Side effects of CoronaVac® COVID-19 vaccination: Investigation in North Jakarta district public health center communities in Indonesia.

Background: The decreasing prevalence of COVID-19 has highlighted the value of vaccinations. CoronaVac® vaccine was one of the most widely used vaccines in Indonesia, in other Southeast Asian countries, as well as in Latin America. However, to date the safety and side effect profiles of CoronaVac® vaccine among the Indonesian population have not been reported. Objective: In this study, the CoronaVac® safety profiles were determined in a community of a public health center in North Jakarta, Indonesia. Method: This is a descriptive cross-sectional questionnaire-based study on vaccine side effects as recorded in the yellow form (MESO). Patients (n = 300) who received CoronaVac® vaccinations between July and August 2021 were enrolled. SPSS was used to analyze the descriptive data. Results: Most respondents were women (72.7 %) between the ages of 17 and 21 years. A significantly (p = 0.009) positive correlation was established between the vaccine side effects (namely pain at the injection site) with the female gender. Other side effects such as fatigue (p = 0.034) and headache (p < 0.001) were also correlated with disease comorbidity. Conclusion: Overall, the side effects following the first and the second doses were generally mild and included fever, pain in the injection area, fatigue, headache, drowsiness, diarrhea, cough, and nausea. Regarding vaccine efficacy, CoronaVac® confers better protection following the second dose administration where the percentage of respondents affected with COVID-19 (26.7 %) decreased to only 20.3 % following the second dose.

A systematic review and meta-analysis of the impacts of germline pharmacogenomics on severe toxicity and symptom burden in adult patients with cancer.

The clinical application of Pharmacogenomics (PGx) has improved patient safety. However, comprehensive PGx testing has not been widely adopted in clinical practice, and significant opportunities exist to further optimize PGx in cancer care. This systematic review and meta-analysis aim to evaluate the safety outcomes of reported PGx-guided strategies (Analysis 1) and identify well-studied emerging pharmacogenomic variants that predict severe toxicity and symptom burden (Analysis 2) in patients with cancer. We searched MEDLINE, EMBASE, CENTRAL, clinicaltrials.gov, and International Clinical Trials Registry Platform from inception to January 2023 for clinical trials or comparative studies evaluating PGx strategies or unconfirmed pharmacogenomic variants. The primary outcomes were severe adverse events (SAE; ≥ grade 3) or symptom burden with pain and vomiting as defined by trial protocols and assessed by trial investigators. We calculated pooled overall relative risk (RR) and 95% confidence interval (95%CI) using random effects models. PROSPERO, registration number CRD42023421277. Of 6811 records screened, six studies were included for Analysis 1, 55 studies for Analysis 2. Meta-analysis 1 (five trials, 1892 participants) showed a lower absolute incidence of SAEs with PGx-guided strategies compared to usual therapy, 16.1% versus 34.0% (RR = 0.72, 95%CI 0.57-0.91, p = 0.006, I2 = 34%). Meta-analyses 2 identified nine medicine(class)-variant pairs of interest across the TYMS, ABCB1, UGT1A1, HLA-DRB1, and OPRM1 genes. Application of PGx significantly reduced rates of SAEs in patients with cancer. Emergent medicine-variant pairs herald further research into the expansion and optimization of PGx to improve systemic anti-cancer and supportive care medicine safety and efficacy.

Therapeutic drug monitoring in anticancer agents: perspectives of Australian medical oncologists.

BACKGROUND: In the development of anticancer agents for solid tumours, body surface area continues to be used to personalise dosing despite minimal evidence for its use over other dosing strategies. With the development of tyrosine kinase inhibitors and other oral targeted anticancer agents, dosing using therapeutic drug monitoring (TDM) is now utilised in many health systems but has had limited uptake in Australia. AIM: To determine attitudes and barriers to the implementation of TDM among Australian oncologists. METHODS: A comprehensive questionnaire was developed by the Dutch Pharmacology Oncology Group from semistructured interviews of stakeholders. Seventy-nine questions across seven domains were developed with three free-text responses. This was rationalised to 17 questions with three free-text responses for Australian medical oncologists who identified limited experience with TDM. RESULTS: Fifty-seven responses were received, with 49 clinicians (86%) identifying limited experience of performing TDM in daily practice. Clinicians were positive (62-91% agree/strongly agree across seven questions) about the advantages of TDM. There was a mixed response for cost-effectiveness and scientific evidence being a barrier to implementation, but strong agreement that prospective studies were needed (75% agreed or strongly agreed); that national treatment guidelines would enable practice (80%) and that a 'pharmacology of oncolytics' education programme would be useful (96%) to provide knowledge for dose individualisation. CONCLUSION: Despite the limited experience of TDM in oncology in Australia, medical oncologists appear positive about the potential benefit to their patients. We have identified three barriers to implementation that could be targeted for increased adoption of TDM in oncology in Australia.

The mechanisms of action of metformin on head and neck cancer in the pre-clinical setting: a scoping review.

This scoping review identifies the mechanistic pathways of metformin when used to treat head and neck cancer cells, in the pre-clinical setting. Understanding the underlying mechanisms will inform future experimental designs exploring metformin as a potential adjuvant for head and neck cancer. This scoping review was conducted according to the Joanna-Briggs Institute framework. A structured search identified 1288 studies, of which 52 studies fulfilled the eligibility screen. The studies are presented in themes addressing hallmarks of cancer. Most of the studies demonstrated encouraging anti-proliferative effects in vitro and reduced tumor weight and volume in animal models. However, a few studies have cautioned the use of metformin which supported cancer cell growth under certain conditions.

A gut microbial signature for combination immune checkpoint blockade across cancer types.

Immune checkpoint blockade (ICB) targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte protein 4 (CTLA-4) can induce remarkable, yet unpredictable, responses across a variety of cancers. Studies suggest that there is a relationship between a cancer patient's gut microbiota composition and clinical response to ICB; however, defining microbiome-based biomarkers that generalize across cohorts has been challenging. This may relate to previous efforts quantifying microbiota to species (or higher taxonomic rank) abundances, whereas microbial functions are often strain specific. Here, we performed deep shotgun metagenomic sequencing of baseline fecal samples from a unique, richly annotated phase 2 trial cohort of patients with diverse rare cancers treated with combination ICB (n = 106 discovery cohort). We demonstrate that strain-resolved microbial abundances improve machine learning predictions of ICB response and 12-month progression-free survival relative to models built using species-rank quantifications or comprehensive pretreatment clinical factors. Through a meta-analysis of gut metagenomes from a further six comparable studies (n = 364 validation cohort), we found cross-cancer (and cross-country) validity of strain-response signatures, but only when the training and test cohorts used concordant ICB regimens (anti-PD-1 monotherapy or combination anti-PD-1 plus anti-CTLA-4). This suggests that future development of gut microbiome diagnostics or therapeutics should be tailored according to ICB treatment regimen rather than according to cancer type.

Early onset pancreatic cancer-exploring contemporary treatment and outcomes using real-world data.

BACKGROUND: Pancreatic cancer incidence is increasing in younger populations. Differences between early onset pancreatic cancer (EOPC) and later onset pancreatic cancer (LOPC), and how these should inform management warrant exploration in the contemporary setting. METHODS: A prospectively collected multi-site dataset on consecutive pancreatic adenocarcinoma patients was interrogated. Patient, tumour, treatment, and outcome data were extracted for EOPC (≤50 years old) vs LOPC (>50 years old). RESULTS: Of 1683 patients diagnosed between 2016 and 2022, 112 (6.7%) were EOPC. EOPC more frequently had the tail of pancreas tumours, earlier stage disease, surgical resection, and trended towards increased receipt of chemotherapy in the curative setting compared to LOPC. EOPC more frequently received 1st line chemotherapy, 2nd line chemotherapy, and chemoradiotherapy than LOPC in the palliative setting. Recurrence-free survival was improved for the tail of pancreas EOPC vs LOPC in the resected setting; overall survival was superior for EOPC compared to LOPC across the resected, locally advanced unresectable and metastatic settings. CONCLUSIONS: EOPC remains a small proportion of pancreatic cancer diagnoses. The more favourable outcomes in EOPC suggest these younger patients are overall deriving benefits from increased treatment in the curative setting and increased therapy in the palliative setting.

Vortex fluidic regulated phospholipid equilibria involving liposomes down to sub-micelle size assemblies.

Conventional channel-based microfluidic platforms have gained prominence in controlling the bottom-up formation of phospholipid based nanostructures including liposomes. However, there are challenges in the production of liposomes from rapidly scalable processes. These have been overcome using a vortex fluidic device (VFD), which is a thin film microfluidic platform rather than channel-based, affording ∼110 nm diameter liposomes. The high yielding and high throughput continuous flow process has a 45° tilted rapidly rotating glass tube with an inner hydrophobic surface. Processing is also possible in the confined mode of operation which is effective for labelling pre-VFD-prepared liposomes with fluorophore tags for subsequent mechanistic studies on the fate of liposomes under shear stress in the VFD. In situ small-angle neutron scattering (SANS) established the co-existence of liposomes ∼110 nm with small rafts, micelles, distorted micelles, or sub-micelle size assemblies of phospholipid, for increasing rotation speeds. The equilibria between these smaller entities and ∼110 nm liposomes for a specific rotational speed of the tube is consistent with the spatial arrangement and dimensionality of topological fluid flow regimes in the VFD. The prevalence for the formation of ∼110 nm diameter liposomes establishes that this is typically the most stable structure from the bottom-up self-assembly of the phospholipid and is in accord with dimensions of exosomes.

Economic evaluation of personalized vs. standard dosing of 5-fluorouracil in first-line chemotherapy for metastatic colorectal cancer in Australia.

AIMS: Using pharmacokinetics (PK)-guided 5-fluorouracil (5-FU) for metastatic colorectal cancer (mCRC) improves overall survival (OS) and decreases toxicity, yet its value for money in the Australian setting is unknown. Our study assesses the cost-effectiveness of PK vs. body surface area (BSA) dosing of 5-FU for patients with mCRC. METHODS: We developed a semi-Markov model with four health states to compare PK-guided dosing within a FOLFOX regimen vs. BSA-guided dosing for mCRC patients from an Australian healthcare system perspective. Transition probabilities were derived from fitted survival models, with utility values obtained directly from published studies. We calculated direct healthcare costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs), and included both one-way and probabilistic sensitivity analyses. RESULTS: BSA-guided FOLFOX provided 1.291 QALYs at a cost of $36 379, compared with PK-guided FOLFOX which delivered 1.751 QALYs at a cost of $32 564. Therefore, PK-guided dosing emerges as the dominant strategy offering both better health outcomes and lower costs. The variables that had the greatest impact on the overall ICER were the adverse event rates in the BSA and PK groups, model time horizon, utility of progression-free survival and PREDICT assay cost. Our univariate and multivariate sensitivity analysis confirmed that the ICER for PK FOLFOX consistently remained below $50 000 per QALY across all tested variables. CONCLUSIONS: PK dose management of 5-FU-based chemotherapy in mCRC patients appears to be a cost-saving strategy in Australia. However, our model estimates are drawn from limited, low-quality evidence. Further evidence from randomized controlled trials (RCTs), directly comparing PK-based to BSA-based dosing across a variety of current regimens, is needed to address our model's uncertainties.

Non-cirrhotic hyperammonaemic encephalopathy secondary to metastatic pancreatic neuroendocrine tumour treated with peptide receptor radio nucleotide therapy and transarterial chemoembolisation.

Neuroendocrine tumours (NETs) are rare cancers which often carry significant morbidity and mortality, frequently related to burden of liver metastases. Hyperammonaemia and subsequent hepatic encephalopathy carries a poor prognosis and has been described in these patients. We discuss a case of a woman in her 50s with hyperammonaemic encephalopathy and a new diagnosis of pancreatic NET with hepatic metastases. She presented with a reduced conscious state a few days post commencing chemotherapy. This was considered to have a multifactorial pathophysiology: the primary driver being large volume hepatic metastases and contributed by portosystemic microshunting, sepsis, severe weight loss and malnutrition. We describe how each of these exacerbating factors was addressed and highlight the effective multimodal treatment approach consisting of sequential transarterial chemoembolisation followed by peptide receptor radio nucleotide therapy, resulting in the resolution of hyperammonaemic encephalopathy and radiological partial metabolic response.

SARS-CoV-2 produces a microRNA CoV2-miR-O8 in patients with COVID-19 infection.

Many viruses produce microRNAs (miRNAs), termed viral miRNAs (v-miRNAs), with the capacity to target host gene expression. Bioinformatic and cell culture studies suggest that SARS-CoV-2 can also generate v-miRNAs. This patient-based study defines the SARS-CoV-2 encoded small RNAs present in nasopharyngeal swabs of patients with COVID-19 infection using small RNA-seq. A specific conserved sequence (CoV2-miR-O8) is defined that is not expressed in other coronaviruses but is preserved in all SARS-CoV-2 variants. CoV2-miR-O8 is highly represented in nasopharyngeal samples from patients with COVID-19 infection, is detected by RT-PCR assays in patients, has features consistent with Dicer and Drosha generation as well as interaction with Argonaute and targets specific human microRNAs.

Impact of neoadjuvant systemic chemotherapy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for appendiceal adenocarcinoma.

AIM: Peritoneal dissemination of infiltrative appendiceal tumors is a rare and poorly understood phenomenon. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a well-recognized treatment option for selected patients. Neoadjuvant systemic chemotherapy (NAC) has been shown to be associated with improved overall survival (OS) in colorectal peritoneal metastases but little is known of the impact of this from an appendiceal adenocarcinoma perspective. METHOD: A prospective database of 294 patients with advanced appendiceal primary tumors undergoing CRS ± HIPEC between June 2009 and December 2020 was reviewed. Baseline characteristics and long-term outcomes were compared between patients with adenocarcinoma who received neoadjuvant chemotherapy or upfront surgery. RESULTS: Eighty-six (29%) patients were histologically diagnosed with an appendiceal cancer. These included intestinal-type adenocarcinoma (11.6%), mucinous adenocarcinoma (43%), and goblet cell adenocarcinoma (GCA) or signet ring cell adenocarcinoma (SRCA) (45.4%). Twenty-five (29%) of these underwent NAC, of which eight (32%) exhibited some degree of radiological response. There was no statistical difference in OS at 3 years between the NAC and upfront surgery groups (47.3% vs. 75.8%, p = 0.372). Appendiceal histology subtypes, particularly GCA and SRCA (p = 0.039) and peritoneal carcinomatosis index >10 (p = 0.009), were factors independently associated with worse OS. CONCLUSION: Administration of NAC did not appear to prolong OS in the operative management of disseminated appendiceal adenocarcinomas. GCA and SRCA subtypes display a more aggressive biological phenotype.

Pharmacogenetics testing (DPYD and UGT1A1) for fluoropyrimidine and irinotecan in routine clinical care: Perspectives of medical oncologists and oncology pharmacists.

BACKGROUND: Despite robust evidence and international guidelines, to support routine pharmacogenetic (PGx) testing, integration in practice has been limited. This study explored clinicians' views and experiences of pre-treatment DPYD and UGT1A1 gene testing and barriers to and enablers of routine clinical implementation. METHODS: A study-specific 17-question survey was emailed (01 February-12 April 2022) to clinicians from the Medical Oncology Group of Australia (MOGA), the Clinical Oncology Society of Australia (COSA) and International Society of Oncology Pharmacy Practitioners (ISOPP). Data were analysed and reported using descriptive statistics. RESULTS: Responses were collected from 156 clinicians (78% medical oncologists, 22% pharmacists). Median response rate of 8% (ranged from 6% to 24%) across all organisations. Only 21% routinely test for DPYD and 1% for UGT1A1. For patients undergoing curative/palliative intent treatments, clinicians reported intent to implement genotype-guided dosing by reducing FP dose for DPYD intermediate metabolisers (79%/94%), avoiding FP for DPYD poor metabolisers (68%/90%), and reducing irinotecan dose for UGT1A1 poor metabolisers (84%, palliative setting only). Barriers to implementation included: lack of financial reimbursements (82%) and perceived lengthy test turnaround time (76%). Most Clinicians identified a dedicated program coordinator, i.e., PGx pharmacist (74%) and availability of resources for education/training (74%) as enablers to implementation. CONCLUSION: PGx testing is not routinely practised despite robust evidence for its impact on clinical decision making in curative and palliative settings. Research data, education and implementation studies may overcome clinicians' hesitancy to follow guidelines, especially for curative intent treatments, and may overcome other identified barriers to routine clinical implementation.

Use of patient-derived explants as a preclinical model for precision medicine in colorectal cancer: A scoping review.

PURPOSE: Whilst the treatment paradigm for colorectal cancer has evolved significantly over time, there is still a lack of reliable biomarkers of treatment response. Treatment decisions are based on high-risk features such as advanced TNM stage and histology. The role of the tumour microenvironment, which can influence tumour progression and treatment response, has generated considerable interest. Patient-derived explant cultures allow preservation of native tissue architecture and tumour microenvironment. The aim of the scoping review is to evaluate the utility of patient-derived explant cultures as a preclinical model in colorectal cancer. METHODS: A search was conducted using Ovid MEDLINE, EMBASE, Web of Science, and Cochrane databases from start of database records to September 1, 2022. We included all peer-reviewed human studies in English language which used patient-derived explants as a preclinical model in primary colorectal cancer. Eligible studies were grouped into the following categories: assessing model feasibility; exploring tumour microenvironment; assessing ex vivo drug responses; discovering and validating biomarkers. RESULTS: A total of 60 studies were eligible. Fourteen studies demonstrated feasibility of using patient-derived explants as a preclinical model. Ten studies explored the tumour microenvironment. Thirty-eight studies assessed ex vivo drug responses of chemotherapy agents and targeted therapies. Twenty-four studies identified potential biomarkers of treatment response. CONCLUSIONS: Given the preservation of tumour microenvironment and tumour heterogeneity, patient-derived explants has the potential to identify reliable biomarkers, treatment resistance mechanisms, and novel therapeutic agents. Further validation studies are required to characterise, refine and standardise this preclinical model before it can become a part of precision medicine in colorectal cancer.

Patient and healthcare professional acceptability of pharmacogenetic screening for DPYD and UGT1A1: A cross sectional survey.

This study explored the acceptability of a novel pharmacist-led pharmacogenetics (PGx) screening program among patients with cancer and healthcare professionals (HCPs) taking part in a multicenter clinical trial of PGx testing (PACIFIC-PGx ANZCTR:12621000251820). Medical oncologists, oncology pharmacists, and patients with cancer from across four sites (metropolitan/regional), took part in an observational, cross-sectional survey. Participants were recruited from the multicenter trial. Two study-specific surveys were developed to inform implementation strategies for scaled and sustainable translation into routine clinical care: one consisting of 21 questions targeting HCPs and one consisting of 17 questions targeting patients. Responses were collected from 24 HCPs and 288 patients. The 5-to-7-day PGx results turnaround time was acceptable to HCP (100%) and patients (69%). Most HCPs (92%) indicated that it was appropriate for the PGx clinical pharmacist to provide results to patients. Patients reported equal preference for receiving PGx results from a doctor/pharmacist. Patients and HCPs highly rated the pharmacist-led PGx service. HCPs were overall accepting of the program, with the majority (96%) willing to offer PGx testing to their patients beyond the trial. HCPs identified that lack of financial reimbursements (62%) and lack of infrastructure (38%) were the main reasons likely to prevent/slow the implementation of PGx screening program into routine clinical care. Survey data have shown overall acceptability from patients and HCPs participating in the PGx Program. Barriers to implementation of PGx testing in routine care have been identified, providing opportunity to develop targeted implementation strategies for scaled translation into routine practice.

Human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma.

Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed of cerebrospinal fluid (CSF). However, the impact of CSF on cancer cells and therapeutic efficacy is unknown. Here, we examined the effect of human CSF on glioblastoma (GBM) tumors from 25 patients. We found that CSF induces tumor cell plasticity and resistance to standard GBM treatments (temozolomide and irradiation). We identified nuclear protein 1 (NUPR1), a transcription factor hampering ferroptosis, as a mediator of therapeutic resistance in CSF. NUPR1 inhibition with a repurposed antipsychotic, trifluoperazine, enhanced the killing of GBM cells resistant to chemoradiation in CSF. The same chemo-effective doses of trifluoperazine were safe for human neurons and astrocytes derived from pluripotent stem cells. These findings reveal that chemoradiation efficacy decreases in human CSF and suggest that combining trifluoperazine with standard care may improve the survival of patients with GBM.

The unmet information needs, quality of life, and care experiences of patients with neuroendocrine tumours (NETs) at follow-up: 6 months from diagnosis.

OBJECTIVES: To identify changes in the healthcare preferences, patient experiences, and quality of life of patients with NETs at 6-month follow-up, informing the design of supportive care services. METHODS: This study presents 6-month follow-up data of a mixed-methods multi-site study. Demographic, clinical, and patient-reported outcome questionnaire data was collected. RESULTS: High percentages of suboptimal experiences of care were reported. Patients reported less positive experiences with being involved in decisions about their care and treatment; their family or someone close to them having the opportunity to talk to their cancer doctor, or having their family or someone close to them receive all the information they need to help care for them at home. Patients also reported negative experiences for on the information about their cancer accessible online and the usefulness of the information they accessed. Differences between baseline and follow-up scores were mostly not significant apart from anxiety and sleep disturbance scales, CONCLUSIONS: Patients with NETs report difficulties in accessing and understanding written information that is persistent over time. PRACTICE IMPLICATIONS: Outcomes will inform the design and development of an informational resource aimed at facilitating improved understanding for patients with NETs.

Risk-Directed Ambulatory Thromboprophylaxis in Lung and Gastrointestinal Cancers: The TARGET-TP Randomized Clinical Trial.

Importance: Thromboprophylaxis for individuals receiving systemic anticancer therapies has proven to be effective. Potential to maximize benefits relies on improved risk-directed strategies, but existing risk models underperform in cohorts with lung and gastrointestinal cancers. Objective: To assess clinical benefits and safety of biomarker-driven thromboprophylaxis and to externally validate a biomarker thrombosis risk assessment model for individuals with lung and gastrointestinal cancers. Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial (Targeted Thromboprophylaxis in Ambulatory Patients Receiving Anticancer Therapies [TARGET-TP]) conducted from June 2018 to July 2021 (with 6-month primary follow-up) included adults aged 18 years or older commencing systemic anticancer therapies for lung or gastrointestinal cancers at 1 metropolitan and 4 regional hospitals in Australia. Thromboembolism risk assessment based on fibrinogen and d-dimer levels stratified individuals into low-risk (observation) and high-risk (randomized) cohorts. Interventions: High-risk patients were randomized 1:1 to receive enoxaparin, 40 mg, subcutaneously daily for 90 days (extending up to 180 days according to ongoing risk) or no thromboprophylaxis (control). Main Outcomes and Measures: The primary outcome was objectively confirmed thromboembolism at 180 days. Key secondary outcomes included bleeding, survival, and risk model validation. Results: Of 782 eligible adults, 328 (42%) were enrolled in the trial (median age, 65 years [range, 30-88 years]; 176 male [54%]). Of these participants, 201 (61%) had gastrointestinal cancer, 127 (39%) had lung cancer, and 132 (40%) had metastatic disease; 200 (61%) were high risk (100 in each group), and 128 (39%) were low risk. In the high-risk cohort, thromboembolism occurred in 8 individuals randomized to enoxaparin (8%) and 23 control individuals (23%) (hazard ratio [HR], 0.31; 95% CI, 0.15-0.70; P = .005; number needed to treat, 6.7). Thromboembolism occurred in 10 low-risk individuals (8%) (high-risk control vs low risk: HR, 3.33; 95% CI, 1.58-6.99; P = .002). Risk model sensitivity was 70%, and specificity was 61%. The rate of major bleeding was low, occurring in 1 participant randomized to enoxaparin (1%), 2 in the high-risk control group (2%), and 3 in the low-risk group (2%) (P = .88). Six-month mortality was 13% in the enoxaparin group vs 26% in the high-risk control group (HR, 0.48; 95% CI, 0.24-0.93; P = .03) and 7% in the low-risk group (vs high-risk control: HR, 4.71; 95% CI, 2.13-10.42; P < .001). Conclusions and Relevance: In this randomized clinical trial of individuals with lung and gastrointestinal cancers who were stratified by risk score according to thrombosis risk, risk-directed thromboprophylaxis reduced thromboembolism with a desirable number needed to treat, without safety concerns, and with reduced mortality. Individuals at low risk avoided unnecessary intervention. The findings suggest that biomarker-driven, risk-directed primary thromboprophylaxis is an appropriate approach in this population. Trial Registration: ANZCTR Identifier: ACTRN12618000811202.

Human gene and microbial analyses in rectal cancer complete responses to radiotherapy.

BACKGROUND: The gold standard treatment for locally advanced rectal cancer is total mesorectal excision after preoperative chemoradiotherapy. Response to chemoradiotherapy varies, with some patients completely responding to the treatment and some failing to respond at all. Identifying biomarkers of response to chemoradiotherapy could allow patients to avoid unnecessary treatment-associated morbidity rate. While previous studies have attempted to identify such biomarkers, none have reached clinical utility, which may be due to heterogeneity of the cancer. In this study, potential human gene and microbial biomarkers were explored in a cohort of rectal cancer patients who underwent chemoradiotherapy. METHODS: RNA sequencing was carried out on matched tumour and adjacent normal rectum biopsies from patients with rectal cancer with varying chemoradiotherapy responses treated between 2016 and 2019 at two institutions. Enriched genes and microbes from tumours of complete responders were compared with those from tumours of others with lesser response. RESULTS: In 39 patients analysed, enriched gene sets in complete responders indicate involvement of immune responses, including immunoglobulin production, B cell activation and response to bacteria (adjusted P values <0.050). Bacteria such as Ruminococcaceae bacterium and Bacteroides thetaiotaomicron were documented to be abundant in tumours of complete responders compared with all other patients (adjusted P value <0.100). CONCLUSION: These results identify potential genetic and microbial biomarkers of response to chemoradiotherapy in rectal cancer, as well as suggesting a potential mechanism of complete response to chemoradiotherapy that may benefit further testing in the laboratory.

Psychoanalytic proof: Revisiting Freud's Tally Argument.

This paper explores the notion of proof in clinical psychoanalysis by reconsidering an argument Freud made concerning the relation between successful psychoanalytic treatment and truth, dubbed the "Tally Argument" by the philosopher Adolf Grünbaum. I first reiterate criticisms of Grünbaum's reconstruction of this argument, which bring out the degree to which he has misunderstood Freud. I then offer my own interpretation of the argument and the reasoning that underlies its key premise. Drawing from this discussion, I explore three forms of proof, each inspired also by analogies with other disciplines. Laurence Perrine's "The Nature of Proof in the Interpretation of Poetry" stimulates my discussion of inferential proof, the relevant form of which involves proving an interpretation through a strong enough Inference to the Best Explanation. Mathematical proof stimulates my discussion of apodictic proof, of which psychoanalytic insight is a fitting example. Finally, holism in legal reasoning stimulates my discussion of holistic proof, which provides a reliable means by which therapeutic success can verify epistemic conclusions. These three forms of proof can play a crucial role in ascertaining psychoanalytic truth.

Elevated basal AMP-activated protein kinase activity sensitizes colorectal cancer cells to growth inhibition by metformin.

Expression and activity of the AMP-activated protein kinase (AMPK) α1 catalytic subunit of the heterotrimeric kinase significantly correlates with poor outcome for colorectal cancer patients. Hence there is considerable interest in uncovering signalling vulnerabilities arising from this oncogenic elevation of AMPKα1 signalling. We have therefore attenuated mammalian target of rapamycin (mTOR) control of AMPKα1 to generate a mutant colorectal cancer in which AMPKα1 signalling is elevated because AMPKα1 serine 347 cannot be phosphorylated by mTORC1. The elevated AMPKα1 signalling in this HCT116 α1.S347A cell line confers hypersensitivity to growth inhibition by metformin. Complementary chemical approaches confirmed this relationship in both HCT116 and the genetically distinct HT29 colorectal cells, as AMPK activators imposed vulnerability to growth inhibition by metformin in both lines. Growth inhibition by metformin was abolished when AMPKα1 kinase was deleted. We conclude that elevated AMPKα1 activity modifies the signalling architecture in such a way that metformin treatment compromises cell proliferation. Not only does this mutant HCT116 AMPKα1-S347A line offer an invaluable resource for future studies, but our findings suggest that a robust biomarker for chronic AMPKα1 activation for patient stratification could herald a place for the well-tolerated drug metformin in colorectal cancer therapy.