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.

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.

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.

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.

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.

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.

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.

Long-Term Follow-Up of Gemogenovatucel-T (Vigil) Survival and Molecular Signals of Immune Response in Recurrent Ovarian Cancer.

AIM: To determine the relationship between gene expression profile (GEP) and overall survival (OS) by NanoString following treatment with Vigil. PATIENTS AND METHODS: Recurrent ovarian cancer patients (n = 21) enrolled in prior clinical trials. RESULTS: GEP stratified by TISHIGH vs. TISLOW demonstrated OS benefit (NR vs. 5.8 months HR 0.23; p = 0.0379), and in particular, MHC-II elevated baseline expression was correlated with OS advantage (p = 0.038). Moreover, 1-year OS was 75% in TISHIGH patients vs. 25% in TISLOW (p = 0.03795). OS was also correlated with positive γ-IFN ELISPOT response, 36.8 vs. 23.0 months (HR 0.19, p = 0.0098). CONCLUSION: Vigil demonstrates OS benefit in correlation with TISHIGH score, elevated MHC-II expression and positive γ-IFN ELISPOT in recurrent ovarian cancer patients.

Corrigendum to "Long-term follow-up of Phase 2A trial results involving advanced ovarian cancer patients treated with Vigil® in frontline maintenance" [Gynecol. Oncol. Rep. 34 (2020) 100648].

[This corrects the article DOI: 10.1016/j.gore.2020.100648.].

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.

Endometriosis-associated colorectal carcinosarcoma: A case report and review of the literature.

•Endometriosis associated intestinal tumors are rare, with 5 cases documented.•Endometriosis associated intestinal tumors might present like colorectal carcinoma.•Endometriosis associated intestinal Carcinoma is associated with poor prognosis.

Current Ovarian Cancer Maintenance Strategies and Promising New Developments.

While ovarian cancer typically responds well to front line treatment, many patients will relapse within 5 years. Treatment options are less effective at each recurrence highlighting the need for novel maintenance therapies. PolyADP-ribose polymerase (PARP) inhibitors have recently gained approval in ovarian cancer maintenance. Niraparib was approved regardless of BRCA mutation status, however impact on overall survival is limited. Oliparib was approved for BRCA mutant and BRCA wildtype/homologous recombination deficient patients. This review will focus on current frontline ovarian cancer treatment as well molecularly based approaches to ovarian cancer management.

BRCA1/2 Mutation Status Impact on Autophagy and Immune Response: Unheralded Target.

BRCA1 and possibly BRCA2 proteins may relate to the regulation of autophagy. Autophagy plays a key role in immune response from both a tumor and immune effector cell standpoint. In cells with BRCA mutations, increased autophagy leads to elevated expression of major histocompatibility complex class II but may cause subclonal neoantigen presentation, which may impair the immune response related to clonal neoantigen visibility. We review evidence of BRCA1/2 regulation of autophagy, immune response, and antigen presentation.