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Interleukin-37 is a cytokine with potent immunosuppressive properties that has been shown to have potential to treat autoimmune and chronic inflammatory diseases, as well as certain types of cancer. IL-37 is a 19 kDa protein which interacts with proteins in receptor-dependent and receptor-independent pathways. The expression of the IL-37 protein cloned into the pET-28a vector was optimized in Rosetta 2(DE3) after comparing its expression with Rosetta-gami 2(DE3) and Rosetta 2(DE3) pLysS, which was then used for the large-scale production of IL-37. IMAC purification of IL-37 yielded > 97% pure 0.9 mg/mL protein from auto-induced fermentation. The IC 50 value of IL-37 was < 1 µM, which was similar to that of doxorubicin, and proliferation of > 80% of all cancer cells was inhibited by 100 µg/mL of IL-37 protein. IL-37 may be a promising theragnostic target for cancer due to its comparable IC 50 value with that of doxorubicin., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Chromosome-containing micronuclei are a hallmark of aggressive cancers. Micronuclei frequently undergo irreversible collapse, exposing their enclosed chromatin to the cytosol. Micronuclear rupture catalyzes chromosomal rearrangements, epigenetic abnormalities, and inflammation, yet mechanisms safeguarding micronuclear integrity are poorly understood. In this study, we found that mitochondria-derived reactive oxygen species (ROS) disrupt micronuclei by promoting a noncanonical function of charged multivesicular body protein 7 (CHMP7), a scaffolding protein for the membrane repair complex known as endosomal sorting complex required for transport III (ESCRT-III). ROS retained CHMP7 in micronuclei while disrupting its interaction with other ESCRT-III components. ROS-induced cysteine oxidation stimulated CHMP7 oligomerization and binding to the nuclear membrane protein LEMD2, disrupting micronuclear envelopes. Furthermore, this ROS-CHMP7 pathological axis engendered chromosome shattering known to result from micronuclear rupture. It also mediated micronuclear disintegrity under hypoxic conditions, linking tumor hypoxia with downstream processes driving cancer progression.

Homologous recombination (HR) deficiency is associated with DNA rearrangements and cytogenetic aberrations 1 . Paradoxically, the types of DNA rearrangements that are specifically associated with HR-deficient cancers only minimally affect chromosomal structure 2 . Here, to address this apparent contradiction, we combined genome-graph analysis of short-read whole-genome sequencing (WGS) profiles across thousands of tumours with deep linked-read WGS of 46 BRCA1- or BRCA2-mutant breast cancers. These data revealed a distinct class of HR-deficiency-enriched rearrangements called reciprocal pairs. Linked-read WGS showed that reciprocal pairs with identical rearrangement orientations gave rise to one of two distinct chromosomal outcomes, distinguishable only with long-molecule data. Whereas one (cis) outcome corresponded to the copying and pasting of a small segment to a distant site, a second (trans) outcome was a quasi-balanced translocation or multi-megabase inversion with substantial (10 kb) duplications at each junction. We propose an HR-independent replication-restart repair mechanism to explain the full spectrum of reciprocal pair outcomes. Linked-read WGS also identified single-strand annealing as a repair pathway that is specific to BRCA2 deficiency in human cancers. Integrating these features in a classifier improved discrimination between BRCA1- and BRCA2-deficient genomes. In conclusion, our data reveal classes of rearrangements that are specific to BRCA1 or BRCA2 deficiency as a source of cytogenetic aberrations in HR-deficient cells., (© 2023. The Author(s).)

Natural killer (NK) cells are considered to be the foremost fighters of our innate immune system against foreign invaders and thus tend to promptly latch onto the virus-infected and tumor/cancerous cells, killing them through phagocytosis. At present, the application of genetically engineered Chimeric antigen receptor (CAR) receptors ensures a guaranteed optimistic response with NK cells and would not allow the affected cells to dodge or escape unchecked. Hence the specificity and uniqueness of CAR-NK cells over CAR-T therapy make them a better immunotherapeutic choice to reduce the load of trafficking of numerous tumor cells near the healthy cell populations in a more intact way than offered by CAR-T immunotherapy. Our review mainly focuses on the preclinical, clinical, and recent advances in clinical research trials and further strategies to achieve an augmented and efficient cure against solid tumors., (© 2023 Wiley Periodicals LLC.)

Patient selection for synthetic lethal-based cancer therapy may be improved by assessment of gene-specific loss of heterozygosity (LOH) and biallelic loss of function (LOF). This report describes SyNthetic lethal Interactions for Precision Diagnostics (SNiPDx), a targeted next-generation sequencing (NGS) panel for detection of LOH and biallelic LOF alterations in 26 target genes focused on DNA damage response pathways, in tumor-only formalin-fixed, paraffin-embedded (FFPE) samples. NGS was performed across all exons of these 26 genes and encompassed a total of 7632 genome-wide single-nucleotide polymorphisms on genomic DNA from 80 FFPE solid tumor samples. The Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing algorithm was optimized to assess tumor purity and copy number based on heterozygous single-nucleotide polymorphisms. SNiPDx demonstrated high sensitivity (95%) and specificity (91%) for LOH detection compared with whole genome sequencing. Positive agreement with local NGS-based testing in the detection of genetic alterations was 95%. SNiPDx detected 93% of biallelic ATM LOF mutations, 100% of ATM single-nucleotide variants and small insertions/deletions, and 100% of all ATM LOH status events identified by orthogonal NGS-based testing. SNiPDx is a novel, clinically feasible test for analysis of allelic status in FFPE tumor samples, which demonstrated high accuracy when compared with other NGS-based approaches in clinical use., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. All rights reserved.)

Background: Up to 10% of patients with ischaemic stroke have comorbid cancer and stroke in these patients is thought to have a poor short-term prognosis. There is little known about the long-term cardiovascular morbidity and mortality outcomes after incident ischaemic stroke in patients with recent cancer history., Objective: To assess the risk of subsequent cardiovascular morbidity and mortality outcomes in patients with an incident ischaemic stroke and recent cancer history., Methods: Patients aged ≥18 years with an incident ischaemic stroke between 1998 and 2017, with any diagnosis of cancer within 12 months before the stroke event, and no prior history of serious vascular event were identified from UK Clinical Practice Research Datalink (CPRD GOLD) linked to Hospital Episode Statistics (HES) data. To minimize selection bias, these patients were propensity-score matched with patients with incident ischaemic stroke and no history of cancer. Propensity-score matching was done using covariates such as demographic data, vascular risk factors, comorbid conditions, and prescribed medication. Multivariable models (Competing risks and Cox regression) were used to determine the risk of subsequent major adverse cardiovascular event (MACE) outcomes and all-cause mortality., Results: Our cohort included 22,460 patients with a median age of 75 (IQR 64-83) years and a follow-up of 12.3 (IQR 7.2-16.7) years. Recent cancer was identified in 1,149 patients (5.1%) at the time of incident ischaemic stroke. The patients with recent cancer history had a lower risk of composite MACE (sub-distribution hazard ratio (SHR) 0.83 [95% CI: 0.75-0.92]) and recurrent stroke (SHR 0.85 95% CI:0.75-0.96]) and a higher risk of all-cause mortality (hazard ratio 1.67 [95% CI:1.47-1.91]). The risk of coronary heart disease, peripheral vascular disease, heart failure, and CVD-related death outcomes did not differ significantly between the groups., Conclusions: After incident ischaemic stroke, patients with recent cancer history have a lower risk of composite MACE and recurrent stroke outcomes but a higher risk of all-cause mortality when compared with patients without a prior history of cancer., (Copyright © 2022. Published by Elsevier B.V.)

In Asia, mulberry has long been used to treat various infectious and internal ailments as a traditional medication. The compounds found in it have the potential to improve human health. Because there is no approved and defined evaluation procedure, it has not been formally or scientifically recognized. As a result of these investigations, a new frontier in traditional Chinese medicine has opened up, with the possibility of modernization, for the interaction between active components of mulberry and their biological activities. These studies have used current biotechnological technologies. For ages, mulberry has been used as an herbal remedy in Asia to cure various diseases and internal disorders. It has a high concentration of bioactive chemicals that benefit human health. The most abundant phenolic components extracted from white mulberry leaves are flavonoids (Kuwanons, Moracinflavans, Moragrols, and Morkotins), phenolic acids, alkaloids, and so forth. Flavonoids, benzofurans, chalcones, and alkaloids have been discovered to have cytotoxic effects on human cancer cell lines. There is growing evidence that mulberry fruits can potentially prevent cancer and other aging-related disorders due to their high concentration of bioactive polyphenolic-rich compounds and macro and micronutrients. Anthocyanins are rapidly absorbed after eating, arriving in the plasmalemma within 15-50 min and entirely removed after 6-8 hr. Due to a lack of an approved and consistent technique for its examination, it has yet to be formally or scientifically recognized. The mulberry plant is commercially grown for silkworm rearing, and less attention is paid to its bioactive molecules, which have a lot of applications in human health. This review paper discusses the phenolic compounds of white mulberry and black mulberry in detail concerning their role in cancer prevention., (© 2023 John Wiley & Sons Ltd.)

In cancer, evolutionary forces select for clones that evade the immune system. Here we analyzed >10,000 primary tumors and 356 immune-checkpoint-treated metastases using immune dN/dS, the ratio of nonsynonymous to synonymous mutations in the immunopeptidome, to measure immune selection in cohorts and individuals. We classified tumors as immune edited when antigenic mutations were removed by negative selection and immune escaped when antigenicity was covered up by aberrant immune modulation. Only in immune-edited tumors was immune predation linked to CD8 T cell infiltration. Immune-escaped metastases experienced the best response to immunotherapy, whereas immune-edited patients did not benefit, suggesting a preexisting resistance mechanism. Similarly, in a longitudinal cohort, nivolumab treatment removes neoantigens exclusively in the immunopeptidome of nonimmune-edited patients, the group with the best overall survival response. Our work uses dN/dS to differentiate between immune-edited and immune-escaped tumors, measuring potential antigenicity and ultimately helping predict response to treatment., (© 2023. The Author(s).)

Background: A major driver of cancer chromosomal instability is replication stress, the slowing or stalling of DNA replication. How replication stress and genomic instability are connected is not known. Aphidicolin-induced replication stress induces breakages at common fragile sites, but the exact causes of fragility are debated, and acute genomic consequences of replication stress are not fully explored., Results: We characterize DNA copy number alterations (CNAs) in single, diploid non-transformed cells, caused by one cell cycle in the presence of either aphidicolin or hydroxyurea. Multiple types of CNAs are generated, associated with different genomic regions and features, and observed copy number landscapes are distinct between aphidicolin and hydroxyurea-induced replication stress. Coupling cell type-specific analysis of CNAs to gene expression and single-cell replication timing analyses pinpointed the causative large genes of the most recurrent chromosome-scale CNAs in aphidicolin. These are clustered on chromosome 7 in RPE1 epithelial cells but chromosome 1 in BJ fibroblasts. Chromosome arm level CNAs also generate acentric lagging chromatin and micronuclei containing these chromosomes., Conclusions: Chromosomal instability driven by replication stress occurs via focal CNAs and chromosome arm scale changes, with the latter confined to a very small subset of chromosome regions, potentially heavily skewing cancer genome evolution. Different inducers of replication stress lead to distinctive CNA landscapes providing the opportunity to derive copy number signatures of specific replication stress mechanisms. Single-cell CNA analysis thus reveals the impact of replication stress on the genome, providing insights into the molecular mechanisms which fuel chromosomal instability in cancer., (© 2022. The Author(s).)

Defects in pathways governing genomic fidelity have been linked to improved response to immune checkpoint blockade therapy (ICB). Pathogenic POLE/POLD1 mutations can cause hypermutation, yet how diverse mutations in POLE/POLD1 influence antitumor immunity following ICB is unclear. Here, we comprehensively determined the effect of POLE/POLD1 mutations in ICB and elucidated the mechanistic impact of these mutations on tumor immunity. Murine syngeneic tumors harboring Pole/Pold1 functional mutations displayed enhanced antitumor immunity and were sensitive to ICB. Patients with POLE/POLD1 mutated tumors harboring telltale mutational signatures respond better to ICB than patients harboring wild-type or signature-negative tumors. A mutant POLE/D1 function-associated signature-based model outperformed several traditional approaches for identifying POLE/POLD1 mutated patients that benefit from ICB. Strikingly, the spectrum of mutational signatures correlates with the biochemical features of neoantigens. Alterations that cause POLE/POLD1 function-associated signatures generate T cell receptor (TCR)-contact residues with increased hydrophobicity, potentially facilitating T cell recognition. Altogether, the functional landscapes of POLE/POLD1 mutations shape immunotherapy efficacy., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Cancer patients, being immunocompromised, are at higher risk of coronavirus disease (COVID-19). The current study determines cancer patients’ knowledge, attitude, perception, and impact of the COVID-19 pandemic. Method: A cross-sectional online survey was conducted in Pakistan from 1 April 2020 to 1 May 2020. The study respondents were cancer patients with ages equal to or greater than 18 years. Following a request for participation, the URL for the survey was distributed on numerous channels. Other social media platforms, including WeChat, WhatsApp, Facebook, Twitter, Instagram, Messenger, and LinkedIn, were used to increase cancer patient interaction. The questionnaire comprised five different sections such as: (1) sociodemographic information, (2) knowledge, (3) attitude, (4) perception, and (5) impact of COVID-19 on cancer patients. Descriptive medical statistics such as frequency, percentage, mean, and standard deviation were used to illustrate the demographic characteristics of the study participants. To compare mean knowledge scores with selected demographic variables, independent sample t-tests and one-way analysis of variance (ANOVA) were used, which are also practical methods in epidemiological, public health and medical research. The cut-off point for statistical significance was set at a p-value of 0.05. Results: More than 300 cancer patients were invited, of which 208 agreed to take part. The response rate was 69.33% (208/300). Gender, marital status, and employment status had a significant association with knowledge scores. Of the total recruited participants, 96% (n = 200) (p < 0.01) knew about COVID-19, and 90% were aware of general symptoms of COVID-19 disease, such as route of transmission and preventive measurements. In total, 94.5% (n = 197) (p < 0.01) were willing to accept isolation if they were infected with COVID-19, and 98% (n = 204) (p < 0.01) had reduced their use of public transportation. More than 90% (n = 188) (p < 0.01) of cancer patients were found to be practicing preventative measures such as using a face mask, keeping social distance, and avoiding handshaking and hugging. Around 94.4% (n = 196) (p < 0.01) of cancer patients had been impacted by, stopped or had changed cancer treatment during this pandemic, resulting in COVID-related anxiety and depression. Conclusion: The included cancer patients exhibited a good level of COVID-19 knowledge, awareness, positive attitude, and perception. Large-scale studies and efforts are needed to raise COVID-19 awareness among less educated and high-risk populations. The present survey indicates that mass-level effective health education initiatives are required for developing countries to improve and reduce the gap between KAP and COVID-19.

Mosaic mutations in normal tissues can occur early in embryogenesis and be associated with hereditary cancer syndromes when affecting cancer susceptibility genes (CSG). Their contribution to apparently sporadic cancers is currently unknown. Analysis of paired tumor/blood sequencing data of 35,310 patients with cancer revealed 36 pathogenic mosaic variants affecting CSGs, most of which were not detected by prior clinical genetic testing. These CSG mosaic variants were consistently detected at varying variant allelic fractions in microdissected normal tissues (n = 48) from distinct embryonic lineages in all individuals tested, indicating their early embryonic origin, likely prior to gastrulation, and likely asymmetrical propagation. Tumor-specific biallelic inactivation of the CSG affected by a mosaic variant was observed in 91.7% (33/36) of cases, and tumors displayed the hallmark pathologic and/or genomic features of inactivation of the respective CSGs, establishing a causal link between CSG mosaic variants arising in early embryogenesis and the development of apparently sporadic cancers., Significance: Here, we demonstrate that mosaic variants in CSGs arising in early embryogenesis contribute to the oncogenesis of seemingly sporadic cancers. These variants can be systematically detected through the analysis of tumor/normal sequencing data, and their detection may affect therapeutic decisions as well as prophylactic measures for patients and their offspring. See related commentary by Liggett and Sankaran, p. 889. This article is highlighted in the In This Issue feature, p. 873., (©2021 American Association for Cancer Research.)

Only a fraction of patients with cancer respond to immune checkpoint blockade (ICB) treatment, but current decision-making procedures have limited accuracy. In this study, we developed a machine learning model to predict ICB response by integrating genomic, molecular, demographic and clinical data from a comprehensively curated cohort (MSK-IMPACT) with 1,479 patients treated with ICB across 16 different cancer types. In a retrospective analysis, the model achieved high sensitivity and specificity in predicting clinical response to immunotherapy and predicted both overall survival and progression-free survival in the test data across different cancer types. Our model significantly outperformed predictions based on tumor mutational burden, which was recently approved by the U.S. Food and Drug Administration for this purpose 1 . Additionally, the model provides quantitative assessments of the model features that are most salient for the predictions. We anticipate that this approach will substantially improve clinical decision-making in immunotherapy and inform future interventions., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Long noncoding RNAs (lncRNAs) are longer than 200 nucleotides in length and undergo splicing, capping, polyadenylation, and editing just like mRNA. Evidence is growing that they regulate transcription, splicing, RNA degradation, and translation of genes and that their expression has been linked to a variety of illnesses, including cancer. The advancement of next-generation and high-throughput sequencing has changed the way lncRNAs are identified and characterized, revealing a relationship between lncRNAs and several tumor types. Since then, they have gained a significant attraction as a promising candidate in cancer diagnosis, prognosis, and therapy. Furthermore, they are a good candidate for consideration as tumor biomarkers due to their high stability, better tissue/cell selectivity, aberrant expression in certain malignancies, and easy and noninvasive detection. In addition, lncRNAs are being examined as therapeutic targets in clinical trials for a variety of malignancies. This review highlights the potential of lncRNAs as biomarkers or therapeutic targets in light of the current progress, clinical investigations, and patents filed so far., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Immune checkpoint blockade (ICB) has improved outcomes for patients with advanced cancer, but the determinants of response remain poorly understood. Here we report differential effects of mutations in the homologous recombination genes BRCA1 and BRCA2 on response to ICB in mouse and human tumors, and further show that truncating mutations in BRCA2 are associated with superior response compared to those in BRCA1. Mutations in BRCA1 and BRCA2 result in distinct mutational landscapes and differentially modulate the tumor-immune microenvironment, with gene expression programs related to both adaptive and innate immunity enriched in BRCA2-deficient tumors. Single-cell RNA sequencing further revealed distinct T cell, natural killer, macrophage, and dendritic cell populations enriched in BRCA2-deficient tumors. Taken together, our findings reveal the divergent effects of BRCA1 and BRCA2-deficiency on ICB outcome, and have significant implications for elucidating the genetic and microenvironmental determinants of response to immunotherapy.

Purpose: Tumor mutational profiling is increasingly performed in patients with advanced cancer. We determined the extent to which germline mutation profiling guides therapy selection in patients with advanced cancer., Methods: Patients with cancer undergoing tumor genomic profiling were prospectively consented for germline cancer predisposition gene analysis (2015-2019). In patients harboring germline likely pathogenic or pathogenic (LP/P) alterations, therapeutic actionability was classified using a precision oncology knowledge base. Patients with metastatic or recurrent cancer receiving germline genotype-directed therapy were determined., Results: Among 11,947 patients across > 50 malignancies, 17% (n = 2,037) harbored a germline LP/P variant. By oncology knowledge base classification, 9% (n = 1042) had an LP/P variant in a gene with therapeutic implications (4% level 1; 4% level 3B; < 1% level 4). BRCA1/2 variants accounted for 42% of therapeutically actionable findings, followed by CHEK2 (13%), ATM (12%), mismatch repair genes (11%), and PALB2 (5%). When limited to the 9,079 patients with metastatic or recurrent cancer, 8% (n = 710) harbored level 1 or 3B genetic findings and 3.2% (n = 289) received germline genotype-directed therapy. Germline genotype-directed therapy was received by 61% and 18% of metastatic cancer patients with level 1 and level 3B findings, respectively, and by 54% of BRCA1/2 , 75% of mismatch repair, 43% of PALB2 , 35% of RAD51C/D , 24% of BRIP1 , and 19% of ATM carriers. Of BRCA1/2 patients receiving a poly(ADP-ribose) polymerase inhibitor, 45% (84 of 188) had tumors other than breast or ovarian cancer, wherein the drug, at time of delivery, was delivered in an investigational setting., Conclusion: In a pan-cancer analysis, 8% of patients with advanced cancer harbored a germline variant with therapeutic actionability with 40% of these patients receiving germline genotype-directed treatment. Germline sequence analysis is additive to tumor sequence analysis for therapy selection and should be considered for all patients with advanced cancer., Competing Interests: Zsofia K. StadlerConsulting or Advisory Role: Allergan (I), Genentech/Roche (I), Regeneron (I), Optos (I), Adverum (I), Novartis (I), Regenxbio (I), Gyroscope (I), Neurogene (I) Debyani ChakravartyConsulting or Advisory Role: Medendi Medical Travel Christopher J. FongStock and Other Ownership Interests: Various biotech ETFsPatents, Royalties, Other Intellectual Property: Ultra-Wideband Radar System for Animals Patent September 11, 2018, Patent issuer and number US20150181840A1, Monitoring Treatment of Peripheral Artery Disease (PAD) using Diffuse Optical Imaging, Imaging interfaces for full finger and full hand optical tomography, Systems and methods for dynamic imaging of tissue using digital optical tomography. Karen CadooHonoraria: OncLiveConsulting or Advisory Role: GlaxoSmithKline/Tesaro, AstraZeneca, MSD, GlaxoSmithKline, MJH Life SciencesResearch Funding: AstraZeneca, Syndax, MSD Ying LiuResearch Funding: AstraZeneca, Tesaro/GSK Maria I. CarloConsulting or Advisory Role: PfizerOther Relationship: Prostate Cancer Foundation, Robert Wood Johnson Foundation Alicia LathamOther Relationship: Conquer Cancer Foundation Ritika KundraStock and Other Ownership Interests: Pfizer Carol AghajanianConsulting or Advisory Role: Mersana, Eisai, Roche, AbbVie, AstraZeneca/Merck, Roche/Genentech, Repare TherapeuticsResearch Funding: Genentech/Roche, AbbVie, Clovis Oncology, AstraZeneca Nadeem Abu-RustumHonoraria: Prime OncologyResearch Funding: Stryker/Novadaq, GrailTravel, Accommodations, Expenses: Prime Oncology Anna VargheseConsulting or Advisory Role: RocheResearch Funding: Lilly, Verastem, BioMed Valley Discoveries, Bristol Myers Squibb, Silenseed, IlluminaTravel, Accommodations, Expenses: Roche Eileen M. O'ReillyConsulting or Advisory Role: Merck, Agios, AstraZeneca, Bayer, BeiGene, Berry Genomics, Celgene, CytomX Therapeutics, Debiopharm Group, Eisai, Exelixis/Ipsen, Flatiron Health, Incyte, Janssen, LAM Therapeutics, Lilly, Loxo, Genentech/Roche, Minapharma, QED Therapeutics, RedHill Biopharma, Sillajen, SOBI, Yiviva, Autem Medical, Gilead Sciences, Ipsen, Silenseed, TheraBionic, twoXAR, Vector HealthResearch Funding: AstraZeneca/MedImmune, Acta Biologica, Bristol Myers Squibb, Celgene, Genentech, Halozyme, MabVax, Roche, Silenseed Michael MorrisConsulting or Advisory Role: Bayer, Endocyte, Advanced Accelerator Applications, ORIC Pharmaceuticals, Johnson & Johnson, Curium Pharma, AthenexResearch Funding: Bayer, Sanofi, Endocyte, Progenics, Corcept Therapeutics, Roche/Genentech, JanssenTravel, Accommodations, Expenses: Endocyte, Fujifilm Wassim AbidaHonoraria: CARET, Roche, Medscape, Aptitude HealthConsulting or Advisory Role: Clovis Oncology, Janssen, MORE Health, ORIC Pharmaceuticals, Daiichi SankyoResearch Funding: AstraZeneca, Zenith Epigenetics, Clovis Oncology, GlaxoSmithKline, ORIC Pharmaceuticals, EpizymeTravel, Accommodations, Expenses: GlaxoSmithKline, Clovis Oncology, ORIC Pharmaceuticals Alexander DrilonHonoraria: Medscape, OncLive, PeerVoice, Physicans' Education Resource, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, PeerviewConsulting or Advisory Role: Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Verastem, Takeda/Millennium, BerGenBio, MORE Health, Lilly, Verastem, AbbVie, 14ner Oncology/Elevation Oncology, Remedica, Archer, Monopteros Therapeutics, Novartis, EMD Serono/Merck, Melendi, Repare TherapeuticsResearch Funding: Foundation MedicinePatents, Royalties, Other Intellectual Property: Wolters Kluwer (Royalties for Pocket Oncology)Other Relationship: Merck, GlaxoSmithKline, Teva, Taiho Pharmaceutical, Pfizer, PharmaMar, Puma Biotechnology Ahmet ZehirStock and Other Ownership Interests: Arcus Biosciences, Mirati TherapeuticsHonoraria: Illumina Marc LadanyiConsulting or Advisory Role: Bristol Myers Squibb, BayerResearch Funding: Loxo, Helsinn Therapeutics, Merus NV, Elevation Oncology David SolitStock and Other Ownership Interests: Loxo, Scorpion Therapeutics, Vividion Therapeutics, Fore TherapeuticsConsulting or Advisory Role: Pfizer, Illumina, Lilly, QED Therapeutics, BridgeBio Pharma, Scorpion Therapeutics, Vividion Therapeutics, Syros Pharmaceuticals Michael F. BergerResearch Funding: GrailPatents, Royalties, Other Intellectual Property: Provisional patent pending for “Systems and Methods for Detecting Cancer via cfDNA Screening” Luis A. DiazLeadership: Personal Genome Diagnostics, Jounce TherapeuticsStock and Other Ownership Interests: PapGene Inc, Personal Genome Diagnostics, Jounce Therapeutics, Zydecom, Thrive Earlier Detection Corp, Neophore, Amgen, Four Paws, Seer, Kinnate BiopharmaConsulting or Advisory Role: Merck, Personal Genome Diagnostics, Zydecom, Neophore, Innovatus Capital Partners, Four Paws, Seer, Kinnate BiopharmaResearch Funding: MerckPatents, Royalties, Other Intellectual Property: US-2010041048-A1—Circulating Mutant DNA to Assess Tumor Dynamics, US-2015344970-A1—Personalized Tumor Biomarkers, WO-2010118016-A2—Digital quantification of DNA methylation, US-2005202465-A1—Thymidylate synthase gene and metastasis, US-2014227271-A1—Somatic mutations in atrx in brain cancer, WO-2012094401-A2—Genes frequently altered in pancreatic neuroendocrine tumors, US-2013323167-A1—Detecting and treating solid tumors through selective disruption of tumor vasculature, EP-2912468-B1—Papanicolaou test for ovarian and endometrial cancers, US-9976184-B2—Mutations in pancreatic neoplasms, US-2017267760-A1—Checkpoint Blockade and Microsatellite Instability, US-2018171413-A1—Head and neck squamous cell carcinoma assays, US-2018086832-A1—HLA-restricted epitopes encoded by somatically mutated genes, US-2018258490-A1—Assaying ovarian cyst fluid, US-2016208340-A1—TERT Promoter Mutations in Urothelial Neoplasia, US-2015252415-A1—Arid1b and neuroblastoma, WO-2018071796-A2—Compositions and methods for identifying functional anti-tumor T cell responses, EP-3322824-A1—Detection of tumor-derived DNA in CSF, US-2016273049-A1—Systems and methods for analyzing nucleic acid, US-2018135044-A1—Non-unique barcodes in a genotyping assay, US-2017016075-A1—Neoantigen analysisTravel, Accommodations, Expenses: Merck Mark RobsonConsulting or Advisory Role: Change HealthCareResearch Funding: AstraZeneca, Pfizer, MerckOther Relationship: Research to Practice, Clinical Care Options, Physicans' Education Resource, Invitae, PfizerUncompensated Relationships: Merck, Pfizer, Daiichi Sankyo, Epic SciencesOpen Payments Link: https://openpaymentsdata.cms.gov/physician/612669/summaryNo other potential conflicts of interest were reported.

High-dose (HD) cisplatin remains the standard of care with chemoradiation for locally advanced oropharyngeal cancer (OPC). Cooperative group trials mandate bolus-HD (100 mg/m 2  × 1 day, every 3 weeks) cisplatin administration at the beginning of the week to optimize radiosensitization-a requirement which may be unnecessary. This analysis evaluates the impact of chemotherapy administration day of week (DOW) on outcomes. We also report our institutional experience with an alternate dosing schedule, split-HD (50 mg/m 2  × 2 days, every 3 weeks). We retrospectively reviewed 435 definitive chemoradiation OPC patients from 10 December 2001 to 23 December 2014. Those receiving non-HD cisplatin regimens or induction chemotherapy were excluded. Data collected included DOW, dosing schedule (bolus-HD vs split-HD), smoking, total cumulative dose (TCD), stage, Karnofsky Performance Status, human papillomavirus status and creatinine (baseline, peak and posttreatment baseline). Local failure (LF), regional failure (RF), locoregional failure (LRF), distant metastasis (DM), any failure (AF, either LRF or DM) and overall survival (OS) were calculated from radiation therapy start. Median follow-up was 8.0 years (1.8 months-17.0 years). DOW, dosing schedule and TCD were not associated with any outcomes in univariable or multivariable regression models. There was no statistically significant difference in creatinine or association with TCD in split-HD vs bolus-HD. There was no statistically significant association between DOW and outcomes, suggesting that cisplatin could be administered any day. Split-HD had no observed differences in outcomes, renal toxicity or TCD compared to bolus-HD cisplatin. Our data suggest that there is some flexibility of when and how to give HD cisplatin compared to clinical trial mandates., (© 2021 UICC.)

Synthetic lethality (SL) provides a conceptual framework for tackling targets that are not classically "druggable," including loss-of-function mutations in tumor suppressor genes required for carcinogenesis. Recent technological advances have led to an inflection point in our understanding of genetic interaction networks and ability to identify a wide array of novel SL drug targets. Here, we review concepts and lessons emerging from first-generation trials aimed at testing SL drugs, discuss how the nature of the targeted lesion can influence therapeutic outcomes, and highlight the need to develop clinical biomarkers distinct from those based on the paradigms developed to target activated oncogenes. SIGNIFICANCE: SL offers an approach for the targeting of loss of function of tumor suppressor and DNA repair genes, as well as of amplification and/or overexpression of genes that cannot be targeted directly. A next generation of tumor-specific alterations targetable through SL has emerged from high-throughput CRISPR technology, heralding not only new opportunities for drug development, but also important challenges in the development of optimal predictive biomarkers., (©2021 American Association for Cancer Research.)

Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS-STING innate immune pathway. How tumors co-opt inflammatory signaling while evading immune surveillance remains unknown. Here, we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune-stimulatory metabolite whose breakdown products include the immune suppressor adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wild-type ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti-PD-1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune-suppressive pathway. SIGNIFICANCE: Chromosomal instability promotes metastasis by generating chronic tumor inflammation. ENPP1 facilitates metastasis and enables tumor cells to tolerate inflammation by hydrolyzing the immunotransmitter cGAMP, preventing its transfer from cancer cells to immune cells. This article is highlighted in the In This Issue feature, p. 995 ., (©2020 American Association for Cancer Research.)

Background: Radiation therapy is one of the most commonly used cancer therapeutics but genetic determinants of clinical benefit are poorly characterized. Pathogenic germline variants in ATM are known to cause ataxia-telangiectasia, a rare hereditary syndrome notable for marked radiosensitivity. In contrast, somatic inactivation of ATM is a common event in a wide variety of cancers, but its clinical actionability remains obscure., Methods: We analyzed 20 107 consecutively treated advanced cancer patients who underwent targeted genomic sequencing as part of an institutional genomic profiling initiative and identified 1085 harboring a somatic or germline ATM mutation, including 357 who received radiotherapy (RT). Outcomes of irradiated tumors harboring ATM loss-of-function (LoF) mutations were compared with those harboring variants of unknown significance. All statistical tests were 2-sided., Results: Among 357 pan-cancer patients who received 727 courses of RT, genetic inactivation of ATM was associated with improved radiotherapeutic efficacy. The 2-year cumulative incidence of irradiated tumor progression was 13.2% vs 27.5% for tumors harboring an ATM LoF vs variant of unknown significance allele, respectively (hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.34 to 0.77, P = .001). The greatest clinical benefit was seen in tumors harboring biallelic ATM inactivation (HR = 0.19, 95% CI = 0.06 to 0.60, P = .005), with statistically significant benefit also observed in tumors with monoallelic ATM inactivation (HR = 0.57, 95% CI = 0.35 to 0.92, P = .02). Notably, ATM LoF was highly predictive of outcome in TP53 wild-type tumors but not among TP53-mutant tumors., Conclusions: We demonstrate that somatic ATM inactivation is associated with markedly improved tumor control following RT. The identification of a radio-sensitive tumor phenotype across multiple cancer types offers potential clinical opportunities for genomically guided RT., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients experience clinical benefit, there is a strong need for biomarkers that are easily accessible across diverse practice settings. Here, in a retrospective cohort study of 1714 patients with 16 different cancer types treated with ICI, we show that higher neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poorer overall and progression-free survival, and lower rates of response and clinical benefit, after ICI therapy across multiple cancer types. Combining NLR with tumor mutational burden (TMB), the probability of benefit from ICI is significantly higher (OR = 3.22; 95% CI, 2.26-4.58; P < 0.001) in the NLR low/TMB high group compared to the NLR high/TMB low group. NLR is a suitable candidate for a cost-effective and widely accessible biomarker, and can be combined with TMB for additional predictive capacity.

In multiple cancer types, high tumor mutational burden (TMB) is associated with longer survival after treatment with immune checkpoint inhibitors (ICIs). The association of TMB with survival outside of the immunotherapy context is poorly understood. We analyzed 10,233 patients (80% non-ICI-treated, 20% ICI-treated) with 17 cancer types before/without ICI treatment or after ICI treatment. In non-ICI-treated patients, higher TMB (higher percentile within cancer type) was not associated with better prognosis; in fact, in many cancer types, higher TMB was associated with poorer survival, in contrast to ICI-treated patients in whom higher TMB was associated with longer survival.

Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g., deletion) or complex (e.g., chromothripsis) structural variant classes. Applying a novel genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,778 tumor whole-genome sequences, we uncovered three novel complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are "towers" of low-JCN duplications associated with early-replicating regions, superenhancers, and breast or ovarian cancers. Rigma comprise "chasms" of low-JCN deletions enriched in late-replicating fragile sites and gastrointestinal carcinomas. Tyfonas are "typhoons" of high-JCN junctions and fold-back inversions associated with expressed protein-coding fusions, breakend hypermutation, and acral, but not cutaneous, melanomas. Clustering of tumors according to genome graph-derived features identified subgroups associated with DNA repair defects and poor prognosis., Competing Interests: Declaration of Interests J.S.R.-F. reports receiving personal/consultancy fees from VolitionRx, Paige.AI, Goldman Sachs, REPARE Therapeutics, GRAIL, Ventana Medical Systems, Roche, Genentech, and InviCRO outside of the scope of the submitted work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The advent of affordable and rapid next-generation DNA sequencing technology, along with the US Supreme Court ruling invalidating gene patents, has led to a deluge of germline and tumor genetic variant tests that are being rapidly incorporated into clinical cancer decision-making. A major concern for clinicians is whether the presence of germline mutations may increase the risk of radiation toxicity or secondary malignancies. Because scarce clinical data exist to inform decisions at this time, the American Society for Radiation Oncology convened a group of radiation science experts and clinicians to summarize potential issues, review relevant data, and provide guidance for adult patients and their care teams regarding the impact, if any, that genetic testing should have on radiation therapy recommendations. During the American Society for Radiation Oncology workshop, several main points emerged, which are discussed in this manuscript: (1) variants of uncertain significance should be considered nondeleterious until functional genomic data emerge to demonstrate otherwise; (2) possession of germline alterations in a single copy of a gene critical for radiation damage responses does not necessarily equate to increased risk of radiation-induced toxicity; (3) deleterious ataxia-telangiesctasia gene mutations may modestly increase second cancer risk after radiation therapy, and thus follow-up for these patients after indicated radiation therapy should include second cancer screening; (4) conveying to patients the difference between relative and absolute risk is critical to decision-making; and (5) more work is needed to assess the impact of tumor somatic alterations on the probability of response to radiation therapy and the potential for individualization of radiation doses. Data on radiosensitivity related to specific genetic mutations is also briefly discussed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Health anxiety is a clinical entity characterized by a pathological fear of illness. Illness cognition refers to persistent positive or negative thoughts an individual has towards illness. Evidence has shown that patients with chronic conditions who possess negative illness cognitions experience greater social, emotional, and physical difficulties than patients with positive illness cognitions. This study aims to measure the prevalence of health anxiety in a population of parents of children with cancer, and investigate the association between positive and negative illness cognitions and health anxiety. Methods: We interviewed 105 parents of children with cancer and administered Arabic versions of the Illness Cognition Questionnaire - Parent Version and the Short Health Anxiety Inventory . Results: The mean parental age was 37.7 years with the majority of participants being mothers (78.1%) and married (94.3%) and with 35.2% having completed university education. The average age of the child with cancer was 8.4 years, with the largest proportion of children suffering from leukemia. The prevalence of health anxiety among parents of children with cancer was 21%. The following two dimensions of illness cognition were significantly associated with health anxiety: Helplessness ( B  = 0.222, p  = 0.021) and lower Acceptance ( B = -0.242, p  = 0.008). Other variables associated with health anxiety were perceived inadequate income ( B  = -0.238, p  = 0.021) and personal illness or illness of a family member/close friend ( B  = 0.251, p  = 0.013). Conclusions: Parents of children with cancer may experience health anxiety. Predictors of health anxiety include feelings of helplessness, lower acceptance, inadequate income, and extended family illnesses.

Extracellular vesicles (EVs) are a heterogeneous group of membrane-bounded vesicles that are believed to be produced and secreted by presumably all cell types under physiological and pathological conditions, including tumors. EVs are very important vehicles in intercellular communications for both shorter and longer distances and are able to deliver a wide range of cargos including proteins, lipids, and various species of nucleic acids effectively. EVs have been emerging as a novel biotherapeutic platform to efficiently deliver therapeutic cargos to treat a broad range of diseases including cancer. This vast potential of drug delivery lies in their abilities to carry a variety of cargos and their ease in crossing the biological membranes. Similarly, their presence in a variety of body fluids makes them a potential biomarker for early diagnosis, prognostication, and surveillance of cancer. Here, we discuss the relatively least and understudied aspects of EV biology and tried to highlight the obstacles and limitations in their clinical applications and also described most of the new warfronts to beat cancer at multiple stages. However, much more challenges still remain to evaluate EV-based therapeutics, and we are very much hopeful that the current work prompts further discovery., Competing Interests: The authors declare no conflict of interests.

Tumors with mismatch repair deficiency (MMR-d) are characterized by sequence alterations in microsatellites and can accumulate thousands of mutations. This high mutational burden renders tumors immunogenic and sensitive to programmed cell death-1 (PD-1) immune checkpoint inhibitors. Yet, despite their tumor immunogenicity, patients with MMR-deficient tumors experience highly variable responses, and roughly half are refractory to treatment. We present experimental and clinical evidence showing that the degree of microsatellite instability (MSI) and resultant mutational load, in part, underlies the variable response to PD-1 blockade immunotherapy in MMR-d human and mouse tumors. The extent of response is particularly associated with the accumulation of insertion-deletion (indel) mutational load. This study provides a rationale for the genome-wide characterization of MSI intensity and mutational load to better profile responses to anti-PD-1 immunotherapy across MMR-deficient human cancers., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Anti-tumor immunity is driven by self versus non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole-genome sequencing and RNA sequencing, we identified a novel gene fusion and demonstrated that it produces a neoantigen that can specifically elicit a host cytotoxic T cell response. In a cohort of head and neck tumors with low mutation burden, minimal immune infiltration and prevalent gene fusions, we also identified gene fusion-derived neoantigens that generate cytotoxic T cell responses. Finally, analyzing additional datasets of fusion-positive cancers, including checkpoint-inhibitor-treated tumors, we found evidence of immune surveillance resulting in negative selective pressure against gene fusion-derived neoantigens. These findings highlight an important class of tumor-specific antigens and have implications for targeting gene fusion events in cancers that would otherwise be less poised for response to immunotherapy, including cancers with low mutational load and minimal immune infiltration.

Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB.

Cancer is fundamentally a disease of the genome and inherited deficiencies in DNA repair pathways are well established to increase lifetime cancer risk. Computational analysis of pan-cancer data has identified signatures of mutational processes thought to be responsible for the pattern of mutations in any given cancer. These analyses identified altered DNA repair pathways in a much broader spectrum of cancers than previously appreciated with significant therapeutic implications. The development of DNA repair deficiency biomarkers is critical to the implementation of therapeutic targeting of repair-deficient tumors, using either DNA damaging agents or immunotherapy for the personalization of cancer therapy.

BRCA1 and BRCA2 are involved in homologous recombination (HR) DNA repair and are germ-line cancer pre-disposition genes that result in a syndrome of hereditary breast and ovarian cancer (HBOC). Whether germ-line or somatic alterations in these genes or other members of the HR pathway and if mono- or bi-allelic alterations of HR-related genes have a phenotypic impact on other cancers remains to be fully elucidated. Here, we perform a pan-cancer analysis of The Cancer Genome Atlas (TCGA) data set and observe that bi-allelic pathogenic alterations in homologous recombination (HR) DNA repair-related genes are prevalent across many malignancies. These bi-allelic alterations often associate with genomic features of HR deficiency. Further, in ovarian, breast and prostate cancers, bi-allelic alterations are mutually exclusive of each other. The combination of these two properties facilitates reclassification of variants of unknown significance affecting DNA repair genes, and may help personalize HR directed therapies in the clinic.Germline mutations in homologous recombination (HR) DNA repair genes are linked to breast and ovarian cancer. Here, the authors show that mutually exclusive bi-allelic inactivation of HR genes are present in other cancer types and associated with genomic features of HR deficiency, expanding the potential use of HR-directed therapies.

Immune checkpoint blockade has demonstrated substantial promise for the treatment of several advanced malignancies. These agents activate the immune system to attack tumor cells. For example, agents targeting CTLA4 and programmed cell death 1 (PD-1) have resulted in impressive response rates and, in some cases, durable remissions. Neoantigens are mutations that encode immunologically active proteins that can cause the immune system to recognize the affected cell as foreign. Recent data have made it clear that these mutations are, in large part, the functional targets of immune checkpoint blockade. This review summarizes the key discoveries leading up to this important conclusion and discusses possible applications of neoantigens in cancer therapy., (© The Japanese Society for Immunology. 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

As tumors accumulate genetic alterations, an evolutionary process occurs in which genetically distinct subclonal populations of cells co-exist, resulting in intratumor genetic heterogeneity (ITH). The clinical implications of ITH remain poorly defined. Data are limited with respect to whether ITH is an independent determinant of patient survival outcomes, across different cancer types. Here, we report the results of a pan-cancer analysis of over 3300 tumors, showing a varied landscape of ITH across 9 cancer types. While some gene mutations are subclonal, the majority of driver gene mutations are clonal events, present in nearly all cancer cells. Strikingly, high levels of ITH are associated with poorer survival across diverse types of cancer. The adverse impact of high ITH is independent of other clinical, pathologic and molecular factors. High ITH tends to be associated with lower levels of tumor-infiltrating immune cells, but this association is not able to explain the observed survival differences. Together, these data show that ITH is a prognostic marker in multiple cancers. These results illuminate the natural history of cancer evolution, indicating that tumor heterogeneity represents a significant obstacle to cancer control.

Mutations, deletions, and changes in copy number of mitochondrial DNA (mtDNA), are observed throughout cancers. Here, we survey mtDNA copy number variation across 22 tumor types profiled by The Cancer Genome Atlas project. We observe a tendency for some cancers, especially of the bladder, breast, and kidney, to be depleted of mtDNA, relative to matched normal tissue. Analysis of genetic context reveals an association between incidence of several somatic alterations, including IDH1 mutations in gliomas, and mtDNA content. In some but not all cancer types, mtDNA content is correlated with the expression of respiratory genes, and anti-correlated to the expression of immune response and cell-cycle genes. In tandem with immunohistochemical evidence, we find that some tumors may compensate for mtDNA depletion to sustain levels of respiratory proteins. Our results highlight the extent of mtDNA copy number variation in tumors and point to related therapeutic opportunities.

Along with graft vasculopathy, malignancies comprise a major complication after heart transplant, with a rate of occurrence of 39.1% in 10 years. Skin cancers and posttransplant lymphoproliferative disorder are more common in adults, whereas lymphoma is more often shown in children. A major cause of malignancies after heart transplant is the use of increased doses of prophylactics needed during immunosuppressive therapy. Data, however, are scarce regarding the association between a particular immunosuppressive drug and a posttransplant malignancy. Compared with the general population, recipients have a higher incidence of malignancies after heart transplant, with an early onset and more aggressive disease. Solid tumors known to occur in heart transplant recipients include lung cancer, bladder and prostate carcinoma, adenocarcinoma of the oral cavity, stomach cancer, and bowel cancer, although the incidence is rare. The risk factors for development of a malignancy after heart transplant are the same as for the nontransplant population.

The first systematic multi-center study of the clinical use of EPR oximetry has begun, with funding as a PPG from the NCI. Using particulate oxygen sensitive EPR, materials in three complementary forms (India Ink, "OxyChips", and implantable resonators) the clinical value of the technique will be evaluated. The aims include using repeated measurement of tumor pO2 to monitor the effects of treatments on tumor pO2, to use the measurements to select suitable subjects for the type of treatment including the use of hyperoxic techniques, and to provide data that will enable existing clinical techniques which provide data relevant to tumor pO2 but which cannot directly measure it to be enhanced by determining circumstances where they can give dependable information about tumor pO2.

Background: Dry tap is an annoying experience in bone marrow (BM) findings, especially in cases where the diagnosis may hinge on BM findings. This study was conducted to determine, on, the basis of bone marrow (BM) trephine biopsy, the frequency of various underlying conditions causing a dry tap, among different age groups., Methods: It was a descriptive study carried out at PAF hospital Mianwali, Pakistan from 1" Jan 2009 to 31 Dec 2012. Record of all BM aspirations and trephine biopsies performed during 4 years was retrieved from hospital's laboratory. Total number of BM aspirations and trephines were counted and the subject's ages and genders recorded. Frequencies and percentages of patients with dry tap, in paediatric group (<15 years of age), young to middle-aged group (15-59 years) and the elderly (> or = 60 years) were calculated. Diagnoses of patients with dry tap made on BM biopsy were noted for each group and their frequencies calculated., Results: Of 548 BM aspirations, dry tap was encountered in 52 (9.5%) cases. Acute lymphoblastic leukaemia (ALL) was the commonest cause of dry tap in paediatric age, seen in 6 (60%) of 10 children. In young to middle-aged group, non Hodgkin lymphoma (NHL) was the commonest cause, found in 6 (30%) of 20 cases. NHL and metastatic tumours, seen in 8 (36.4%) and 6 (27.3%) of 22 patients respectively, were the most frequent causes of dry tap in the elderly., Conclusion: Dry tap, in most of the cases, is like a diagnostic alert for the presence of an underlying BM pathology, nature of which depends upon age group.

Ethnic disparities in use of cancer genetics services raise concerns about equitable opportunity to benefit from familial cancer risk assessment, improved survival and quality of life. This paper considers available research to explore what may hinder or facilitate minority ethnic access to cancer genetics services. We sought to inform service development for people of South Asian, African or Irish origin at risk of familial breast, ovarian, colorectal and prostate cancers in the UK. Relevant studies from the UK, North America and Australasia were identified from six electronic research databases. Current evidence is limited but suggests low awareness and understanding of familial cancer risk among minority ethnic communities studied. Socio-cultural variations in beliefs, notably stigma about cancer or inherited risk of cancer, are identified. These factors may affect seeking of advice from providers and disparities in referral. Achieving effective cross-cultural communication in the complex contexts of both cancer and genetics counselling, whether between individuals and providers, when mediated by third party interpreters, or within families, pose further challenges. Some promising experience of facilitating minority ethnic access has been gained by introduction of culturally sensitive provider and counselling initiatives, and by enabling patient self-referral. However, further research to inform and assess these interventions, and others that address the range of challenges identified for cancer genetics services are needed. This should be based on a more comprehensive understanding of what happens at differing points of access and interaction at community, cancer care and genetic service levels.

Background: To investigate the feasibility and dosimetric improvements of a novel technique to temporarily displace critical structures in the pelvis and abdomen from tumor during high-dose radiotherapy., Methods: Between 2010 and 2012, 11 patients received high-dose image-guided intensity-modulated radiotherapy with temporary organ displacement (TOD) at our institution. In all cases, imaging revealed tumor abutting critical structures. An all-purpose drainage catheter was introduced between the gross tumor volume (GTV) and critical organs at risk (OAR) and infused with normal saline (NS) containing 5-10% iohexol. Radiation planning was performed with the displaced OARs and positional reproducibility was confirmed with cone-beam CT (CBCT). Patients were treated within 36 hours of catheter placement. Radiation plans were re-optimized using pre-TOD OARs to the same prescription and dosimetrically compared with post-TOD plans. A two-tailed permutation test was performed on each dosimetric measure., Results: The bowel/rectum was displaced in six patients and kidney in four patients. One patient was excluded due to poor visualization of the OAR; thus 10 patients were analyzed. A mean of 229 ml (range, 80-1000) of NS 5-10% iohexol infusion resulted in OAR mean displacement of 17.5 mm (range, 7-32). The median dose prescribed was 2400 cGy in one fraction (range, 2100-3000 in 3 fractions). The mean GTV Dmin and PTV Dmin pre- and post-bowel TOD IG-IMRT dosimetry significantly increased from 1473 cGy to 2086 cGy (p=0.015) and 714 cGy to 1214 cGy (p=0.021), respectively. TOD increased mean PTV D95 by 27.14% of prescription (p=0.014) while the PTV D05 decreased by 9.2% (p=0.011). TOD of the bowel resulted in a 39% decrease in mean bowel Dmax (p=0.008) confirmed by CBCT. TOD of the kidney significantly decreased mean kidney dose and Dmax by 25% (0.022)., Conclusions: TOD was well tolerated, reproducible, and facilitated dose escalation to previously radioresistant tumors abutting critical structures while minimizing dose to OARs.

Active-site mTOR inhibitors (asTORi) hold great promise for targeting dysregulated mTOR signaling in cancer. Because of the multifaceted nature of mTORC1 signaling, identification of reliable biomarkers for the sensitivity of tumors to asTORi is imperative for their clinical implementation. Here, we show that cancer cells acquire resistance to asTORi by downregulating eukaryotic translation initiation factor (eIF4E)-binding proteins (4E-BPs-EIF4EBP1, EIF4EBP2). Loss of 4E-BPs or overexpression of eIF4E renders neoplastic growth and translation of tumor-promoting mRNAs refractory to mTOR inhibition. Conversely, moderate depletion of eIF4E augments the anti-neoplastic effects of asTORi. The anti-proliferative effect of asTORi in vitro and in vivo is therefore significantly influenced by perturbations in eIF4E/4E-BP stoichiometry, whereby an increase in the eIF4E/4E-BP ratio dramatically limits the sensitivity of cancer cells to asTORi. We propose that the eIF4E/4E-BP ratio, rather than their individual protein levels or solely their phosphorylation status, should be considered as a paramount predictive marker for forecasting the clinical therapeutic response to mTOR inhibitors.

Studies in the past several years highlight important features of the messenger RNA (mRNA) export process. For instance, groups of mRNAs acting in the same biochemical processes can be retained or exported in a coordinated manner thereby impacting on specific biochemistries and ultimately on cell physiology. mRNAs can be transported by either bulk export pathways involving NXF1/TAP or more specialized pathways involving chromosome region maintenance 1 (CRM1). Studies on primary tumor specimens indicate that many common and specialized mRNA export factors are dysregulated in cancer including CRM1, eukaryotic translation initiation factor 4E (eIF4E), HuR, nucleoporin 88, REF/Aly, and THO. This positions these pathways as potential therapeutic targets. Recently, specific targeting of the eIF4E-dependent mRNA export pathway in a phase II proof-of-principle trial with ribavirin led to impaired eIF4E-dependent mRNA export correlating with clinical responses including remissions in leukemia patients. Here, we provide an overview of these mRNA export pathways and highlight their relationship to cancer., (Copyright © 2011 John Wiley & Sons, Ltd.)

Checkpoint inhibitors potentially could be used to enhance cell killing by DNA-targeted therapeutic modalities such as radiotherapy. UCN-01 (7-hydroxystaurosporine) inhibits S and G2 checkpoint arrest in the cells of various malignant cell lines and has been investigated in combination with chemotherapy. However, little is known about its potential use in combination with radiotherapy. We report the effect of 20 Gy radiation given in conjunction with UCN-01 on the pO2 and growth of subcutaneous RIF-1 tumors. Multisite EPR oximetry was used for repeated, non-invasive tumor pO2 measurements. The effect of UCN-01 and/or 20 Gy on tumor pO2 and tumor volume was investigated to determine therapeutic outcomes. Untreated RIF-1 tumors were hypoxic with a tissue pO2 of 5-7 mmHg. Treatment with 20 Gy or UCN-01 significantly reduced tumor growth, and a modest increase in tumor pO2 was observed in tumors treated with 20 Gy. However, irradiation with 20 Gy 12 h after UCN-01 treatment resulted in a significant inhibition of tumor growth and a significant increase in tumor pO2 to 16-28 mmHg from day 1 onward compared to the control, UCN-01 or 20-Gy groups. Treatment with UCN-01 12 h after 20 Gy also led to a similar growth inhibition of the tumors and a similar increase in tumor pO2. The changes in tumor pO2 observed after the treatment correlated inversely with the tumor volume in the groups receiving UCN-01 with 20 Gy. This multimodal approach could be used to enhance the outcome of radiotherapy. Furthermore, tumor pO2 could be a potential marker of therapeutic response.

Systematic collection of family history is a prerequisite for identifying genetic risk. This study reviewed tools applicable to the primary care assessment of family history of breast, colorectal, ovarian, and prostate cancer. MEDLINE, EMBASE, CINAHL, and Cochrane Central were searched for publications. All primary study designs were included. Characteristics of the studies, the family history collection tools, and the setting were evaluated. Of 40 eligible studies, 18 relevant family history tools were identified, with 11 developed for use in primary care. Most collected information on more than one cancer and on affected relatives used self-administered questionnaires and paper-based formats. Eleven tools had been evaluated relative to current practice, demonstrating 46-78% improvement in data recording over family history recording in patient charts and 75-100% agreement with structured genetic interviews. Few tools have been developed specifically for primary care settings. The few that have been evaluated performed well. The very limited evidence, which depends in part on extrapolation from studies in settings other than primary care, suggests that systematic tools may add significant family health information compared with current primary care practice. The effect of their use on health outcomes has not been evaluated.

Objectives: This systematic review aimed to evaluate, within unselected populations: the (1) performance of family history (FHx)-based models in predicting cancer risk; (2) overall benefits and harms associated with established cancer prevention interventions; (3) impact of FHx-based risk information on the uptake of preventive interventions; and (4) potential for harms associated with collecting cancer FHx., Data Sources: MEDLINE, EMBASE, CINAHL, Cochrane Central, Cochrane Database of Systematic Reviews, and PsycINFO were searched from 1990 to June 2008 inclusive. Cancer guidelines and recommendations were searched from 2002 forward and systematic reviews from 2003 to June 2008., Review Methods: Standard systematic review methodology was employed. Eligibility criteria included English studies evaluating breast, colorectal, ovarian, or prostate cancers. Study designs were restricted to systematic review, experimental and diagnostic types. Populations were limited to those unselected for cancer risk. Interventions were limited to collection of cancer FHx; primary and/or secondary prevention interventions for breast, colorectal, ovarian, and prostate cancers., Results: Accuracy of models. Seven eligible studies evaluated systems based on the Gail model, and on the Harvard Cancer Risk Index. No evaluations demonstrated more than modest discriminatory accuracy at an individual level. No evaluations were identified relevant to ovarian or prostate cancer risk. Efficacy of preventive interventions. From 29 eligible systematic reviews, seven found no experimental studies evaluating interventions of interest. Of the remaining 22, none addressed ovarian cancer prevention. The reviews were generally based on limited numbers of randomized or controlled clinical trials. There was no evidence either to support or refute the use of selected chemoprevention interventions, there was some evidence of effectiveness for mammography and fecal occult blood testing. Uptake of intervention. Three studies evaluated the impact of FHx-based risk information on uptake of clinical preventive interventions for breast cancer. The evidence is insufficient to draw conclusions on the effect of FHx-based risk information on change in preventive behavior. Potential harms of FHx taking. One uncontrolled trial evaluated the impact of FHx-based breast cancer risk information on psychological outcomes and found no evidence of significant harm., Conclusions: Our review indicates a very limited evidence base with which to address all four of the research questions: 1) the few evaluations of cancer risk prediction models do not suggest useful individual predictive accuracy; 2) the experimental evidence base for primary and secondary cancer prevention is very limited; 3) there is insufficient evidence to assess the effect of FHx-based risk assessment on preventive behaviors; 4) there is insufficient evidence to assess whether FHx-based personalized risk assessment directly causes adverse outcomes.

Eukaryotic translation initiation factor 4E (eIF4E) is encoded by a potent oncogene which is highly elevated in many human cancers. Few studies have investigated how the level, and thus activity, of eIF4E is regulated in healthy (noncancerous) cells and how they become elevated in malignant cells. Here, our studies reveal a novel mechanism by which eIF4E levels are regulated at the level of mRNA stability. Two factors known to modulate transcript stability, HuR and the p42 isoform of AUF1, compete for binding to the 3' untranslated regions (3'UTRs) of eIF4E mRNAs. We identified a distinct AU-rich element in the 3'UTR of eIF4E which is responsible for HuR-mediated binding and stabilization. Our studies show that HuR is upregulated in malignant cancer specimens characterized by high eIF4E levels and that its depletion leads to reduction in eIF4E levels. Further, HuR and eIF4E regulate a common set of transcripts involved in cellular proliferation (cyclin D1 and c-myc) and neoangiogenesis (vascular endothelial growth factor), which suggests a functional connection between HuR and eIF4E in the regulation of these important processes. In summary, we present a novel model for the regulation of eIF4E expression and show that this model is relevant to elevation of eIF4E levels in malignant cells.