Applying Lean Six Sigma to Improve Depression Screening and Follow-Up in Oncology Clinics.

ABSTRACT: Depression is a common and serious illness that impairs the health of individuals and societies globally. It is associated with a significant economic burden, with productivity losses exceeding $40 billion dollars annually in the United States (U.S.) alone. This project focused on the use of a systematic, data-driven approach to improve the screening rate for depression in an academic, metropolitan cancer center located in North Texas. A multidisciplinary team collaboratively applied Lean Six Sigma education, methods, and tools within oncology and psychiatry clinics to address the increased risk of depression among oncology patients. Improving the standardization of screening and follow-up processes, resulted in a 44% sustained increase in the depression screening and follow-up performance rate. This improvement was verified to be statistically significant through the use of control charts toward the end of the project.

A Phase I/Ib Trial of PD 0332991 (Palbociclib) and T-DM1 in HER2-Positive Advanced Breast Cancer After Trastuzumab and Taxane Therapy.

BACKGROUND: Preclinical breast cancer models with acquired HER2 resistance exhibit decreased proliferation with CDK4/6 inhibition in tumors with intact Rb and low p16 levels. Adding cytotoxic agents like T-DM1 enhances the inhibitory CDK4/6 cytostatic effect. PATIENTS AND METHODS: A phase I/Ib 3+3 dose escalation/expansion trial of palbociclib and T-DM1 identified 150 mg on days 5 to 18 as the palbociclib maximal tolerated dose combined with day 1 intravenous T-DM1 in 21-day treatment cycles. Patients were previously treated with trastuzumab and a taxane with no limitation on prior therapy lines, including prior pertuzumab, lapitinib, neratinib, and T-DM1. Median age was 54 years and two-thirds were estrogen receptor positive. Primary objectives included maximum tolerated dose as determined by dose-limiting toxicity, and secondary end points of safety, toxicity, response rate, response duration, and progression-free survival. RESULTS: From May 2014 to August 2018, 18 total patients were treated. The median number of cycles was 6.5 (1-22). A maximum tolerated dose was not reached. The most common G3 toxicity of more than 10% incidence was hematologic. Overall response rate (complete response + partial response) was 33% (95% confidence interval, 13%-59%). Median duration of response in responders was not reached and median-progression free survival was 6 months (95% confidence interval, 2.5-11.6). CONCLUSIONS: The combination of day 1 T-DM1 and days 5 to 18 palbociclib is safe, tolerable, and active in previously treated HER2-positive relapsed patients. Observed hematologic toxicity is manageable. The trial response rate confirms that a CDK 4/6 inhibitor can resensitize HER2-resistant breast cancer.

Impact of a Cancer Urgent Care Clinic on Regional Emergency Department Visits.

PURPOSE: Did the creation of an urgent care clinic specifically for patients with cancer affect emergency department visits among adults newly diagnosed with cancer? PATIENTS AND METHODS: We applied an interrupted time series analysis to adjusted monthly emergency department visits made by adults age 18 years or older who were diagnosed with cancer between 2009 and 2016 at a comprehensive cancer center. Cancer registry patients were linked to a longitudinal regional database of emergency department and hospital visits. Because the urgent care clinic was closed on weekends, we took advantage of the natural experiment by comparing weekend visits as a control group. Our primary outcome was emergency department visits within 180 days after a cancer diagnosis, compiled as adjusted monthly rates of emergency department visits per 1,000 patient-months. We analyzed subsequent hospitalizations as a secondary outcome. RESULTS: The rate of weekday emergency department visits was increasing at a rate of 0.43 visits (95% CI, 0.29 to 0.57 visits) per month before May 2012, then fell in half to a rate of 0.19 visits (95% CI, 0.11 to 0.28 visits) per month (P = .007) after the urgent care clinic was established. In contrast, the weekend visit rate was growing at a rate of 0.08 visits (95% CI, -0.03 to 0.19 visits) per month before May 2012 and 0.05 (95% CI, -0.02 to 0.13 visits; P = .533) afterward. By the end of 2016, there were 15.3 fewer monthly weekday emergency department visits than expected (P = .005). Trends in weekday hospitalizations were not significantly changed. CONCLUSION: Although only one in eight emergency department-visiting patients also used the urgent care clinic, the growth rate of emergency department visits fell by half after the urgent care clinic was established.

Ibrutinib Use Complicated by Progressive Multifocal Leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease associated with immunocompromised states. We describe a case of PML, which developed after prolonged ibrutinib use and a low burden of chronic lymphocytic leukemia disease. The delay in diagnosis of the patient despite multiple presentations to medical providers across different facilities suggests that there is a lack of awareness of PML as a potential complication of ibrutinib. Treatments with postulated anti-John Cunningham polyomavirus agents and IL-2 were ineffective, likely due to the advanced state of the patient's disease. Although recent evidence indicates that ibrutinib may enhance cell-mediated immunity, consistent with elevated CD4+ and CD8+ T cells and appropriate T-cell response to mitogens in the patient, ibrutinib-mediated inhibition of the humoral function may contribute to PML pathogenesis. As the duration of ibrutinib use is often indefinite, and the number of indications for ibrutinib continues to grow, recognition and further evaluation of the link between PML and ibrutinib is warranted.

Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint Therapy Efficacy in Melanoma Patients.

This is the first prospective study of the effects of human gut microbiota and metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma patients. Whereas many melanoma patients exhibit profound response to ICT, there are fewer options for patients failing ICT-particularly with BRAF-wild-type disease. In preclinical studies, specific gut microbiota promotes regression of melanoma in mice. We therefore conducted a study of the effects of pretreatment gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid Tumors response in 39 metastatic melanoma patients treated with ipilimumab, nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67% responses and 8% stable disease; P achieved 23% responses and 23% stable disease. ICT responders for all types of therapies were enriched for Bacteroides caccae. Among IN responders, the gut microbiome was enriched for Faecalibacterium prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P responders, the microbiome was enriched for Dorea formicogenerans. Unbiased shotgun metabolomics revealed high levels of anacardic acid in ICT responders. Based on these pilot studies, both additional confirmatory clinical studies and preclinical testing of these bacterial species and metabolites are warranted to confirm their ICT enhancing activity.

Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma Patients.

This is the first prospective study of a combination therapy involving a cardenolide and a MEK inhibitor for metastatic melanoma. Whereas BRAF mutant melanomas can exhibit profound responses to treatment with BRAF and MEK inhibitors, there are fewer options for BRAF wild-type melanomas. In preclinical studies, we discovered that cardenolides synergize with MEK inhibitor to promote the regression of patient-derived xenografts irrespective of BRAF mutation status. We therefore conducted a phase 1B study of digoxin 0.25 mg and trametinib 2 mg given orally once daily in 20 patients with advanced, refractory, BRAF wild-type melanomas. The most common adverse events were rash, diarrhea, nausea, and fatigue. The response rate was 4/20 or 20% with response durations of 2, 4, 6, and 8 months. The disease control rate (including partial responses and stable disease) was 13/20 or 65% of patients, including 5/6 or 83% of patients with NRAS mutant melanomas and 8/14 or 57% of NRAS wild-type melanomas. Patients with stable disease had disease control for 2, 2, 2, 4, 5, 6, 7, 10, and 10 months. Xenografts from four patients recapitulated the treatment responses observed in patients. Based on these pilot results, an expansion arm of digoxin plus MEK inhibitor is warranted for NRAS mutant metastatic melanoma patients who are refractory or intolerant of immunotherapy. KEY POINTS: Digoxin plus trametinib is well tolerated and achieves a high rate of disease control in BRAF wild-type metastatic melanoma patients.

ATP-competitive LRRK2 inhibitors interfere with monoclonal antibody binding to the kinase domain of LRRK2 under native conditions. A method to directly monitor the active conformation of LRRK2?

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. LRRK2 kinase activity is required for toxicity in neuronal cell cultures suggesting that selective kinase inhibitors may prevent neurodegeneration in patients. Directly monitoring LRRK2 activity in cells would be advantageous for the development of small molecule LRRK2 inhibitors. Here, we demonstrate that a monoclonal anti-LRRK2 antibody directed against the activation segment binds less efficiently to native LRRK2 protein in the presence of ATP-competitive LRRK2 inhibitors. Since kinase inhibitors prevent autophosphorylation and refolding of the activation segment, we hypothesize that the antibody preferentially binds to the active conformation of LRRK2 under native conditions.

Hybridization probe pairs and single-labeled probes: an alternative approach for genotyping and quantification.

Real-time polymerase chain reaction (PCR) has become a standard tool in both quantitative gene expression and genetic variation analysis. Data collection is performed throughout the PCR process, thus combining amplification and detection into a single step. This can be achieved by combining a variety of different fluorescent chemistries that correlate the concentration of an amplified PCR product to changes in fluorescence intensity. Hybridization probe pairs and single-labeled probes are sequence-specific, dye-labeled oligonucleotides, used in real-time PCR approaches, in particular for genotyping of single nucleotide polymorphisms (SNPs). In that case, a detector probe is designed to cover the polymorphism. Allelic variants are identified and differentiated via post-PCR melting curve analysis. A single melting curve can distinguish different T (m)s, and differently labeled probes may be used, theoretically allowing multiplexed genotyping of several SNPs.