Entrectinib in ROS1-positive advanced non-small cell lung cancer: the phase 2/3 BFAST trial.

Although comprehensive biomarker testing is recommended for all patients with advanced/metastatic non-small cell lung cancer (NSCLC) before initiation of first-line treatment, tissue availability can limit testing. Genomic testing in liquid biopsies can be utilized to overcome the inherent limitations of tissue sampling and identify the most appropriate biomarker-informed treatment option for patients. The Blood First Assay Screening Trial is a global, open-label, multicohort trial that evaluates the efficacy and safety of multiple therapies in patients with advanced/metastatic NSCLC and targetable alterations identified by liquid biopsy. We present data from Cohort D (ROS1-positive). Patients ≥18 years of age with stage IIIB/IV, ROS1-positive NSCLC detected by liquid biopsies received entrectinib 600 mg daily. At data cutoff (November 2021), 55 patients were enrolled and 54 had measurable disease. Cohort D met its primary endpoint: the confirmed objective response rate (ORR) by investigator was 81.5%, which was consistent with the ORR from the integrated analysis of entrectinib (investigator-assessed ORR, 73.4%; data cutoff May 2019, ≥12 months of follow-up). The safety profile of entrectinib was consistent with previous reports. These results demonstrate consistency with those from the integrated analysis of entrectinib in patients with ROS1-positive NSCLC identified by tissue-based testing, and support the clinical value of liquid biopsies to inform clinical decision-making. The integration of liquid biopsies into clinical practice provides patients with a less invasive diagnostic method than tissue-based testing and has faster turnaround times that may expedite the reaching of clinical decisions in the advanced/metastatic NSCLC setting. ClinicalTrials.gov registration: NCT03178552 .

Salvage of a severely mangled limb following traumatic injury.

Management of a severely damaged extremity poses a dilemma-whether to perform a primary amputation or attempt limb salvage. A multitude of factors-such as the extent of neurovascular injury, limb ischaemia time, severity of bone and soft tissue loss, physiological reserve of the patient and availability of surgical expertise and resources-influence this decision. The Mangled Extremity Severity Score (MESS) was developed as a predictor of the need for limb amputation, and a MESS of 7 or more is considered a predictor of primary amputation. Here we describe a case where a man in his 20s sustained traumatic avulsion of his right ankle with severe neurovascular damage and multiple tendon injuries onboard a ship at high sea. Despite a MESS of 10, limb ischaemia time of more than 10 hours and injuries to all three extremity vessels (anterior tibial, posterior tibial and peroneal arteries), limb salvage was successfully carried out at a level-II trauma centre.

High-dose alectinib for RET fusion-positive non-small cell lung cancer in the Blood First Assay Screening Trial.

Introduction: This paper presents results from Cohort B (rearranged during transfection [RET], fusion-positive) of the Blood First Assay Screening Trial in patients with advanced non-small cell lung cancer (NSCLC) screened for genetic alterations using blood-based next-generation sequencing. Material and methods: Adults with advanced RET fusion-positive NSCLC received alectinib 900 mg twice daily (BID) in Phase I. Enrolment closed prematurely with Phase II uninitiated. Results: Among eight treated patients, confirmed best overall responses in evaluable patients were stable disease (4/5) and progressive disease (1/5). One dose-limiting toxicity (death, unknown cause) was considered by the investigator to be related to treatment and underlying disease. Serious adverse events (SAEs) occurred in five patients, and SAEs that may be related to treatment occurred in two patients. Conclusions: Alectinib showed limited activity in advanced RET fusion-positive NSCLC, and further investigation was not conducted due to the development of selective RET inhibitors pralsetinib and selpercatinib. No new safety signals were observed, and the safety profile of alectinib was in line with previous reports at the 600 mg BID dose.

Association of Sociodemographic Parameters With Depression, Anxiety, Stress, Sleep Quality, Psychological Trauma, Mental Well-Being, and Resilience During the Second Wave of COVID-19 Pandemic: A Cross-Sectional Survey From India.

Objective This study was conducted to assess the traumatic impact of the second wave of coronavirus disease 2019 (COVID-19) pandemic on depression, anxiety, stress, sleep quality, mental well-being, and resilience among the general population of India. Methods An online cross-sectional survey was conducted in May-June, 2021 via Google Forms, which included adult individuals who were willing to participate in the study. The purposive and snowball sampling technique was used to ensure the principle of maximum diversity. Standardised tools [Depression Anxiety and Stress Scale (DASS), Pittsburgh Sleep Quality Index (PSQI), Impact of Event-Revised (IES-R), Short Warwick-Edinburgh Mental Well-being Scale (SWEMWBS), and the Brief Resilience Scale (BRS)] were used to collect data. Results A total of 1,109 responses were analysed for this study. Participants of different age groups (mean age: 32.98 ±14.72 years) and different sociodemographics were enrolled. The younger population group (18-34 years) was found to be the most affected among all the age groups. The findings revealed that 44.18% showed posttraumatic stress disorder (PTSD)-like symptoms. About 48.87%, 65.56%, and 22.09% of the participants had significant depression, anxiety, and stress symptoms respectively, and 11.27% had disturbed sleep patterns. Mental well-being was found to be disturbed for 74.75% of the study population, out of which only 4.15% showed high resilience capacity. Conclusion The associated collective psychological trauma mapped out by this paper is a pandemic in itself and needs to be addressed on a scale similar to the efforts being made to curb the physical symptoms of COVID-19.

First-in-human phase I study of immunomodulatory E7046, an antagonist of PGE2-receptor E-type 4 (EP4), in patients with advanced cancers.

BACKGROUND: E7046 is a highly selective, small-molecule antagonist of the E-type prostanoid receptor 4 (EP4) for prostaglandin E2, an immunosuppressive mediator of the tumor immune microenvironment. This first-in-human phase 1 study assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD) and recommended phase 2 dose of E7046. METHODS: This first-in-human study enrolled 30 patients with advanced tumors of cancer types associated with high levels of myeloid infiltrates. E7046 was administered orally once-daily in sequential escalating dose cohorts (125, 250, 500, and 750 mg) with ≥6 patients per cohort. Tumor assessments were performed every 6 weeks. Paired tumor biopsies and blood samples, before and on treatment, were collected for pharmacokinetic and pharmacodynamic characterization of the treatment. RESULTS: No dose-limiting toxicities were observed, and the MTD was not reached. E7046 had an elimination half-life (t1/2) of 12 hours, and drug exposure increased dose-dependently from 125 to 500 mg. Target modulation by E7046 was supported by changes in genes downstream of EP4 with concurrent enhanced antitumoral immune responses. A best response of stable disease (per irRECIST) was reported in 23% of patients treated with E7046 (n=30) (125 mg: n=2; 250 mg: n=2; 750 mg: n=3). Over half (4/7) of the patients with stable disease had treatment duration of 18 weeks or more, and three patients (3/15; 20%) achieved metabolic responses. CONCLUSIONS: In this first-in-human study, E7046 administered orally once daily demonstrated manageable tolerability, immunomodulatory effects, and a best response of stable disease (≥18 weeks) in several heavily pretreated patients with advanced malignancies. The 250 and 500 mg doses are proposed for further development in the combination setting. TRIAL REGISTRATION NUMBER: NCT02540291.

Stress and Quality of Life in Cancer Patients: Medical and Psychological Intervention.

BACKGROUND: Cancer pervades many dimensions of an individual's life - demanding a holistic treatment approach. However, studies with combined medical and psychological interventions (MPIs) are sparse. High-level stress and poor quality of life (QoL) can hinder patients' prognosis. The study thus aimed to analyze the impact of combined medical and psychological (psychoeducation, relaxation technique-guided imagery, and cognitive therapy) interventions on stress and QoL of cancer patients - head and neck, breast, and lung cancers. METHODS: The study was conducted in cancer hospitals employing one-group pretest-posttest-preexperimental design. Descriptive statistics, paired t-test, Cohen's d, and bar graphs were used to analyze the data. RESULTS: Findings showed high impact of the combined MPIs in reducing both the overall stress as well as the various components of the stress scale-fear, psychosomatic complaints, information deficit, and everyday life restrictions. Significant changes were also seen in QoL and its domains - global health status, besides functional and symptom scales. Results showed a significant improvement in physical, role and emotional functioning scale, while decrement in fatigue, pain, insomnia, appetite loss, diarrhea, and constipation of symptoms scales. CONCLUSIONS: It can be concluded that combined MPI has a positive impact - decreasing stress and improving QoL in cancer patients, which can further enhance their prognosis.

Pediatric emergency transport: communication and coordination are key to improving outcomes.

Pediatric patients who are critically ill or who require urgent subspecialty evaluation or specialized imaging, equipment, or procedures must often be transferred to tertiary care centers. The safe execution of interfacility transfer requires the coordination between the facility healthcare teams at each end of the transfer as well as the transport team. This issue discusses the process of interfacility transfer, the required services, the role of the emergency clinician, the role of the pediatric transport team, and the commonly used diagnostic studies and treatment needed during interfacility transfers of pediatric patients.

CD40mAb adjuvant induces a rapid antibody response that may be beneficial in post-exposure prophylaxis.

Active vaccination can be effective as a post-exposure prophylaxis, but the rapidity of the immune response induced, relative to the incubation time of the pathogen, is critical. We show here that CD40mAb conjugated to antigen induces a more rapid specific antibody response than currently used immunological adjuvants, alum and monophosphoryl lipid A.

Electrical isolation during radiofrequency ablation: 5% dextrose in water provides better protection than saline.

We quantify the ability of 0.9% NaCl (saline) and 5% dextrose in water (D5W) to protect tissues during RF ablation. Using computer simulations and phantom experiments, we determined that D5W provides significantly more electrical isolation than saline, which reduces unwanted heating of the adjacent tissue. Saline actually increased the amount of RF current in the adjacent tissue. Based on these results, we conclude that D5W is preferable to saline as a protective fluid.