trans retinoic acid (ATRA) in combination with a fixed dose of daratumumab in the treatment of relapsed or refractory multiple myeloma. The primary objective of the study is to identify a dose that maximizes efficacy and has an acceptable level of toxicity. The toxicity endpoint is observed in one cycle of therapy (i.e., 4 weeks) while the efficacy endpoint is assessed after 8 weeks of treatment. The difference in endpoint observation windows causes logistical challenges in conducting the trial, since it is not practical to wait until both outcomes for each patient have been fully observed before sequentially assigning the dose of a newly eligible patient. In order to avoid delays in treatment for newly enrolled patients and to accelerate trial progress, we generalize the time-to-event continual reassessment method (TITE-CRM) to bivariate outcomes. Simulation studies are conducted to evaluate the proposed method, and we found that the proposed design is able to accurately select doses that maximize efficacy and have acceptable toxicity, while using all available information in allocating patients at the time of dose assignment. We compare the proposed methodology to two existing methods in the area.

Improved adaptive randomization strategies for a seamless Phase I/II dose-finding design.

In this article, we propose and evaluate three alternative randomization strategies to the adaptive randomization (AR) stage used in a seamless Phase I/II dose-finding design. The original design was proposed by Wages and Tait in 2015 for trials of molecularly targeted agents in cancer treatments, where dose-efficacy assumptions are not always monotonically increasing. Our goal is to improve the design's overall performance regarding the estimation of optimal dose as well as patient allocation to effective treatments. The proposed methods calculate randomization probabilities based on the likelihood of every candidate model as opposed to the original design which selects the best model and then randomizes doses based on estimations from the selected model. Unlike the original method, our proposed adaption does not require an arbitrarily specified sample size for the adaptive randomization stage. Simulations are used to compare the proposed strategies and a final strategy is recommended. Under most scenarios, our recommended method allocates more patients to the optimal dose while improving accuracy in selecting the final optimal dose without increasing the overall risk of toxicity.

RNF185 modulates JWA ubiquitination and promotes gastric cancer metastasis.

Gastric cancer (GC) is one of the most common malignant cancers worldwide. Metastasis leads to poor prognoses in GC patients in advanced stages. Our previous studies have demonstrated that JWA functions as a tumour suppressor and that low expression of JWA in GC tissues is significantly correlated with shorter overall survival (OS) as well as with advanced clinicopathologic features in patients. However, the mechanism of dysregulation of JWA in cancers is not clear. In the present study, we found that an E3 ubiquitin ligase, RNF185, directly interacted with JWA and promoted its ubiquitination at the K158 site, resulting in subsequent degradation. Moreover, the protein level of RNF185 was negatively correlated with JWA in tumour tissues from GC patients. High RNF185 expression was significantly correlated with shorter OS. Additionally, increased RNF185 expression facilitated GC cell migration in vitro and promoted GC metastasis in vivo by downregulating JWA expression. However, this effect was reversed by replenishment of JWA. In conclusion, our findings highlight the following: (1) RNF185 promotes GC metastasis by mediating JWA degradation via a ubiquitin-proteasome pathway; (2) the K158 site of JWA is essential for its ubiquitination in GC cells. These findings suggest that RNF185 is a novel candidate prognostic marker and potential therapeutic target for GC.

Inhibition of PARP1 activity enhances chemotherapeutic efficiency in cisplatin-resistant gastric cancer cells.

Cisplatin (DDP) is the first line chemotherapeutic drug for several cancers, including gastric cancer (GC). Unfortunately, the rapid development of drug resistance remains a significant challenge for the clinical application of cisplatin. There is an urgent need to develop new strategies to overcome DDP resistance for cancer treatment. In this study, four types of human GC cells have been divided into naturally sensitive or naturally resistant categories according to their responses to cisplatin. PARP1 activity (poly (ADP-ribose), PAR) was found to be greatly increased in cisplatin-resistant GC cells. PARP1 inhibitors significantly enhanced cisplatin-induced DNA damage and apoptosis in the resistant GC cells via the inhibition of PAR. Mechanistically, PARP1 inhibitors suppress DNA-PKcs stability and reduce the capability of DNA double-strand break (DSB) repair via the NHEJ pathway. This was also verified in BGC823/DDP GC cells with acquired cisplatin resistance. In conclusion, we identified that PARP1 is a useful interceptive target in cisplatin-resistant GC cells. Our data provide a promising therapeutic strategy against cisplatin resistance in GC cells that has potential translational significance.