Search

This is a descriptive study to characterize rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pediatric solid organ transplant (SOT) recipients during the early days of the pandemic. We hypothesized that asymptomatic infection may represent a large proportion of SARS-CoV-2 infection in pediatric SOT recipients.We queried Organ Transplant Tracking Record (OTTR) for all pediatric SOT recipients followed at our center and reviewed medical records to identify patients tested for SARS-CoV-2 between March 15, 2020 and June 30, 2021. Patients were tested by polymerase chain reaction (PCR): prior to planned procedures or because of symptoms; OR: tested by measurement of IgG to spike protein with their routine labs q 2-monthly. A positive PCR was called acute infection. A positive IgG with negative PCR was called convalescence. For immunologic studies, blood was obtained when the PCR or IgG was positive. Statistical comparisons were made between (1) acute infection versus convalescence; (2) acute infection versus SOT recipients without infection (called healthy controls); (3) liver transplant (LT) versus small bowel (SB)/multivisceral transplant (MVT); (4) positive versus negative test result.Of 257 LT recipients, 99 were tested: 6 were PCR positive, 13 were antibody positive. Of 150 SB/MVT recipients, 55 were tested: 4 were PCR positive, 6 were antibody positive. Of 8 simultaneous liver, kidney transplant recipients, 3 were tested: 1 was PCR positive. Symptoms when present were mostly mild. Patients with a positive test result were younger (6.3 vs 10.0 years; P = 0.017). We observed a rapid decline in viral load within 96 hours without a change in immunosuppression. Antibody lasted8 months beyond the time it was monitored. Acute infection was associated with increased CD4 and CD8 T EM cell frequency ( P = 0.04, P = 0.03, respectively), decreased interferon (IFN)-γ production from T-cells (2.8% vs 11.3%; P = 0.006), and decreased CD8 TEMRA frequency (4.56% vs 11.70%; P = 0.006).Early in the pandemic, COVID-19 disease was mostly mild in pediatric SOT recipients with no rejection, patient death, or graft loss observed.

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: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. Methods: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. Findings: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7–30·4). Median overall survival was 12·7 months (95% CI 11·5–13·6) in the pembrolizumab group versus 10·9 months (9·9–11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72–0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. Interpretation: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Nanocomposite tectons (NCTs) are nanocomposite building blocks consisting of nanoparticle cores functionalized with a polymer brush, where each polymer chain terminates in a supramolecular recognition group capable of driving particle assembly. Like other ligand-driven nanoparticle assembly schemes (for example those using DNA-hybridization or solvent evaporation), NCTs are able to make colloidal crystal structures with precise particle organization in three dimensions. However, despite the similarity of NCT assembly to other methods of engineering ordered particle arrays, the crystallographic symmetries of assembled NCTs are significantly different. In this study, we provide a detailed characterization of the dynamics of hybridizations through universal (independent of microscopic details) parameters. We perform rigorous free energy calculations and identify the persistence length of the ligand as the critical parameter accounting for the differences in the phase diagrams of NCTs and other assembly methods driven by hydrogen bond hybridizations. We also report new experiments to provide direct verification for the predictions. We conclude by discussing the role of non-equilibrium effects and illustrating how NCTs provide a unification of the two most successful strategies for nanoparticle assembly: solvent evaporation and DNA programmable assembly.

BACKGROUND: Metastatic pancreatic ductal adenocarcinoma (mPDAC) is highly lethal. Combination chemotherapy regimens improve overall survival (OS). Historically, only one third of mPDAC patients in Victoria received chemotherapy (1) . AIM: To describe current Australian chemotherapy utilisation and outcomes in patients with mPDAC using the multi-site PURPLE (Pancreatic cancer: Understanding Routine Practice and Lifting End Results) registry. METHODS: PURPLE collects longitudinal data on consecutive patients with pancreatic cancer seen since January 2016. Data was collated for patients with mPDAC from six Victorian sites, and analysed descriptively. RESULTS: Three-hundred-and-sixty-three patients with mPDAC were identified. Median age was 70 years (20-94). First line chemotherapy was administered in 195 patients (54%). Prevalent regimens included gemcitabine-nab-paclitaxel (71%), gemcitabine alone (10%) and FOLFIRINOX (6%). Sixty-two of 195 (32%) patients who received first line treatment have proceeded to second line chemotherapy. Chemotherapy treated patients were younger (69 versus 73 years, p

In the current work, we examine a possible source of gender disparities in pay even when women manage to reach similar levels of the organizational ladder as men. We refer to the concept of “span of control,” or the number of subordinates a leader oversees, and propose that in addition to differences in how high men and women climb up the organizational hierarchy, differences in managers’ span of control can also contribute to the gender pay gap. We suggest that people hold gender stereotypes about managers’ relational model tendencies, or how men and women interact with people they manage, and these stereotypes correspond with people’s lay beliefs about relational models utilized in small and large spans of control: smaller groups are thought to operate based more on communal sharing principles while larger groups are thought to operate based more on authority ranking principles. Because span of control affects compensation, a gender difference in span of control can contribute to gender differences in pay. We found support for these hypotheses in an archival dataset of MBA alumni (N = 1838) and three additional experiments (N = 799).

Purpose: Phyllodes tumor (PT) of the breast is a fibroepithelial neoplasm with incidence of around 1%. In 1-2% of PTs, a concomitant breast carcinoma is incidentally found encapsulated within the PT. Here, we present a rare case of an infiltrating ductal carcinoma (IDC) and ductal carcinoma in situ (DCIS) found within a borderline phyllodes tumor (bPT). Methods: Medical records were queried for this patient who received care at our facility in 2022. Results: A 32-year-old Asian female presented to our breast surgery center for bilateral masses present for 2 years. She denied any remarkable family history, use of hormonal therapy, and had no history of breast or ovarian cancers. Multiple initial core needle biopsies (CNB) revealed non-concerning fibroadenomas in both breasts. Eighteen months later, she noted a rapid increase in her left breast, prompting biopsy which revealed a borderline phyllodes tumor, removed intraoperatively shortly after. Surgical pathology reported an incidentally found IDC and DCIS, both encapsulated within the bPTand a positive superior margin. Re-excision and sentinel lymph node biopsy was performed and pathology was without any residual tumors and all lymph nodes were negative. Closure was achieved by plastic surgery with local tissue rearrangement in both surgeries. To our knowledge, the patient has not had any complications and her right breast lesions are stable. Conclusions: There are currently no treatment guidelines for encapsulated IDC and DCIS. While these cases are exceedingly rare, breast surgeons should be aware of the possible PT disease course and how to counsel their patient if an encapsulated breast carcinoma is found.

Treatment with cetuximab provides a survival benefit for patients with RAS wild-type metastatic colorectal cancer (mCRC). Practice-defining cetuximab studies utilised weekly (q1w) administration. More convenient second weekly (q2w) administration is supported by pharmacokinetic data and a recent meta-analysis, but large head-to-head studies have not been conducted. Therapeutic Goods Association (TGA) prescribing information states cetuximab be administered q1w for all indications.To assess the real-world use of q1w versus q2w cetuximab schedule and any difference in outcomes.We analysed data from a prospective mCRC database at seven Melbourne hospitals from January 2010 to August 2019. Characteristics and outcomes for cetuximab-treated patients were examined, comparing q1w versus q2w schedules. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints.Of 214 eligible patients, 103 (48%) received q1w and 111 (52%) received q2w cetuximab. Q2w cetuximab has been used in70% of patients from 2015. Q2w was more commonly used in public patients (70% vs 13% in private, P 0.001), in left-sided primary tumours (83% vs 68%, P = 0.025) and in combination with chemotherapy (73% q2w vs 40% q1w, P 0.001). Q2w treatment was less common in BRAFV600E mutated tumours (4% vs 13%, P = 0.001). PFS was similar across all lines of therapy, including when analyses were limited to a left-sided primary and there was no difference in OS in multivariate analysis.This real-world analysis shows q2w cetuximab has become the dominant method of administration, despite TGA guidance. Our outcome data adds to other data supporting the use of q2w cetuximab as the standard option. Consideration could be given to modifying current TGA advice.