CNS Cancer Research Articles

Proceedings of the Survivorship Care in Neuro-Oncology Workshop sponsored by the Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT).

Survivorship for those living with primary CNS cancers begins at diagnosis, continues throughout a person's life, and includes caregivers. Opportunities and challenges exist to advance survivorship care for those living with primary CNS cancers that necessitate stakeholder involvement. In June 2021, NCI-CONNECT convened a two-day virtual workshop about survivorship care in neuro-oncology. Two expert panels provided key recommendations and five working groups considered critical questions to identify strengths, weaknesses, opportunities, and threats to the advancement of survivorship care and developed recommendations and action items. The following action items emanated from the workshop: seek endorsement of meeting report from stakeholder organizations; address barriers in access to survivorship care and provider reimbursement; advance survivorship research through NIH and private grant support; develop a survivorship tool kit for providers, people living with primary CNS cancers and their caregivers; provide accessible educational content for neuro-oncology, neurology, and oncology community providers about survivorship care in neuro-oncology; and establish core competencies for survivorship care for neuro-oncology providers to be included in training and standardized exams. Action items aim to address access and reimbursement barriers, expand patient and provider education, develop core competencies, and support survivorship research through funding and other supports.

Development of a Semiautomated Search Tool to Identify Grading From Pathology Reports for Tumors of the CNS and Prostate Cancers.

This study demonstrates the functionality of semiautomated algorithms to classify cancer-specific grading from electronic pathology reports generated from military treatment facilities. Two Perl-based algorithms are validated to classify WHO grade for tumors of the CNS and Gleason grades for prostate cancer. Case-finding cohorts were developed using diagnostic codes and matched by unique identifiers to obtain pathology records generated in the Military Health System for active duty service members from 2013 to 2018. Perl-based algorithms were applied to classify document-based pathology reports to identify malignant CNS tumors and prostate cancer, followed by a hand-review process to determine accuracy of the algorithm classifications. Inter-rater reliability, sensitivity, specificity, positive predictive values (PPVs), and negative predictive values were computed following abstractor adjudication. The high PPV for the Perl-based algorithms to classify CNS tumors (PPV > 98%) and prostate cancer (PPV > 99%) supports this approach to classify malignancies for cancer surveillance operations, mediated by a hand-reviewed semiautomated process to increase sensitivity by capturing ungraded cancers. Early detection was pronounced where 33.6% and 50.7% of malignant records retained a CNS WHO grade of II or a Gleason score of 6, respectively. Sensitivity metrics met criteria (> 75%) for brain (79.9%, 95% CI, 73.0 to 85.7) and prostate (96.7%, 95% CI, 94.9 to 98.0) cancers. Semiautomated, document-based text classification using Perl coding successfully leveraged identification of WHO and Gleason grades to classify pathology records for CNS tumors and prostate cancer. The process is recommended for data quality initiatives to support cancer reporting functions, epidemiology, and research.

Abstract P059: Exploiting mutant PPM1D-induced metabolic defects with nanoparticle-encapsulated NAMPT inhibitors

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is a leading cause of death in pediatric cancer, with an abysmal <1% 5-year survival rate due to lack of effective treatment options. A significant effort is needed to understand the genetic landscape of this disease to develop novel therapeutic strategies and modalities. Recently, the Bindra laboratory found that a truncation mutation in the gene PPM1D, found in ~30% of DIPG cases, causes global epigenetic alterations that lead to therapeutic vulnerabilities. They found that mutant PPM1D activity results in loss of the NAD+ biogenesis protein NAPRT that can be therapeutically targeted by inhibitors of another protein in the NAD+ biogenesis pathway NAMPT (NAMPTi), providing a viable therapeutic strategy for these cancers. Some NAMPTis have been FDA-approved for clinical usage, but present with systemic and retinal toxicity. Moreover, while there are few NAMPTis that can pass the blood brain barrier through systemic delivery, studies show diminished concentrations at the target site. Together, current studies show that the use of NAMPTis for precision targeting of CNS cancers such as DIPG with mutant PPM1D status is a promising therapeutic strategy, but impractical given the limitations of these drugs. However, recent developments in drug delivery systems offer a chance to overcome these issues. Tools such as nanoparticle (NP) drug delivery and unique injection set-ups such as convection-enhanced delivery (CED) allow for drugs such as NAMPTis to be reconsidered for clinical usage. To circumvent the challenges presented by these drugs, we have developed and characterized nanoparticles that encapsulate NAMPTis (NAMPTi-NP) and use CED for sustained intratumoral delivery. Thus far, we have fabricated and optimized PLA-PEG copolymeric nanoparticles capable of encapsulating the NAMPTi, GMX-1778. We characterized these nanoparticles based on (1) hydrodynamic diameter, (2) zeta potential, and (3) stability within an artificial cerebrospinal fluid solution. We have performed both in vitro and in vivo assays to determine the functionality of the NAMPTi-NPs through (1) cellular uptake studies via immunofluorescence, (2) functional analysis via NAD+ quantification, (3) short- and long-term cell viability assays to determine sensitivity to the NAMPTi-NP, and (4) in vivo biodistribution studies to assess sustained retention of NAMPTi-NP with CED intracranial injections. We find that NAMPTi-NPs have immediate and sustained cellular uptake, loss of NAD+ post-treatment indicating effective targeting, and enhanced sensitivity in long-term viability studies in mutant PPM1D models. Lastly, these NAMPTi-NP display prolonged retention in brain tissue compared to free drug injection over time. With further in vivo validation, this NP-based strategy will be a powerful tool for targeting mutant PPM1D DIPG and other cancers. Citation Format: Matthew A. Murray, Yazhe Wang, Ranjini Sundaram, Jason Beckta, Mark Saltzman, Ranjit Bindra. Exploiting mutant PPM1D-induced metabolic defects with nanoparticle-encapsulated NAMPT inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P059.

Family Formation and Socio-Economic Status among 35-Year-Old Men Who Have Survived Cancer in Childhood and Early Adulthood: A Register-Based Cohort Study

Introduction: The number of children and young adults who survive cancer has steadily increased over the past decades. Consequently, life circumstances after cancer have gained increasing importance. The aim of this study was to explore family formation and socio-economic status among 35-year-old men having survived cancer in childhood or early adulthood compared to an age-matched comparison group. Methods: This study is a national, register-based cohort study among 35-year-old men. Men diagnosed with cancer in childhood and early adulthood were registered between 1978 and 2016. At the time of diagnosis, each patient was randomly matched with 150 men without cancer from the background population within the same birth year. Those still alive at the age of 35 years were included in the study population. Results: The study population consisted of 4,222 men diagnosed with cancer in childhood or early adulthood and 794,589 men in the age-matched comparison group. Men who have survived cancer during childhood or early adulthood have a reduced probability of having children, and lower probability of getting married or of cohabitation than those from an age-matched comparison group. Men who have survived CNS cancer also have a lower probability of having a higher education than high school and a higher probability of being outside the workforce than those from an age-matched comparison group. Discussion/Conclusion: Many men who have survived cancer during childhood or early adulthood are influenced by their cancer later in life, which was apparent in family formation, educational achievements, and labour market attachment. Continued focus on rehabilitation and needs for support among the male survivors of childhood and youth cancer is warranted.

INNV-37. XCELSIOR: A REAL-TIME, REAL-WORLD LEARNING PLATFORM FOR PATIENTS WITH ADVANCED CANCER

Abstract xCures operates a direct-to-patient, real-world evidence platform for decentralized clinical research. The platform leverages a nationwide observational research protocol (XCELSIOR, NCT03793088) to aggregate, normalize, and analyze N-of-1 clinical outcomes to continuously learn from and inform treatment decisions. Individual data elements are extracted directly from medical documents such as clinic notes, and radiology, genomics, and pathology reports. The data elements are standardized to established biomedical ontologies and stored in a validated and part 11 compliant electronic database, suitable for statistical analyses and regulatory filings. This permits comparison of patient outcomes across institutions and removes the burden of data entry from oncologists and their staff. As an extremely efficient real-world data solution, we have utilized this platform to accelerate both academic- and commercial-sponsored clinical research, prospectively integrating diagnostics and algorithms with interventional treatments. For each patient that participates in XCELSIOR, artificial intelligence-powered clinical decision support algorithms suggest testing and treatment options. These options and supporting treatment rationales are sourced from key opinion leaders, tumor boards, clinical researchers, practicing oncologists, and published literature, and ranked using the real-world outcomes data from the registry. At the conference, we will present an overview of this real-time learning infrastructure and report on clinical case studies for pharma and non-profit groups including over 75 virtual tumor boards and real-world evidence generated from over 150 patients with CNS cancers that we have helped in partnership with Cancer Commons and The Musella Foundation for Brain Tumor Research and Education. Outcomes analyses stratified by therapeutic interventions and biomarkers will be reported, including frequency of adverse events, time to treatment failure, time to disease progression, and overall survival. Interventions include standard-of-care chemotherapies as well as therapies accessed by clinical trial, expanded access, and off-label prescription.

Click Chemistry-Based Synthesis of New 1-formyl-naphthalen-2-yloxymethyl-1,2,3-triazoles, Anticancer Screening and 2D-NMR Studies

A series of 10 various 2-[5-(1-formyl-naphthalen-2-yloxymethyl)-[1,2,3]triazole-1-yl]-substituted phenyl acetamides (5a-5j) were synthesized through copper(I)-catalyzed 1,3-dipolar cycloaddition reaction of 2-(prop-2-ynyloxy)naphthalene-1-carbaldehyde (2) and different 2-azido-N-phenylacetamide derivatives (4) under the assorted click chemistry pathway. Its specific biocompatibility to solidify more effectual lead discovery procedures in medicinal chemistry has its own space in the anticancer drugs discovery module. The structural compatibility was studied by HMBC and APT type of NMR techniques. In vitro, the anticytotoxic evaluation indicated that some of the synthesized molecules exhibited potent inhibitory activities in various cancer cell lines. It has been found that out of 10 screened molecules, 5a and 5h demonstrated good cytotoxic potential against CNS, Melanoma, and Breast cancer panel. Derivatives 5e and 5i, bearing 4-fluoro and 4-bromo groups, respectively, demonstrated average cytotoxic potential against CNS, Ovarian, and Renal cancer.

Synthesis and study of the anticancer activity of some new 7H-[1,2,4]triazolo [3,4-b][1,3,4]thiadiazines

The problem of finding effective low-toxic anticancer agents is one of the most important in modern medicine and pharmacy. Despite a large selection of anticancer drugs and a variety of mechanisms of their action, the effectiveness of existing drugs continues to be insufficient. Among the numerous natural and synthetic heterocyclic compounds that exhibit anticancer activity, 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives, which are able to initiate different pathways of tumor cell death. Based on this, the synthesis of new derivatives of this class of compounds and the study of their anticancer properties is relevant. The aim of the work is to synthesis of new 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines and study their anticancer activity. Materials and methods. It was used methods of organic synthesis, physical and chemical methods of analysis organic compounds (1H NMR spectroscopy, elemental analysis). Results. In order to obtain new 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines, the interaction implemented of 4-amino-4H-[1,2,4]triazole-3-thiols with the corresponding bromoacetophenones. The reaction proceeds by heating the above reagents in alcohol with the closure of the thiadiazine ring and the formation of 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine systems. The structure of all synthesized compounds was confirmed by 1H NMR spectroscopy and elemental analysis data. The study of the anticancer activity of the synthesized compounds was carried out in the framework of the international scientific program DTP (Developmental Therapeutics Program) of the National Cancer Institute (NCI, Bethesda, Maryland, USA). It was found that the synthesized compounds exhibited different levels of anticancer activity. The most active among the tested substances was compound 3j with an average GP value of 28.73. The most sensitive to it were the lines of melanoma MDA-MB-435 and SK-MEL-2, kidney cancer A498 and RXF 393, CNS cancer SNB-75, and non-small cell lung cancer NCI-H522. The secondary stage of studies of this compound confirmed its high anticancer activity against most cancer cell lines. Conclusions. As a result of the interaction of 4-amino-4H-[1,2,4]triazole-3-thiols with the relevant bromoacetophenones, a series of new triazolo[3,4-b][1,3,4]thiadiazines was not described in the literature was synthesized. Testing the synthesized compounds for the antitumor activity made it possible to isolate 1 highly active compound with a pronounced anticancer effect, which in terms of activity approaches or exceeds the known drugs 5-fluorouracil (5-FU) and cisplatin, as well as an anticancer agent, curcumin.

Near-Infrared MAO A Inhibitor (NMI) Outperformed FDA-Approved Chemotherapeutic Agents in Brain and Other Cancers: A Bioinformatic Analysis of NCI60 Screening Data.

Our previous work has shown that monoamine oxidase A (MAO A) is overexpressed in glioma and prostate cancer. Near-infrared dye conjugate MAO A Inhibitor (NMI) inhibited the growth of these cancers. This study investigated the effects of NMI on other cancers by NCI60 screening. Our results showed that 48 out of 59 screened cell lines from nine types of cancer had 100% growth inhibition at 10 μM NMI treatment. The in vitro efficacy of NMI determined by growth inhibition (GI50 and TGI) and lethal doses (LC50) has been further studied in various cell lines of CNS cancer, prostate cancer, and non-small cell lung cancer (NSCLC), these three cancers showed increased MAO A expression in tumors compared to normal tissues. Based on the waterfall plots and the 3D scatter plot of GI50, TGI, and LC50 data, NMI showed higher potency to several CNS cancer and NSCLC cell lines than prostate cancer cell lines. In vitro efficacy of NMI outperformed FDA-approved drugs for CNS cancer, prostate cancer, and NSCLC, respectively. The Pairwise Pearson Correlation Coefficient (PCC) showed that NMI has a unique mechanism compared to the existing anticancer drugs. This study shows that NMI is a novel theragnostic drug with high potency and unique mechanisms for brain, prostate, NSCLC, and other cancers.

Female participation in U.S. oncology clinical trials registered on ClinicalTrials.gov from 2008 to 2020.

85 Background: Females are thought to be underrepresented in clinical trials, which may lead to care disparities. We characterized female enrollment trends in U.S. oncology trials registered on ClinicalTrials.gov and identified features associated with accurate representation. Methods: We employed a cross-sectional study design with descriptive, logistic regression, and cox regression analyses. We downloaded 270,172 studies registered on the Aggregate Analysis of the ClinicalTrials.gov database from October 1, 2008 to March 9, 2020, excluding non-interventional and reproductive organ specific trials. We then applied cancer/oncology specific Medical Subject Heading terms and manually reviewed the remaining 27,521 trials for true oncology content. Prevalence-corrected estimates for female participation were calculated as the percentage of females among trial participants divided by the percentage of females in the disease population per U.S. Surveillance, Epidemiology, and End Results Program (SEER) data (participation to prevalence ratio [PPR]), with a range between 0.8 and 1.2 reflecting accurate female representation in the trial. Results: Of 26,894 trials meeting eligibility criteria, 9,059 trials were completed in the U.S., 2,499 trials reported completed study status, and only 1,256 trials reported sex. Among 1,256 oncology trials and 229,056 participants, overall female representation was 46.9% (95% CI, 45.4-48.4%). 43% of trials were industry funded, 29% academic, and 28% U.S. government. Females were underrepresented compared to their disease burden in anal canal (PPR 0.21), thyroid (PPR 0.57), stomach (PPR 0.68), kidney (PPR 0.77), and bone (PPR 0.79) cancer trials. They were accurately represented in head and neck (PPR 0.80), lung (PPR 0.84), bladder (PPR 0.85), skin (PPR 0.88), pancreas (PPR 0.88), colon (PPR 0.90), hematologic (PPR 0.91), liver (PPR 1.01), CNS (PPR 1.03), soft tissue (PPR 1.05), and esophagus (PPR 1.05) cancer trials. Accurate representation was significantly associated with industry funding and pancreas cancer trial focus, but not associated with trial type (medical, surgical, radiation, other invasive, other) (Table). Conclusions: Females are underrepresented compared to their disease burden in many solid tumor clinical trials. Stakeholders can look to industry funded and pancreas cancer trials as models of improvement, but must increase female representation in clinical trials to improve cancer care. [Table: see text]

New model for an epoxy-based brachytherapy source to be used in spinal cancer treatment

The present work described the cold fabrication of a P-32 radioactive source to be used in CNS cancer using epoxy resin. The epoxy plaque fabricated with Teflon mold presented better agreement. MCNP simulation evaluated the radiation dose. Special attention was given to factors that can impact dose distribution. Average dose was 16.44 ± 2.89% cGy/s. Differences of less than 0.01 cm in thickness within the plaque lead to differences of up to 12% in the dose rate.

The Synthesis and Anticancer Potentials of Quinoline Analogues: A Review of Literature

New drugs introduced in the market each year, have privileged structures specifically for anticancer targets, of which quinoline-based analogues also play an important role. This review highlights quinoline and its derivatives, which have great potency against various cancer cells, including prostate cancer, breast cancer, colon cancer, pancreas cancer, and many more. This review describes the most preferred process-scale synthetic approaches of quinoline and its derivatives having a specific pharmacophore for anticancer targets. It also describes the undergoing development and recently approved drugs in tabular form. Quinoline moiety as a privileged structural pharmacophore has the most effective activity against different cancer cell lines like prostate cancer, breast cancer, stomach cancer, pancreas cancer, Colon cancer, CNS cancer, and renal cancer. It can be used as a lead compound for further research on anticancer drug discovery.

Synthesis and Anticancer Evaluations of Novel Thiazole Derivatives Derived from 4-Phenylthiazol-2-amine

Many novel thiazole derivatives were designed and synthesized using 4-phenylthiazol-2-amine. The reactivity of the latter compound toward different chemical reagents was studied. The structure of the newly synthesized compounds was established based on elemental analysis and spectral data. Furthermore, twenty compounds of the synthesized systems were selected and evaluated in (µM) as significant anticancer agents towards three human cancer cell lines [MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), and SF-268 (CNS cancer)] and normal fibroblasts human cell line (WI-38). The results showed that compounds 9 and 14a displayed higher effeciency than the reference doxorubicin.

Development of New Meridianin/Leucettine-Derived Hybrid Small Molecules as Nanomolar Multi-Kinase Inhibitors with Antitumor Activity.

Although the sea ecosystem offers a broad range of bioactivities including anticancer, none of the FDA-approved antiproliferative protein kinase inhibitors are derived from a marine source. In a step to develop new marine-inspired potent kinase inhibitors with antiproliferative activities, a new series of hybrid small molecules (5a–5g) was designed and synthesized based on chemical moieties derived from two marine natural products (Meridianin E and Leucettamine B). Over a panel of 14 cancer-related kinases, a single dose of 10 µM of the parent hybrid 5a possessing the benzo[d][1,3]dioxole moiety of Leucettamine B was able to inhibit the activity of FMS, LCK, LYN, and DAPK1 kinases with 82.5 ± 0.6, 81.4 ± 0.6, 75.2 ± 0.0, and 55 ± 1.1%, respectively. Further optimization revealed the most potent multiple kinase inhibitor of this new series (5g) with IC50 values of 110, 87.7, and 169 nM against FMS, LCK, and LYN kinases, respectively. Compared to imatinib (FDA-approved multiple kinase inhibitor), compound 5g was found to be ~ 9- and 2-fold more potent than imatinib over both FMS and LCK kinases, respectively. In silico docking simulation models of the synthesized compounds within the active site of FMS, LCK, LYN, and DAPK1 kinases offered reasonable explanations of the elicited biological activities. In an in vitro anticancer assay using a library of 60 cancer cell lines that include blood, lung, colon, CNS, skin, ovarian, renal, prostate, and breast cancers, it was found that compound 5g was able to suppress 60 and 70% of tumor growth in leukemia SR and renal RXF 393 cell lines, respectively. Moreover, an ADME study indicated a suitable profile of compound 5g concerning cell permeability and blood-brain barrier (BBB) impermeability, avoiding possible CNS side effects. Accordingly, compound 5g is reported as a potential lead towards novel antiproliferative marine-derived kinase modulators.

Design, synthesis, and biological evaluation of N-(4-substituted)-3-phenylisoxazolo[5,4–d]pyrimidin-4-amine derivatives as apoptosis-inducing cytotoxic agents

A library of new 3-phenylisoxazolo[5,4–d]pyrimidines (8–10) was designed based on a scaffold hybridization technique incorporating the important pharmacophoric features of 4-aminopyrimidine and phenyl isoxazole scaffold which is renowned for its BET inhibition activity. The designed molecules were synthesized and evaluated with the NCI-60 cell line panel. Examination by NCI-60 cell lines at single-dose and the five-dose study showed that compound 10h exhibited promising growth inhibitory effects with GI50 values on various cancer cell lines such as HCT-15 (Colon Cancer)-0.0221 μM, MDA-MB-435 (Melanoma) − 0.0318 μM, SNB-75(CNS Cancer)-0.0263 μM, and MCF7 (Breast Cancer)-0.0372 μM. Further studies to know the mechanism of action of 10h based on the phase-contrast microscopic evaluation, DAPI, acridine orange/ethidium bromide (AO/EB) staining, and annexin V-FITC assays revealed that elevation in the intracellular ROS leads to alteration in mitochondrial membrane potential which in turn induced the apoptosis in BT-474 cancer cells, which could be the plausible mechanism of action for compound 10h.

Novel thienopyrimidine-aminothiazole hybrids: Design, synthesis, antimicrobial screening, anticancer activity, effects on cell cycle profile, caspase-3 mediated apoptosis and VEGFR-2 inhibition

A series of novel hybrid compounds of hexahydrobenzo[4,5]thieno[2,3-d]pyrimidine with aminothiazole scaffolds were synthesized. The synthesized compounds were evaluated for their cytotoxic activity against the NCI-60 human tumor cell line panel. Compounds 7c, 7d and 7e exhibited significant antiproliferative activities at 10−5 M dose. Compound 7c exhibited excellent cytotoxic activity against CNS cancer cell lines including SNB-75 and SF-295 as well as renal cancer cell line CAKI-1 when compared with sorafenib as standard anticancer drug. In addition, compound 7d showed almost comparable anticancer activity to sorafenib against SNB-75 cell line and displayed moderate activity against SF-295 and CAKI-1 cell lines in comparison to sorafenib. Compound 7c inhibited the vascular endothelial growth factor receptor 2 (VEGFR-2) with IC50 of 62.48 ± 3.7 nM and decreased both total VEGFR-2 and phosphorylated VEGFR-2 in treated SNB-75 cells suggesting its ability to down regulate cell proliferation, growth, and survival.. The flow cytometric analysis showed that 7c displayed its cytotoxic activity through the reduction of the cellular proliferation and induction of cell cycle arrest at the G2/M phase. Compound 7c clearly boosted the level of the apoptotic caspase-3. All the synthesized compounds were also screened for their antibacterial and antifungal activity against four pathogenic strains of both Gram-positive and Gram-negative as well as Candida albicans. Only compound 7d exhibited antifungal activity against Candida albicans compared to nystatin as the standard antifungal compound.

A Bioinformatics Analysis of the Potential Roles of Aquaporin 4 in Human Brain Tumors: An Immune-Related Process.

Aquaporin 4 (AQP4) is an ubiquitously expressed membrane protein channel found in the central nervous system and mainly on astrocytes. Recent studies on AQP4 has implicated it in tumorigenesis. It is of interest to determine the potential value of AQP4 in identifying, guiding treatment and prognosticating various types of CNS cancers. This investigation systematically investigated the oncogenic role of AQP4 across 33 CNS tumors found in GEO and TCGA datasets. We found that CNS tumors strongly expressed AQP4. There appeared to be a strong link between the prognosis of patients with a CNS malignancy and degree of AQP4 expression. AQP4 expression influences the degree of CD8+ T-cell infiltration level as well as cancer-associated fibroblast infiltration in CNS tumors. Moreover, synaptic vesicle cycle and phosphatidylinositol signaling system-associated functions were also found to be related to AQP4 functional mechanisms. Furthermore, potential AQP4 inhibitors have also been explored by using Specs data base and virtual screening technique. This study contributes toward current knowledge regarding the role of AQP4 in CNS tumors.

End-of-life care for pediatric patients with CNS cancer: description and comparison based on palliative care provision.

End-of-life care for pediatric patients with CNS cancer: description and comparison based on palliative care provision.

The impact of COVID-19 on clinical cancer care: An individual-patient level analysis.

1533 Background: At the outset of the COVID-19 pandemic, concerns for the safety of patients receiving anti-cancer treatment coupled with pressures on healthcare services prompted review of standard clinical care pathways in the UK. Revised consensus treatment guidelines were generated. Individual patient-level data regarding actual treatment modifications implemented in clinical practice are lacking. Methods: All anti-cancer treatment plans of patients with breast, lung, renal, hepatopancreatobiliary, CNS cancers and melanoma attending a single academic cancer centre in the UK between 16 March and 31 May 2020 were reviewed and any modifications to standard practice were documented. The effect of patient (age, ECOG performance status [PS], sex) and cancer (site, stage, treatment intent) characteristics on likelihood of treatment modifications were analysed using univariable and multivariable models. Results: Treatment plans for 925 patients were reviewed: median patient age was 63 (range 19-97); 66% were female; 73% were PS 0-1; 45% were on a curative pathway. Overall, 47% of all patients had one or more modifications made to their treatment plans: 53% of surgeries (primarily being delayed); 41% of radiotherapy (primarily reduced fractions delivered); 39% of systemic therapy prescriptions. 96-100% of all systemic therapy modifications resulted in treatment de-escalation, excluding endocrine therapy used as a bridge to defer primary breast cancer surgery. Biological therapy was predominantly interrupted (49%), immunotherapy was mostly omitted entirely (36%), and chemotherapy varied between interruptions (39%) or omissions (31%). Relative to the likelihood of modification to chemotherapy, surgery was significantly more likely to be modified (OR 1.69 95%CI 1.20-2.38). Chemotherapy, radiotherapy, biological therapy and immunotherapy were all modified to a similar degree. Multivariate analysis identified PS ≥2 (OR 1.79, 95% CI 1.18–2.75), but not patient age, as a predictor of treatment modification. Some tumour types were less likely to undergo any modification: stage 1-3 lung (OR 0.13, 95%CI 0.04-0.37), stage 4 lung (OR 0.26 95%CI 0.24–0.60) and stage 4 renal cancer (OR 0.22 95%CI 0.09-0.52). Conclusions: This single centre analysis demonstrated almost half of cancer patients had their treatment modified, the overwhelming majority resulting in treatment de-escalation. The impact of the treatment modifications on overall cancer patient outcomes remains to be determined.

Cryptic Biosynthesis of the Berkeleypenostatins from Coculture of Extremophilic Penicillium sp.

Coculture fermentation of Penicillium fuscum and P. camembertii/clavigerum yielded berkeleypenostatins A-G (1-7) as well as the previously reported berkeleylactones A-H, the known macrolide A26771B, citrinin, and patulin. As was true with the berkeleylactones, there was no evidence of the berkeleypenostatins in either axenic culture. The structures were deduced from analyses of spectral data, and the absolute configuration of berkeleypenostatin A (1) was determined by single-crystal X-ray crystallography. Berkeleypenostatins A (1) and E (5) inhibited migration of human pancreatic carcinoma cells (HPAF-II). Both compounds were tested by the NCI Developmental Therapeutics Program. In the NCI 60 cell five-dose screen, berkeleypenostatin E (5) was the more active of the two, with 1-10 μM total growth inhibition (TGI) of all leukemia cell lines, as well as the majority of colon, CNS, melanoma, ovarian, prostate, renal, and breast cancer cell lines.

Expression patterns and clinical significances of PBK in lung cancer: an analysis based on Oncomine database.

BackgroundBased on both biological and clinical perspectives, lung cancer is a diverse disease with varied histological subtypes. At present, molecular-targeted drugs have broad application prospects in lung cancer clinical therapy. Here, we explored the expression profile of PDZ-binding kinase (PBK) in lung cancer along with its prognostic potential.MethodsWe employed the Oncomine web resource to explore the differential expression of PBK in LC tissues. Additionally, the prognostic capacity of PBK in lung cancer was explored via the Kaplan-Meier Plotter web resource.ResultsOverall, 80 studies documented remarkable differences in the expression of PBK in tumor tissue and healthy control tissue. In all studies, 63 studies showed that PBK was upregulated and 17 studies demonstrated that PBK was downregulated. Of the 80 studies, 63 studies showed an increase in PBK expression in diverse kinds of tumor tissues including the following: bladder cancer, gastric cancer, brain and CNS cancer, cervical cancer, esophageal cancer, head and neck cancer, liver cancer, breast cancer, lung cancer, colorectal cancer, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma and others. In addition, PBK expression was increased in 774 lung cancer tissues (P<0.05). Kaplan-Meier Plotter web resource analysis, revealed that PBK levels were negatively linked to the total survival period of individuals with lung cancer (P<0.05). Subgroup evaluations demonstrated that the prognostic significance of PBK was more obvious in individuals with lung adenocarcinoma. In lung cancer categorized by gender, level I-III differentiation, and stage 1 and stage 3 of clinical staging, the survival advantage of the PBK high-expression group was remarkably lower than that of the low-expression group lung cancer patients (P<0.05).ConclusionsPBK is an oncogene that is markedly upregulated in lung cancer tissues, and it is correlated with poor prognosis. PBK can be employed as a target in the design of new drugs for lung cancer treatment.