To find fault is easy, to find no-fault is fair.

The inequity of medical negligence-based adversarial litigation in the USA, UK and Australia is a recognised target for reform. Plaintiff autonomy is weakened by a dispute resolution system that has evolved around lawyers, opposed experts and indemnity insurers; the need to prove breach and causation excludes compensation for other categories of medical injury; and patient access to the system is restricted by high entry costs. Two strategies towards reform are raised here.

Synonymous alterations of cancer-associated Trp53 CpG mutational hotspots cause fatal developmental jaw malocclusions but no tumors in knock-in mice.

Intragenic CpG dinucleotides are tightly conserved in evolution yet are also vulnerable to methylation-dependent mutation, raising the question as to why these functionally critical sites have not been deselected by more stable coding sequences. We previously showed in cell lines that altered exonic CpG methylation can modify promoter start sites, and hence protein isoform expression, for the human TP53 tumor suppressor gene. Here we extend this work to the in vivo setting by testing whether synonymous germline modifications of exonic CpG sites affect murine development, fertility, longevity, or cancer incidence.

Development and Validation of a Machine Learning Approach Leveraging Real-World Clinical Narratives as a Predictor of Survival in Advanced Cancer.

Purpose: Predicting short-term mortality in patients with advanced cancer remains challenging. Whether digitalized clinical text can be used to build models to enhance survival prediction in this population is unclear.

Materials And Methods: We conducted a single-centered retrospective cohort study in patients with advanced solid tumors.

How aging of the global population is changing oncology.

Population aging is causing a demographic redistribution with implications for the future of healthcare. How will this affect oncology? First, there will be an overall rise in cancer affecting older adults, even though age-specific cancer incidences continue to fall due to better prevention. Second, there will be a wider spectrum of health functionality in this expanding cohort of older adults, with differences between "physiologically older" and "physiologically younger" patients becoming more important for optimal treatment selection.

The secret identities of TMPRSS2: Fertility factor, virus trafficker, inflammation moderator, prostate protector and tumor suppressor.

The human TMPRSS2 gene is pathogenetically implicated in both coronaviral lung infection and prostate cancer, suggesting its potential as a drug target in both contexts. SARS-COV-2 spike polypeptides are primed by the host transmembrane TMPRSS2 protease, triggering virus fusion with epithelial cell membranes followed by an endocytotic internalisation process that bypasses normal endosomal activation of cathepsin-mediated innate immunity; viral co-opting of TMPRSS2 thus favors microbial survivability by attenuating host inflammatory responses. In contrast, most early hormone-dependent prostate cancers express TMPRSS2:ERG fusion genes arising from deletions that eliminate the TMPRSS2 coding region while juxtaposing its androgen-inducible promoter and the open reading frame of ERG, upregulating pro-inflammatory ERG while functionally disabling TMPRSS2.

2b or Not 2b: How Opposing FGF Receptor Splice Variants Are Blocking Progress in Precision Oncology.

More than ten thousand peer-reviewed studies have assessed the role of fibroblast growth factors (FGFs) and their receptors (FGFRs) in cancer, but few patients have yet benefited from drugs targeting this molecular family. Strategizing how best to use FGFR-targeted drugs is complicated by multiple variables, including RNA splicing events that alter the affinity of ligands for FGFRs and hence change the outcomes of stromal-epithelial interactions. The effects of splicing are most relevant to FGFR2; expression of the FGFR2b splice isoform can restore apoptotic sensitivity to cancer cells, whereas switching to FGFR2c may drive tumor progression by triggering epithelial-mesenchymal transition.

Cancer Care Treatment Outcome Ontology: A Novel Computable Ontology for Profiling Treatment Outcomes in Patients With Solid Tumors.

Purpose: There is as yet no computer-processable resource to describe treatment end points in cancer, hindering our ability to systematically capture and share outcomes data to inform better patient care. To address these unmet needs, we have built an ontology, the Cancer Care Treatment Outcome Ontology (CCTOO), to organize high-level concepts of treatment end points with structured knowledge representation to facilitate standardized sharing of real-world data.

Methods: End points from oncology trials in ClinicalTrials.

Beyond BCG: the approaching era of personalised bladder-sparing therapies for non-muscle-invasive urothelial cancers.

Progress in the management of non-muscle invasive bladder cancer has been slow. Despite longstanding use of intravesical therapies (e.g.

Thyroid cancer in a patient with Lynch syndrome - case report and literature review.

Lynch syndrome describes a familial cancer syndrome comprising germline mutations in one of four DNA mismatch repair genes, , , , and and is characterized by colorectal, endometrial, and other epithelial malignancies. Thyroid cancer is not usually considered to be part of the constellation of Lynch syndrome cancers nor have Lynch syndrome tumor gene mutations been reported in thyroid malignancies. This study reports a woman with Lynch syndrome (colonic cancer and a DNA mismatch repair mutation in the gene) with a synchronous papillary thyroid cancer.

TEPAPA: a novel in silico feature learning pipeline for mining prognostic and associative factors from text-based electronic medical records.

Vast amounts of clinically relevant text-based variables lie undiscovered and unexploited in electronic medical records (EMR). To exploit this untapped resource, and thus facilitate the discovery of informative covariates from unstructured clinical narratives, we have built a novel computational pipeline termed Text-based Exploratory Pattern Analyser for Prognosticator and Associator discovery (TEPAPA). This pipeline combines semantic-free natural language processing (NLP), regular expression induction, and statistical association testing to identify conserved text patterns associated with outcome variables of clinical interest.

Cancer and the omics revolution.

Background: Internal medicine is in flux because of the 'omics revolution', with cancer medicine being a good example. Molecular technologies that detect alterations in gene-based structure or function are having an impact on diagnosis, prognosis and treatment of cancer.

Objective: In this article, recent advances in gene-based characterisation of cancer are presented, and illustrated where possible by clinical applications.

Computational prediction of multidisciplinary team decision-making for adjuvant breast cancer drug therapies: a machine learning approach.

Background: Multidisciplinary team (MDT) meetings are used to optimise expert decision-making about treatment options, but such expertise is not digitally transferable between centres. To help standardise medical decision-making, we developed a machine learning model designed to predict MDT decisions about adjuvant breast cancer treatments.

Methods: We analysed MDT decisions regarding adjuvant systemic therapy for 1065 breast cancer cases over eight years.

Damage-inducible intragenic demethylation of the human TP53 tumor suppressor gene is associated with transcription from an alternative intronic promoter.

Wild-type TP53 exons 5-8 contain CpG dinucleotides that are prone to methylation-dependent mutation during carcinogenesis, but the regulatory effects of methylation affecting these CpG sites are unclear. To clarify this, we first assessed site-specific TP53 CpG methylation in normal and transformed cells. Both DNA damage and cell ageing were associated with site-specific CpG demethylation in exon 5 accompanied by induction of a truncated TP53 isoform regulated by an adjacent intronic promoter (P2).

A periodic table for cancer.

Cancers exhibit differences in metastatic behavior and drug sensitivity that correlate with certain tumor-specific variables such as differentiation grade, growth rate/extent and molecular regulatory aberrations. In practice, patient management is based on the past results of clinical trials adjusted for these biomarkers. Here, it is proposed that treatment strategies could be fine-tuned upfront simply by quantifying tumorigenic spatial (cell growth) and temporal (genetic stability) control losses, as predicted by genetic defects of cell-cycle-regulatory gatekeeper and genome-stabilizing caretaker tumor suppressor genes, respectively.

Lobular breast cancers lack the inverse relationship between ER/PR status and cell growth rate characteristic of ductal cancers in two independent patient cohorts: implications for tumor biology and adjuvant therapy.

Background: Although invasive lobular carcinoma (ILC) of the breast differs from invasive ductal carcinoma (IDC) in numerous respects - including its genetics, clinical phenotype, metastatic pattern, and chemosensitivity - most experts continue to manage ILC and IDC identically in the adjuvant setting. Here we address this discrepancy by comparing early-stage ILC and IDC in two breast cancer patient cohorts of differing nationality and ethnicity.

Methods: The clinicopathologic features of 2029 consecutive breast cancer patients diagnosed in Hong Kong (HK) and Australia (AUS) were compared.

Efficacy and tolerability of adjuvant oral capecitabine plus intravenous oxaliplatin (XELOX) in Asian patients with colorectal cancer: 4-year analysis.

Background: Although FOLFOX (infusional fluorouracil/leucovorin plus oxaliplatin) is established as a standard chemotherapeutic regimen, the long term efficacy of adjuvant XELOX (oral capecitabine plus intravenous oxaliplatin) in Asian colorectal cancer (CRC) patients remains anecdotal. Moreover, uncertainties persist as to whether pharmacogenetic differences in Asian populations preclude equally tolerable and effective administration of these drugs.

Method: One hundred consecutive patients with resected colorectal cancer received adjuvant XELOX (oxaliplatin 130 mg/m2 on day 1 plus capecitabine 900 mg/m2 twice daily on day 1 to 14 every 3 weeks for 8 cycles) at Queen Mary Hospital, Hong Kong.

The unpluggable in pursuit of the undruggable: tackling the dark matter of the cancer therapeutics universe.

The notion that targeted drugs can unplug gain-of-function tumor pathways has revitalized pharmaceutical research, but the survival benefits of this strategy have so far proven modest. A weakness of oncogene-blocking approaches is that they do not address the problem of cancer progression as selected by the recessive phenotypes of genetic instability and apoptotic resistance which in turn arise from loss-of-function - i.e.

Papillomavirus-associated squamous skin cancers following transplant immunosuppression: one Notch closer to control.

The frequent occurrence of cutaneous squamous cell carcinomas (SCCs) containing weakly tumorigenic human papillomaviruses (HPVs) following iatrogenic immunosuppression for organ transplantation remains incompletely understood. Here we address this problem in the light of recent insights into (1) the association of low-risk β-HPVs with skin SCCs in the rare genetic syndromes of epidermodysplasia verruciformis and xeroderma pigmentosum, (2) the frequent recovery of post-transplant tumor control on substituting calcineurin-inhibitory with mTOR-inhibitory immunosuppression, (3) the unexpectedly favorable prognosis of node-positive SCCs containing high-risk α-HPVs originating in the activated immune niche of the oropharynx, (4) the rapid occurrence of HPV-negative SCCs in ultraviolet (UV)-damaged skin of melanoma patients receiving Raf-inhibitory drugs, and (5) the selective ability of β-HPV E6 oncoproteins to inhibit Notch tumor-suppressive signaling in cutaneous and mesenchymal tissues. The crosstalk so implied between oncogenic UV-induced mutations, defective host immunity, and β-HPV-dependent stromal-epithelial signaling suggests that immunosuppressants such as calcineurin inhibitors intensify mitogenic signalling in TP53-mutant keratinocytes while also abrogating immune-dependent Notch-mediated tumor repression.

Conserved nonsense-prone CpG sites in apoptosis-regulatory genes: conditional stop signs on the road to cell death.

Methylation-prone CpG dinucleotides are strongly conserved in the germline, yet are also predisposed to somatic mutation. Here we quantify the relationship between germline codon mutability and somatic carcinogenesis by comparing usage of the nonsense-prone CGA (→TGA) codons in gene groups that differ in apoptotic function; to this end, suppressor genes were subclassified as either apoptotic (gatekeepers) or repair (caretakers). Mutations affecting CGA codons in sporadic tumors proved to be highly asymmetric.

Complete Radiologic Response of Bulky Cerebral Metastases From Newly Diagnosed HER2-Positive Breast Cancer to Upfront Trastuzumab-Based Chemotherapy.

The blood-brain barrier is traditionally regarded as an insurmountable obstacle to the effective drug therapy of brain metastases from solid tumors. Here we describe a striking case of complete radiologic response to chemotherapy, and propose that the critical success factors include the large tumor size, HER2-positivity, and concomitant use of trastuzumab.

Modernising the regulation of medical migration: moving from national monopolies to international markets.

Background: Traditional top-down national regulation of internationally mobile doctors and nurses is fast being rendered obsolete by the speed of globalisation and digitisation. Here we propose a bottom-up system in which responsibility for hiring and accrediting overseas staff begins to be shared by medical employers, managers, and insurers.

Discussion: In this model, professional Boards would retain authority for disciplinary proceedings in response to local complaints, but would lose their present power of veto over foreign practitioners recruited by employers who have independently evaluated and approved such candidates' ability.