Panitumumab in the treatment of metastatic colorectal cancer, including wild-type RAS, KRAS and NRAS mCRC.

The humanized monoclonal antibody panitumumab, targeted against EGFR, plays an important role in patients with metastatic colorectal cancer. This article reviews the body of evidence for panitumumab which demonstrates significant benefits across multiple lines of therapy in those without an extended RAS mutation. The use of panitumumab with RAS mutations is not beneficial and possibly harmful. Panitumumab is well tolerated with manageable toxicities. The role of panitumumab continues to evolve as understanding of sequencing of therapies grows. There is evidence for use as maintenance therapy and conversion therapy for unresectable liver metastases. Future research is likely to focus on biomarkers for improved patient selection and the development of novel therapeutic strategies to overcome resistance.

Dual αV-integrin and neuropilin-1 targeting peptide CEND-1 plus nab-paclitaxel and gemcitabine for the treatment of metastatic pancreatic ductal adenocarcinoma: a first-in-human, open-label, multicentre, phase 1 study.

BACKGROUND: CEND-1 is a novel cyclic peptide that targets αV integrins and neuropilin-1 and enhances tumour delivery of co-administered anticancer drugs. We investigated the safety, tolerability, and biological activity of CEND-1 in patients with metastatic pancreatic ductal adenocarcinoma in combination with nab-paclitaxel and gemcitabine. METHODS: This open-label, multicentre, phase 1 study, conducted at three hospitals in Australia, enrolled participants aged 18 years or older with histologically confirmed metastatic pancreatic ductal adenocarcinoma who had one or more lesions measurable on MRI or CT, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a life expectancy of at least 3 months. Exclusion criteria included previous chemotherapy and brain metastases or other malignancy (unless receiving curative intent). There was no randomisation or masking. CEND-1 monotherapy was given as an intravenous fluid bolus on day 1 of a run-in phase of 7 days (0·2-3·2 mg/kg) followed by CEND-1 plus intravenous gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 8, and 15 of 28-day treatment cycles until disease progression. The primary safety endpoints were incidence, severity, and duration of treatment-emergent and treatment-related adverse events; overall survival; and clinical laboratory results, which were all assessed in the safety population. This study is registered with ClinicalTrials.gov, NCT03517176, and the Australian New Zealand Clinical Trials Registry, ACTRN12618000804280. FINDINGS: Between Aug 13, 2018, and Nov 30, 2019, 31 patients were enrolled (eight in the dose-escalation phase [cohort 1a] and 23 in the expansion phase [cohort 1b]). Two patients were excluded from the efficacy population. No CEND-1 dose-limiting toxicities were observed in the safety population (n=31). The most common grade 3 or 4 events were neutropenia (17 [55%] patients), anaemia (eight [26%]), leukopenia (five [16%]), and pulmonary embolism (four [13%]). Serious adverse events occurred in 22 (71%) patients, mostly related to disease progression. Ten deaths occurred during the study due to progression of metastatic pancreatic cancer (n=9) and a left middle cerebral artery stroke (n=1). In the efficacy population (n=29), 17 (59%) patients had an objective response, including one complete response and 16 partial responses. After a median follow-up of 26 months (IQR 24-30), median overall survival was 13·2 months (95% CI 9·7-22·5). INTERPRETATION: CEND-1 with nab-paclitaxel and gemcitabine has an acceptable safety profile, with no dose-limiting toxicities and encouraging activity. Adverse events were generally consistent with those seen with nab-paclitaxel and gemcitabine. Further randomised trials to determine the efficacy of CEND-1 are warranted. FUNDING: DrugCendR Australia Pty.

Optimal fluid control can normalize cardiovascular risk markers and limit left ventricular hypertrophy in thrice weekly dialysis patients.

Increased hemodialysis frequency can make fluid overload easier to treat, although most patients are still treated thrice weekly. Chronic fluid overload is associated with left ventricular hypertrophy and elevated serum cardiac biomarkers, recognized as mortality risk factors. Serum cardiac troponin T (cTnT), N-terminal prohormone brain natriuretic peptide (NT-proBNP), left ventricular mass index by cardiac magnetic imaging, and ambulatory blood pressure was measured in 30 thrice weekly hemodiafiltration patients. Time-averaged fluid overload (TAFO) was quantified by bioimpedance spectroscopy. In the study group, left ventricular hypertrophy was found to be 26% by cardiac magnetic resonance. Ambulatory blood pressure was 130 mmHg (112-151) requiring a low equivalent dose of medication of 0.25 units (0-1). Significantly, lower levels of left ventricular mass index (P < 0.05) were associated in those patients with TAFO <1 L or NT-proBNP <1200 pg/mL or cTnT <0.1 ug/L. In the subgroups, 16 patients had normal cTnT (<0.03 ug/L), 16 patients had NT-proBNP <400 pg/mL, and 20 patients had TAFO <1 L. Nine patients had both cTnT <0.03 ug/L and NT-proBNP <400 pg/mL. Normally hydrated thrice-weekly hemodiafiltration patients can have cardiac biomarker and TAFO levels indistinguishable from the normal healthy population. Obtaining TAFO by bioimpedance monitoring can offer a practical alternative to serum cardiac biomarkers.

Expertise in ill-defined problem-solving domains as effective strategy use.

Expertise consists of many different cognitive structures. Lemaire and Siegler (1995) have proposed a four-layered account of expertise from a strategies perspective: Experts have better strategies, tend to use strategies that are better overall more often, are better able to select the circumstances to which a strategy best applies, and are better able to execute a given strategy. Originally, this account came from work in simple, well-defined domains. We explored this account in the complex, ill-defined domain of platoon leadership. In Experiment 1A, we elicited free-text responses to leadership scenarios from novices, intermediates, and experts, finding expertise effects for strategy base rates and choice, but not for strategy existence or the number of strategies used. In Experiment 1B, we used a new group of experts to gather ratings of the execution accuracy of the responses in Experiment 1A and found expertise differences in the ability to execute the same strategies. We propose several elaborations to the original four-layered strategies account of expertise on the basis of these results.