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The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood.We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use.Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 [noninferiority margin, -8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not.A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.).

Background The COVID‐19 pandemic has challenged cancer care globally, introducing resource limitations and competing risks into clinical practice. Aims To describe the COVID‐19 impact on medical oncology care provision in an Australian setting. Methods Calvary Mater Newcastle and Newcastle Private Hospital medical oncology data from 1 February to 31 April 2019 versus 2020 were retrospectively analysed. Results Three hundred and sixty‐four inpatient admissions occurred in 2020, 21% less than in 2019. Total inpatient days decreased by 22% (2842 vs 2203). April was most impacted (36% and 44% fewer admissions and inpatient days respectively). Mean length of stay remained unchanged (6.4 vs 6.2 days, P = 0.7). In all, 5072 outpatient consultations were conducted, including 417 new‐patient consultations (4% and 6% increase on 2019 respectively). Telephone consultations (0 vs 1380) replaced one‐quarter of face‐to‐face consultations (4859 vs 3623, −25%), with minimal telehealth use (6 vs 69). Day Treatment Centre encounters remained stable (3751 vs 3444, −8%). The proportion of new patients planned for palliative treatment decreased (35% vs 28%, P = 0.04), observation increased (16% vs 23%, P = 0.04) and curative intent treatment was unchanged (both 41%). Recruiting clinical trials decreased by one‐third (45 vs 30), two trials were activated (vs 5 in 2019) and 45% fewer patients consented to trial participation (62 vs 34). Conclusion Our medical oncology teams adapted rapidly to COVID‐19 with significant changes to care provision, including fewer hospital admissions, a notable transition to telephone‐based outpatient clinics and reduced clinical trial activity. The continuum of care was largely defended despite pandemic considerations and growing service volumes.

Fetal development may be compromised by adverse events at the placental interface between mother and fetus. However, it is still unclear how the communication between mother and fetus occurs through the placenta. In vitro - models of the human placental barrier, which could help our understanding and which recreate three-dimensional (3D) structures with biological functionalities and vasculatures, have not been reported yet. Here we present a 3D-vascularized human primary placental barrier model which can be constructed in 1 day. We illustrate the similarity of our model to first trimester human placenta, both in its structure and in its ability to respond to altered oxygen and to secrete factors that cause damage cells across the barrier including embryonic cortical neurons. We use this model to highlight the possibility that both the trophoblast and the endothelium within the placenta might play a role in the fetomaternal dialogue.

A 72-year-old male patient was receiving second-line chemotherapy for metastatic squamous cell carcinoma of the skin (SCCS) when he was diagnosed with concurrent metastatic melanoma (BRAF mutant). Chemotherapy was ceased and he was treated with 4 cycles of ipilimumab immunotherapy. The patient experienced clinical benefit and durable remission in both malignancies and remains free of cancer progression 8 months after the last cycle of ipilimumab. Response of SCCS to ipilimumab has not been previously described, however this case and recent reports of pembrolizumab efficacy confirm the critical role of the immune system in SCCS pathogenesis and suggest further exploration of checkpoint immunotherapy for the treatment of this disease.

Activation of the canonical TGF-β signaling pathway provides growth inhibitory signals in the normal intestinal epithelium. Colorectal cancers (CRCs) frequently harbor somatic mutations in the pathway members TGFBR2 and SMAD4, but to what extent mutations in SMAD2 or SMAD3 contribute to tumorigenesis is unclear. A cohort of 744 primary CRCs and 36 CRC cell lines were sequenced for SMAD4, SMAD2, and SMAD3 and analyzed for allelic loss by single-nucleotide polymorphism (SNP) microarray analysis. Mutation spectra were compared between the genes, the pathogenicity of mutations was assessed, and relationships with clinicopathologic features were examined. The prevalence of SMAD4, SMAD2, and SMAD3 mutations in sporadic CRCs was 8.6% (64 of 744), 3.4% (25 of 744), and 4.3% (32 of 744), respectively. A significant overrepresentation of two genetic hits was detected for SMAD4 and SMAD3, consistent with these genes acting as tumor suppressors. SMAD4 mutations were associated with mucinous histology. The mutation spectra of SMAD2 and SMAD3 were highly similar to that of SMAD4, both in mutation type and location within the encoded proteins. In silico analyses suggested the majority of the mutations were pathogenic, with most missense changes predicted to reduce protein stability or hinder SMAD complex formation. The latter altered interface residues or disrupted the phosphorylation-regulated Ser-Ser-X-Ser motifs within SMAD2 and SMAD3. Functional analyses of selected mutations showed reductions in SMAD3 transcriptional activity and SMAD2–SMAD4 complex formation. Joint biallelic hits in SMAD2 and SMAD3 were overrepresented and mutually exclusive to SMAD4 mutation, underlining the critical roles of these three proteins within the TGF-β signaling pathway. Cancer Res; 73(2); 725–35. ©2012 AACR.

Purpose Universal screening for chronic hepatitis B virus (HBV) infection before chemotherapy has been recommended. We evaluated the cost-effectiveness of HBV screening before chemotherapy given for nonhematopoietic solid tumors (STs). Methods A decision-analytic model was used to compare the cost-effectiveness of universal screening conducted per professional guidelines versus no screening in hypothetical patient cohorts beginning adjuvant chemotherapy for early breast cancer or palliative chemotherapy for advanced non–small-cell lung cancer. Survival times were extrapolated using Markov models. Probabilities were derived from published studies and costs estimated from the perspective of the Australian health care system. One-way and probabilistic sensitivity analyses were performed, including with the application of an alternative HBV screening strategy. Results Using an incremental cost-effectiveness ratio threshold of $50,000 (Australian dollars) per life-year (LY) saved, universal HBV screening was not cost-effective for adjuvant patients ($88,224/LY, 13% probability of being cost-effective), palliative patients ($1,344,251/LY, 0%), or pooled (all) patients ($149,857/LY, 1%). Sensitivity analyses found that screening approached cost-effectiveness among adjuvant patients with the highest reported rates of undiagnosed chronic HBV (65%, $59,445/LY) or HBV reactivation with chemotherapy (41%, $56,537/LY). Cost- effectiveness was also significantly influenced by HBV population prevalence. An alternative screening strategy using hepatitis B surface antigen testing only produced the most economically favorable results, with $30,126/LY (80% probability) for adjuvant patients and $51,201/LY (43%) for the pooled cohort. Conclusion Universal HBV screening conducted per current guidelines is not cost-effective in patients with STs. Screening may be economically favorable in selected patient subpopulations and/or with simplification of the screening strategy.

Universal screening for chronic hepatitis B virus (HBV) before chemotherapy has been recommended by the Centers for Disease Control. We sought to determine the prac- tice of Australian oncologists with regard to HBV screening in patients with solid tumors (STs) and their clinical experience of HBV reactivation (HBVR). Methods: A survey was sent to all consultant members of the Medical Oncology Group of Australia. One hundred eighty-eight responses (63% response rate) were received. We also reviewed the incidence of HBV in patients with STs screened at the Peter MacCallum Cancer Centre (Melbourne, Australia). Results: Fifty-three percent of medical oncologists screen for HBV, but only 19% screen all patients. The most common rea- sons given for performing screening were anecdotal experience of HBVR (46%) and perceived sufficient evidence for screening of some patient subgroups (42%). Sixty-five percent of those who screened did so only in subgroups, usually selecting patients on the basis of ethnicity (82%). Oncologists who did not screen most commonly cited inadequate evidence for a benefit of screening (72%). Twenty-two percent of oncologists had wit- nessed one or more HBVR events, representing one event per 45 years of respondents' practice. HBVR events reported (n 54) consisted of asymptomatic liver test abnormalities only (44%), symptomatic hepatitis (28%), decompensated liver failure (19%), and death (7%). In 206 patients with STs screened for HBV, 1.0% (n 2) were HBV surface antigen positive, and 14.9% hepatitis B core antibody positive. Conclusion: The majority of Australian medical oncologists have not adopted universal HBV screening before chemothera- py. Further evidence of the benefit and cost effectiveness of universal screening in patients with STs will be required to alter practice.

INTRODUCTION: The skeletal survey is widely used as the principal radiological investigation in suspected physical abuse of infants and young children. However, the evidence on which current guidelines are based is limited, especially for siblings of index cases. We conducted a retrospective study to describe the characteristics of children who underwent skeletal surveys for suspected non-accidental injury (NAI) in the Edinburgh area; to evaluate the diagnostic efficacy of skeletal surveys; and to identify any predictive factors that might guide clinical practice. METHODS: All skeletal surveys performed at the Royal Hospital for Sick Children in Edinburgh for suspected non-accidental injury between 1/1/99 and 31/12/03 were reviewed. RESULTS: Seventy-seven children underwent skeletal surveys for suspected NAI. Data were available for 76 (70 index cases and 6 siblings). Of the index cases, 17 (24%) skeletal surveys were positive, with a mean of 2.5 fractures per child (range 0-9). The age of positive cases ranged from 2 weeks to 36 months with the majority (14, 82%) being under 12 months of age. Nine (53%) were boys. In index children with positive results, indications for skeletal survey were head injury (skull fracture in 2, 12%; intracranial injury in 4,24%); skeletal fracture (excluding skull fracture) in 6 (35%) and bruising in 4 (24%). chi(2) analysis revealed no significant differences in age, sex or primary reason for skeletal survey between those with a negative and positive skeletal survey. Six skeletal surveys were performed on siblings of children with known or suspected NAI. The siblings' ages ranged from 1 to 36 months although 3 (50%) were under 12 months of age. One (17%) of the siblings' surveys (a twin) was positive. CONCLUSION: The age of a child (

The B-type Raf kinase (BRAF) V600E mutation is a well-established biomarker for poor prognosis in metastatic colorectal cancer (mCRC) and is a highly attractive drug target. A barrier to the development of new therapies targeting BRAF V600E in mCRC is the low prevalence of mutations (approximately 10 %) and the current need for access to sequencing-based technologies which are not routinely available outside of large cancer centres. Availability of a standardised immunohistochemistry (IHC) test, more suited to routine pathology practice, would provide much broader access to patient identification. We sought to evaluate the accuracy and clinical utility of a recently developed BRAF V600E IHC method as a prognostic biomarker in a large cohort of community-based CRC patients. Archival tumour samples from 505 patients with stage I-IV CRC were immunohistochemically tested with two antibodies, pBR1 for total BRAF and VE1 for BRAF V600E. Cases were assessed by two blinded pathologists, and results were compared to BRAF V600E mutation status determined using DNA sequencing. Discordant cases were retested with a BRAF V600E SNaPshot assay. BRAF mutation status was correlated with overall survival (OS) in stage IV CRC. By DNA sequencing and IHC, 505 and 477 patients were respectively evaluable. Out of 477 patients, 56 (11. 7 %) had BRAF V600E mutations detected by sequencing and 63 (13.2 %) by IHC. Using DNA sequencing results as the reference, sensitivity and specificity for IHC were 98.2 % (55/56) and 98.1 % (413/421), respectively. IHC had a positive predictive value (PPV) of 87.3 % (55/63) and a negative predictive value (NPV) of 99.8 % (413/414). Compared to DNA sequencing plus retesting of available discordant cases by SNaPshot assay, IHC using the VE1 antibody had a 100 % sensitivity (59/59), specificity (416/416), NPV (416/416) and PPV (59/59). Stage IV CRC patients with BRAF V600E protein detected by IHC exhibited a significantly shorter overall survival (hazard ratio = 2.20, 95 % CI 1.26-3.83, p = 0.005), consistent with other published series. Immunohistochemistry using the BRAF V600E VE1 antibody is an accurate diagnostic assay in CRC. The test provides a simple, clinically applicable method of testing for the BRAF V600E mutation in routine practice.