Solvent-Driven Self-Assembly of One-Dimensional Lepidocrocite Titanium-Oxide-Based Nanofilaments.

Herein, the self-assembly of one-dimensional titanium oxide lepidocrocite nanofilaments in 10 different water miscible organic solvents was investigated. The nanofilament snippets, with minimal cross sections of ∼5 × 7 Å2 and lengths around 30 nm, begin as an aqueous colloidal suspension. Upon addition, and brief mixing, of the colloidal suspension into a given solvent, a multitude of morphologies─seemingly based on the hydrophilicity and polarity of the solvent─emerge. These morphologies vary between sheets, highly networked webs, and discrete fibers, all with no apparent change in the lepidocrocite structure. On the micro- and nanoscale, the morphologies are reminiscent of biological, rather than inorganic, materials. The results of this work give insight into the self-assembly of these materials and offer new pathways for novel macrostructures/morphologies assembled from these highly adsorbent and catalytically active low-dimensional materials.

Targeted Combination of Poly(ADP-ribose) Polymerase Inhibitors and Immune Checkpoint Inhibitors Lacking Evidence of Benefit: Focus in Ovarian Cancer.

The emergence of targeted therapeutics in ovarian cancer, particularly poly (ADP-ribose) polymerase inhibitors (PARPi's), has created additional opportunities for patients seeking frontline and recurrent disease management options. In particular, PARPi's have shown clinical benefits in BRCA mutant and/or homologous recombination deficient (HRD) ovarian cancer. Until recently, response was thought to be limited in BRCA wild-type, homologous recombination proficient (HRP) cancers. Therefore, attempts have been made at combination therapy involving PARPi to improve patient outcomes. Additionally, immune checkpoint inhibitors (ICIs) have demonstrated underwhelming results involving ovarian cancer. Many are searching for reliable biomarkers of immune response to increase efficacy of ICI therapy involving ovarian cancer. In this review, we examine the evidence supporting the combination of PARPi and ICIs in ovarian cancer, which is still lacking.

Insurance denials and diagnostic rates in a pediatric genomic research cohort.

PURPOSE: This study aimed to assess the amount and types of clinical genetic testing denied by insurance and the rate of diagnostic and candidate genetic findings identified through research in patients who faced insurance denials. METHODS: Analysis consisted of review of insurance denials in 801 patients enrolled in a pediatric genomic research repository with either no previous genetic testing or previous negative genetic testing result identified through cross-referencing with insurance prior-authorizations in patient medical records. Patients and denials were also categorized by type of insurance coverage. Diagnostic findings and candidate genetic findings in these groups were determined through review of our internal variant database and patient charts. RESULTS: Of the 801 patients analyzed, 147 had insurance prior-authorization denials on record (18.3%). Exome sequencing and microarray were the most frequently denied genetic tests. Private insurance was significantly more likely to deny testing than public insurance (odds ratio = 2.03 [95% CI = 1.38-2.99] P = .0003). Of the 147 patients with insurance denials, 53.7% had at least 1 diagnostic or candidate finding and 10.9% specifically had a clinically diagnostic finding. Fifty percent of patients with clinically diagnostic results had immediate medical management changes (5.4% of all patients experiencing denials). CONCLUSION: Many patients face a major barrier to genetic testing in the form of lack of insurance coverage. A number of these patients have clinically diagnostic findings with medical management implications that would not have been identified without access to research testing. These findings support re-evaluation of insurance carriers' coverage policies.

Association between Serum Biomarkers with Postoperative Complications and Delay of Adjuvant Chemotherapy Initiation in Ovarian Cancer Patients Undergoing Primary Cytoreductive Surgery: A Pilot Study.

This study sought to describe and relate the factors associated with complications and delays in adjuvant chemotherapy in patients with ovarian cancer treated with primary cytoreductive surgery. Serum from patients diagnosed with ovarian cancer scheduled for primary cytoreductive surgery were analyzed for prealbumin, 25-OH Vitamin D, intracellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), interleukin 8 (IL-8), monocyte chemoattractant protein 1 (MCP-1), monocyte chemoattractant protein 2 (MCP-2), macrophage derived chemokine (MDC). Postoperative complications were identified using common terminology criteria for adverse events 4.0 and 30 day after surgery. Delays in adjuvant chemotherapy were defined as >1 week interval between surgery and initiation. Patients with postoperative complications (39.6%) were significantly older, had lower serum prealbumin levels, and higher serum IL-6 and IL-8 than those without. Univariate logistic regression found that age (OR: 1.12, 95%CI: 1.00-1.35) and IL-6 (OR: 1.02, 95%CI: 0.99-1.05) were associated with postoperative complications, whereas age remained significant after multivariate analysis (OR:1.14, 95%CI: 1.00-1.29). Patients with delays in chemotherapy exhibited greater BMI and lower 25-OH Vitamin D than those without. Multivariate analysis found that increasing levels of 25-OH Vitamin D were associated with a lower risk of delayed chemotherapy initiation after controlling for age, body mass index, and tumor grade (OR: 0.93, 95%CI:0.87-0.99). This work suggests that in addition to age being predictive of postoperative complications, serum 25-OH Vitamin D may a provide insight into a patient's risk for postsurgical delays in chemotherapy initiation. These findings should, however, be confirmed in a larger study including robust survival analysis.

In a small cohort, increasing age was associated with postsurgical complications in patients with ovarian cancer following primary cytoreductive surgery.In patients with ovarian cancer following primary cytoreductive surgery delays in adjuvant chemotherapy initiation were inversely associated with serum 25-OH vitamin D status.

Gemogenovatucel-T (Vigil) maintenance immunotherapy: 3-year survival benefit in homologous recombination proficient (HRP) ovarian cancer.

OBJECTIVE: Previously, Vigil demonstrated clinical benefit to prolong relapse free and overall survival in the BRCA wild-type (BRCA-wt), homologous recombination proficient (HRP) patient population. Here we provide long term follow up of 3 years in the HRP patient population enrolled in the Phase 2b VITAL study. METHODS: HRP patients treated with Vigil (n = 25) or placebo (n = 20) who were enrolled in the Phase 2b, double-blind, placebo-controlled (VITAL study, NCT02346747) were followed for safety, OS and RFS. OS and RFS from time of randomization (immediately prior to maintenance therapy) and from debulking tissue procurement time points were analyzed by Kaplan-Meier (KM) and restricted mean survival time (RMST) analysis. RESULTS: OS for Vigil treated patients at 3 years has not yet reached median OS time point (95% CI 41.6 months to not achieved) compared to 26.9 (95% CI 17.4 months to not achieved) in placebo treated patients (HR 0.417 p = 0.020). Three year RFS also showed benefit to Vigil (stratified HR 0.405, p = 0.011) and no long term toxicity to Vigil was observed. Three year OS for Vigil of 70% vs. 40% for placebo from time of randomization was observed (p = 0.019). RMST analysis was also significant for OS (45.7 vs. 32.8 months, p = 0.008) and RFS (p = 0.025). CONCLUSION: In conclusion, results suggest durable activity of Vigil on RFS and OS and support further evaluation of Vigil in HRP ovarian cancer.

Gemogenovatucel-T (Vigil) immunotherapy demonstrates clinical benefit in homologous recombination proficient (HRP) ovarian cancer.

OBJECTIVE: Recently, Vigil showed significant clinical benefit with improvement in relapse free (RFS) and overall survival (OS) in pre-planned subgroup analysis in stage III/IV newly diagnosed ovarian cancer patients with BRCA wild type (BRCA-wt) molecular profile. Here we analyze homologous recombination (HR) status of patients enrolled in the Phase 2b VITAL study and determine clinical benefit of Vigil in HR proficient (P) patients. METHODS: Patients were previously enrolled in a Phase 2b, double-blind, placebo-controlled trial. All were in complete response with Stage III/IV high grade serious, endometroid or clear cell ovarian cancer. HR status was determined using MyChoice®CDx score (<42 = HRP) (Myriad Genetics, Inc., UT). Post-hoc analyses were carried out using Kaplan Meier and restricted mean survival time (RMST) analysis to evaluate RFS and OS based on HR deficiency (D) status. RESULTS: RFS was improved with Vigil (n = 25) in HRP patients compared to placebo (n = 20) (HR = 0.386; 90% CI 0.199-0.750; p = 0.007), results were verified by RMST (p = 0.017). Similarly, OS benefit was observed in Vigil group compared to placebo (HR = 0.342; 90% CI 0.141-0.832; p = 0.019). Results with OS were also verified with RMST (p = 0.008). CONCLUSION: Vigil exhibited clinical benefit in HRP molecular profile patients.

Contribution of age to clinical trial enrollment and tolerance with ovarian cancer.

INTRODUCTION: Increasing age has been correlated with shorter survival in ovarian cancer patients, a finding attributed to diminished tolerance of standard therapy. Elderly patients, however, are less likely to enroll on clinical trials; thus, limited data exists to evaluate their response to front line treatment. This study describes how elderly patients on trial fared, with respect to toxicity and response, compared to younger women. METHODS: A retrospective cohort study was performed of ovarian cancer patients enrolled in front line chemotherapy trials at our institution between 2000 and 2013. Patients were dichotomized by age: <70 and ≥70years. Clinical, pathologic, and treatment characteristics were recorded and analyzed using SAS version 9.3. RESULTS: 336 patients were enrolled. Of these, 79 (23.5%) were ≥70yrs. Demographics were similar between the two groups. Compared to patients <70, those ≥70 completed a comparable number of chemotherapy cycles (p=0.16) and had similar numbers of dose modifications (p=0.40) and delays (p=0.26). Both hematologic and non-hematologic toxicities occurred at similar rates as well. Age≥70 (HR 1.8, 95% CI 1.27-2.54, p=0.0009), stage III/IV (HR 3.44, 95% CI 1.08-10.95, p=0.036), and residual disease (HR 2.63, 95% CI 1.82-3.78, p<0.0001) were independently predictive of shorter overall survival. CONCLUSION: Our data continues to support reports of shorter survival for older women with ovarian cancer. With physician bias removed and similar chemotherapy tolerance noted, our study suggests that inherent tumor biology may be a significant contributor. Further research is needed to identify the mechanisms which contribute to the inequality that age imposes on outcomes.

Post-intensive care unit syndrome in gynecologic oncology patients.

PURPOSE: The purposes of the present study are to describe the demographic and treatment characteristics of women on the gynecologic oncology service who required intensive care and assess prevalence of risk factors for post-intensive care syndrome (PICS). METHODS: A retrospective chart review was performed encompassing patients requiring admission to the intensive care unit (ICU) on the gynecology oncology service between 1/2008 and 12/2012. Descriptive statistics were computed using SAS version 9.3. RESULTS: One hundred eleven patients met study criteria. Most were Caucasian (85 %), were married (50 %), and had stage III/IV disease (82 %). Risk factors for PICS were as follows: 9 % had baseline anxiety, 20 % had baseline depression, 21 % were taking an SSRI prior to admission, and 18 % took other psychiatric medications. Most ICU admissions (47 %) were for planned post-operative management. Thirty-seven percent required mechanical ventilation for a median of 1 day (range, 1-24). Twenty percent required new scheduled psychiatric medications while in the ICU, and 8.1 % of patients were discharged with a newly prescribed antidepressant. Of patients, 15.3 % had consultations with psychiatry or social work. Six percent of patients expired, and 18 % had a nontraditional discharge disposition. Overall, 60 % of the patients had at least one recognized risk factor for PICS. CONCLUSIONS: Given the preponderance of psychiatric disorders and mechanical ventilation during post-operative ICU care in patients with gynecologic cancer, prospective evaluation of risk factors and utility of risk-reducing interventions for PICS is warranted. Long-term cognitive or physical disability is known to hasten mortality; thus, preventative strategies may increase the survival and quality of life for this patient population.

Central nervous system metastasis in gynecologic cancer: symptom management, prognosis and palliative management strategies.

INTRODUCTION: CNS metastasis (CNSmet) with gynecologic malignancy (GM) is associated with poor prognosis and symptom burden. Two prognostic indices, the recursive partitioning analysis (RPA) and graded prognostic assessment (GPA), used in other solid tumors to guide intervention options were evaluated among GM patients. METHODS: Retrospective chart review was performed to identify patients with primary GM diagnosed with CNSmet from 2005-2014. RPA and GPA were applied and evaluated for goodness of fit. Long-term survivors (LTS) were those with survival time from CNSmet ≥9 months. RESULTS: 35 patients were identified with median age of 62 years (range, 41-78). The majority had ovarian cancer (54%). Median survival was 4.5 months (0.1-25.9), and median time from initial diagnosis was 2.6 years (0-19.6). Presenting symptoms varied but headache (57%) and altered mental status (23%) were most common. 37% had a solitary CNS lesion, 31% had 2-8, and 31% >8. 57% were treated with WBRT, 14% with stereotactic radiosurgery (SRS), and 20% with combinations of treatments, and 2 elected for hospice. 27% (9/33) of the patients were LTS. The GPA was not significantly associated with patient outcome (p=0.46). The RPA predicted time to death (p=.0010). CONCLUSION: Prognostic indices used to guide therapeutic interventions perform poorly in GM. Detection and aggressive symptom management are critical in maintaining QOL. Multidisciplinary consultation is critical to optimize outcomes and symptom control.

Comparison of time-motion analysis of conventional stool culture and the BD MAX™ Enteric Bacterial Panel (EBP).

BACKGROUND: Conventional bacterial stool culture is one of the more time-consuming tests in a routine clinical microbiology laboratory. In addition, less than 5 % of stool cultures yield positive results. A molecular platform, the BD MAX™ System (BD Diagnostics, Sparks, MD) offers the potential for significantly more rapid results and less hands-on time. Time-motion analysis of the BD MAX Enteric Bacterial Panel (EBP) (BD Diagnostics, Quebec, Canada) on the BD MAX System was compared to conventional stool culture in the microbiology laboratory of a tertiary care pediatric hospital. METHODS: The process impact analysis of time-motion studies of conventional cultures were compared to those of EBP with 86 stool specimens. Sample flow, hands-on time, processing steps, and overall turnaround time were determined and analyzed. Data were obtained and analyzed from both standard operating procedures and direct observation. A regression analysis was performed to ensure consistency of measurements. Time and process measurements started when the specimens were logged into the accessioning area of the microbiology laboratory and were completed when actionable results were generated. RESULTS: With conventional culture, negative culture results were available from 41:14:27 (hours:minutes:seconds) to 54:17:19; with EBP, positive and negative results were available from 2:28:40 to 3:33:39. CONCLUSIONS: This study supports the suggestion that use of the EBP to detect commonly encountered stool pathogens can result in significant time savings and a shorter time-to-result for patients with acute bacterial diarrhea.

Scaling hypertension treatment in 24 low-income and middle-income countries: economic evaluation of treatment decisions at three blood pressure cut-points.

OBJECTIVE: Estimate the incremental costs and benefits of scaling up hypertension care in adults in 24 select countries, using three different systolic blood pressure (SBP) treatment cut-off points-≥140, ≥150 and ≥160 mm Hg. INTERVENTION: Strengthening the hypertension care cascade compared with status quo levels, with pharmacological treatment administered at different cut-points depending on the scenario. TARGET POPULATION: Adults aged 30+ in 24 low-income and middle-income countries spanning all world regions. PERSPECTIVE: Societal. TIME HORIZON: 30 years. DISCOUNT RATE: 4%. COSTING YEAR: 2020 USD. STUDY DESIGN: DATA SOURCES: Institute for Health Metrics and Evaluation's Epi Visualisations database-country-specific cardiovascular disease (CVD) incidence, prevalence and death rates. Mean SBP and prevalence-National surveys and NCD-RisC. Treatment protocols-WHO HEARTS. Treatment impact-academic literature. Costs-national and international databases. OUTCOME MEASURES: Health outcomes-averted stroke and myocardial infarction events, deaths and disability-adjusted life-years; economic outcomes-averted health expenditures, value of averted mortality and workplace productivity losses. RESULTS OF ANALYSIS: Across 24 countries, over 30 years, incremental scale-up of hypertension care for adults with SBP≥140 mm Hg led to 2.6 million averted CVD events and 1.2 million averted deaths (7% of expected CVD deaths). 68% of benefits resulted from treating those with very high SBP (≥160 mm Hg). 10 of the 12 highest-income countries projected positive net benefits at one or more treatment cut-points, compared with 3 of the 12 lowest-income countries. Treating hypertension at SBP≥160 mm Hg maximised the net economic benefit in the lowest-income countries. LIMITATIONS: The model only included a few hypertension-attributable diseases and did not account for comorbid risk factors. Modelled scenarios assumed ambitious progress on strengthening the care cascade. CONCLUSIONS: In areas where economic considerations might play an outsized role, such as very low-income countries, prioritising treatment to populations with severe hypertension can maximise benefits net of economic costs.

3D engineered scaffold for large-scale Vigil immunotherapy production.

Previously, we reported successful cellular expansion of a murine colorectal carcinoma cell line (CT-26) using a three-dimensional (3D) engineered extracellular matrix (EECM) fibrillar scaffold structure. CCL-247 were grown over a limited time period of 8 days on 3D EECM or tissue culture polystyrene (TCPS). Cells were then assayed for growth, electroporation efficiency and Vigil manufacturing release criteria. Using EECM scaffolds, we report an expansion of CCL-247 (HCT116), a colorectal carcinoma cell line, from a starting concentration of 2.45 × 105 cells to 1.9 × 106 cells per scaffold. Following expansion, 3D EECM-derived cells were assessed based on clinical release criteria of the Vigil manufacturing process utilized for Phase IIb trial operation with the FDA. 3D EECM-derived cells passed all Vigil manufacturing release criteria including cytokine expression. Here, we demonstrate successful Vigil product manufacture achieving the specifications necessary for the clinical trial product release of Vigil treatment. Our results confirm that 3D EECM can be utilized for the expansion of human cancer cell CCL-247, justifying further clinical development involving human tissue sample manufacturing including core needle biopsy and minimal ascites samples.

Clonal Neoantigen: Emerging "Mechanism-based" Biomarker of Immunotherapy Response.

Clonal mutations represent the initiating molecular defects related to cellular transition of a normal phenotype to a malignant phenotype. Molecular genomic assessment utilizing next generation and whole exome sequencing is now being increasingly applied to biomarker determination to refine the use of targeted immune therapies. Case examples followed by retrospective study assessment have convincingly demonstrated clonal neoantigens provide a relevant predictor of response to checkpoint inhibition. A meta-analysis, by Litchfield et al., of over 1000 cancer patients from 12 landmark trials demonstrated no clinical benefit to checkpoint inhibitor (CPI) therapy in correlation to high subclonal tumor mutational burden (TMB), whereas high clonal TMB was found to be significantly correlated with better overall survival (p = 0.000000029). We discuss the mechanism of clonal vs. subclonal neoantigen targeting relationship to homologous recombination proficient (HRP) profile, evidence of preclinical and clinical benefit related to clonal neoantigens, and review a novel developing therapy called Vigil®, designed to expand the clonal neoantigen targeting effector cell populations. Vigil® is an autologous cellular immunotherapy which is designed to carry the full set of personal clonal neoantigens. Phase 2b results demonstrate a durable recurrence-free survival (RFS) and overall survival (OS) advantage for Vigil® in a subset ovarian cancer population with an HRP cancer profile.

Advances in Targeted Therapy for the Treatment of Cervical Cancer.

Cervical cancer is an international public health crisis, affecting several hundred thousand women annually. While not universally protective due to other risk factors, many such cases are preventable with vaccination against high-risk serotypes of the human papilloma virus (HPV 6, 11, 16, 18, 31, 33, 45, 53, 58). Advanced-stage and recurrent cervical cancers are typically lethal and have been the focus in recent years of the integration of immune checkpoint inhibitors (CPIs) to improve survival. We have consolidated information regarding the role of the immune system in both disease progression and disease clearance with the aid of targeted therapies and immunotherapeutic agents. Additionally, we have characterized the treatment modalities currently indicated as the standard of care-such as bevacizumab and the immune CPIs-and those recently approved or in development, including Tivdak, Vigil, and chimeric antigen receptor (CAR) T-cells.

Systemic benefit of radiation therapy via abscopal effect.

Evidence of a systemic response related to localized radiation therapy (RT) in cancer management is rare. However, enhancing the immune response via immunotherapy followed by localized RT has shown evidence of tumor shrinkage to non-irradiated metastatic disease thereby inducing an "abscopal effect." Combined induction of the cGAS-STING pathway and activation of IFN-gamma signaling cascade related to RT within an activated immune environment promotes neoantigen presentation and expansion of cytotoxic effector cells enabling enhancement of systemic immune response. A proposed mechanism, case examples, and clinical trial evidence of "abscopal effect" benefit are reviewed. Results support strategic therapeutic testing to enhance "abscopal effect."

ENTPD1/CD39 as a predictive marker of treatment response to gemogenovatucel-T as maintenance therapy in newly diagnosed ovarian cancer.

Background: Broadened use of predictive molecular and phenotypic profiling amongst oncologists has facilitated optimal integration of targeted- and immuno-therapeutics into clinical care. However, the use of predictive immunomarkers in ovarian cancer (OC) has not consistently translated into clinical benefit. Vigil (gemogenovatucel-T) is a novel plasmid engineered autologous tumor cell immunotherapy designed to knock down the tumor suppressor cytokines, TGFß1 and TGFß2, augment local immune function via increased GMCSF expression and enhance presentation of clonal neoantigen epitopes. Methods: All patients enrolled in the VITAL trial (NCT02346747) of maintenance Vigil vs. placebo as front-line therapy with homologous recombination proficient (HRP) stage IIIB-IV newly diagnosed ovarian cancer underwent NanoString gene expression analysis. Tissue was obtained from surgically resected ovarian tumor tissue following surgical debulking. A statistical algorithm was used to analyze the NanoString gene expression data. Results: Using the NanoString Statistical Algorithm (NSA), we identify high expression of ENTPD1/CD39 (which functions as the rate-limiting step in the production of the immune suppressor adenosine from ATP to ADP) as a presumptive predictor of response to Vigil versus placebo regardless of HRP status on the basis of relapse free survival (median not achieved vs 8.1 months, p = 0.00007) and overall survival (median not achieved vs 41.4 months, p = 0.013) extension. Conclusion: NSA should be considered for application to investigational targeted therapies in order to identify populations most likely to benefit from treatment, in preparation for efficacy conclusive trials.

Treatment options are limited in patients with advanced stage ovarian cancer. Treatments that stimulate the immune system to target the cancer are sometimes effective, however determining which patients will have benefit has been difficult. It is therefore important to develop new markers to predict which patients will respond to therapy. In this study, we looked at the levels of a large number of genes in tumors from patients treated with Vigil (gemogenovatucel-T), a treatment that modifies patient's own tumor cells to activate the immune system. We demonstrate that high expression of a gene named ENTPD1/CD39 predicts a positive response to Vigil therapy. This finding could help clinicians to determine which patients might benefit from Vigil treatment and therefore might guide decisions on who should receive this treatment.

Proof of principle study of sequential combination atezolizumab and Vigil in relapsed ovarian cancer.

Vigil® is a personalized vaccine that enhances tumor neoantigen expression. We investigated for the first time safety and efficacy of Vigil in combination with atezolizumab in relapsed ovarian cancer (OC) patients. This is a randomized, Phase 1 study of Vigil, an autologous tumor tissue transfected vaccine encoding for GMCSF and bi-shRNA-furin thereby creating enhanced immune activation and TGFß expression control. Part 1 is a safety assessment of Vigil (1 × 10e7 cells/mL/21 days) plus atezolizumab (1200 mg/21 days). Part 2 is a randomized study of Vigil first (Vigil-1st) or atezolizumab first (Atezo-1st) for two cycles followed by the combination of both agents. The primary endpoint of the study was the determination of safety. Twenty-four patients were enrolled in the study; three patients to Part 1 and 21 to Part 2. Patients in Part 1 completed combination therapy without dose-limiting toxicity justifying expansion to Part 2. Twenty-one patients were randomized (1:1) to Part 2 to Vigil-1st (n = 11) or Atezo-1st (n = 10). Grade 3/4 treatment-related adverse events of Atezo-1st vs. Vigil-1st were 17.2% vs. 5.1%. Median overall survival (OS) was not reached (NR) (Vigil-1st) vs. 10.8 months (Atezo-1st) (hazard ratio [HR] 0.33). The exploratory subset analysis of BRCAwt suggested improved OS benefit [NR in Vigil-1st vs. 5.2 months in Atezo-1st, HR 0.16, p 0.027]. The Vigil-1st combination therapy with atezolizumab was safe and results in support continued investigation in BRCAwt patients.