Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial.

BACKGROUND: RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. PATIENTS AND METHODS: ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. RESULTS: Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. CONCLUSIONS: Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.

[Staging with 18F-FDG-PET/CT influences stage-specific survival in advanced non-small cell lung cancer (NSCLC)]. / Der Einfluss des F-18-FDG-PET/CT auf das stadienbezogene Gesamtüberleben beim fortgeschrittenen nicht-kleinzelligen Lungenkarzinom (NSCLC).

BACKGROUND: PET/CT investigation with 18F-fluorodeoxyglucose (FDG) has a high sensitivity (89 - 100 %) and good specificity (79 - 95 %) for the diagnosis of NSCLC. Currently, it is mainly used in preoperative staging. This leads in approximately 15 % of these cases to the diagnosis of metastatic disease that was neither clinically suspected nor seen in previously performed conventional imaging. We hypothesised that including these cases in the palliative stage IV group would have an influence on overall survival. AIM: The aim of this study was to compare the overall survival (OS) of patients with stage IV NSCLC who underwent FDG-PET/CT staging with patients in whom conventional imaging procedures were performed. METHODS: We analysed the OS of all stage IV NSCLC patients diagnosed in our clinic in 2009 (n = 254), 96/254 (38 %) patients were staged with PET/CT and 158/254 (62 %) with conventional imaging (CT group). Survival data were compared by Kaplan-Meier statistics. RESULTS: Patients in the PET/CT group were younger (65 ± 11) than in the CT group (68 ± 10 years; p = 0.008). The median OS of all patients was 246 (range: 217 - 275) days; 338 (range: 247 - 429) days in the PET/CT group and 207 (range: 161 - 253) days in the CT group (p = 0.001), stating a difference of 131 days (4.4 months) in median OS. CONCLUSION: The use of FDG-PET/CT staging mainly in the preoperative setting leads to stage migration of patients with a better prognosis into the worst stage (IV) and thus longer survival within this subgroup. This survival benefit is unrelated to treatment and needs to be addressed in future studies.

The cytological effect of ecdysterone on the midgut cells of the flesh-fly Sarcophaga bullata.

Larvae of the flesh-fly, Sarcophaga bullata, were injected with the synthetic moulting hormone ecdysterone or saline at the beginning of the third and final larval instar. One group was left untreated. The ecdysterone-injected larvae showed an increase in number of secondary lysosomes in the midgut epithelial cells similar to that observed at the onset of metamorphosis, an event which would normally occur about 48 hr later in these larvae.

Intestinal microvilli: responses to feeding and fasting.

Membrane-bound bodies are formed individually and in groups from the plasma membrane surrounding the microvilli in cells of hamster small intestine. These bodies are vesiculate structures, are slightly smaller in diameter than the microvilli from which they are released, and retain at least a portion of glycocalyx. The production of the membrane-bodies occurs regularly, perhaps continuously in vivo, and appears to be related to the feeding cycle. The brush border of jejunal cells from animals which had been feeding ad lib contained more membrane-bodies andhad taller microvilli than comparable cells from those which had been fasted for 48 hours. Since membrane-bodies are also found among the microvilli of cells which have no digestive function, we propose that their formation and release may be of general significance in the normal functioning of active epithelial cells.

Is in-hospital stroke mortality an accurate measure of quality of care?

We examined the validity of using in-hospital stroke mortality as predicted by the Cleveland Hospital Outcomes Indicators of Care Evaluations (CHOICE) model as a measure of quality of care. A total of 223 patients admitted to the hospital for stroke were evaluated by the CHOICE model, which predicted that 19 stroke deaths would occur. We reviewed the 19 patients with the highest predicted mortality, according to CHOICE, and three additional patients who died following stroke. We found that The CHOICE model accurately predicts in-hospital stroke mortality for large populations but not for individual patients. CHOICE and other stroke outcome models rely heavily on early Do Not Resuscitate orders and coma but exclude important variables found in the literature on stroke. No correlation between in-hospital stroke mortality and quality of care was demonstrated. Mortality prediction models used to guide consumers on where to receive stroke care are potentially misleading, as they do not assess functional neurologic recovery or the process of care that are essential elements of quality.

Cystoid macular edema associated with latanoprost in aphakic and pseudophakic eyes.

PURPOSE: To describe four patients who developed cystoid macular edema shortly after onset of treatment with latanoprost. METHOD: Retrospective review of medical records of patients with open-angle glaucoma who developed cystoid macular edema shortly after starting latanoprost. RESULTS: The use of topical latanoprost was temporally related to the development of cystoid macular edema in four patients (six eyes; two aphakic eyes and four pseudophakic eyes). Cystoid macular edema resolved in all patients after latanoprost was discontinued. CONCLUSIONS: Cystoid macular edema is a potential complication of latanoprost therapy. Further observations are needed to determine if the risk of cystoid macular edema is limited to or greatest in patients who are pseudophakic or aphakic.

Great expectations: mistaken beliefs of beginning psychodynamic psychotherapists.

Beginning psychotherapists often have mistaken assumptions about what it is that constitutes good psychotherapy and a good psychotherapist. These mistaken beliefs are counterproductive and may inhibit the development of appropriate psychotherapeutic skills as well as delay, or even prevent, the acquisition of an appropriate identity as a psychotherapist. This paper explores six common mistaken beliefs on the part of neophyte psychotherapists, providing a basis for exploration and discussion of key developmental issues in the genesis of a competent psychotherapist.

Basic strategies of dynamic supportive therapy.

Supportive therapy is the psychotherapeutic approach employed with the majority of mentally ill individuals. Nevertheless, most mental health professional training programs dedicate little time and effort to the teaching and learning of supportive therapy, and many mental health professionals are unable to clearly and concisely articulate the nature or process of supportive work. Although supportive therapy incorporates many specific techniques from a wide variety of psychotherapy schools, it can be conceptualized as consisting of a more limited number of underlying strategies. The fundamental strategies that underpin effective supportive therapy with mentally ill individuals are described.

Pseudo-endophthalmitis caused by intravitreal lipid transudation in association with proliferative diabetic retinopathy and hyperlipidemia.

A 20-year-old woman with a 13-year history of insulin-dependent diabetes mellitus presented with a history of malaise, fever, a non-healing ulcer of the great toe, and an insect bite incurred during recent travel to a foreign country. Milky white infiltrates accompanied by inflammatory cells located within close proximity to neovascular fronds in both vitreous cavities led to the suspicion of bilateral metastatic endophthalmitis. Studies conducted during hospitalization failed to show evidence of systemic blood born infection. A diagnostic vitrectomy in one eye failed to grow organisms, though lipid laden macrophages were identified by electron microscopy. The clinical appearance improved in both eyes during her hospitalization coincident with improved diabetic control. It was later concluded that the milky white infiltrates were associated with hyperlipidemia as a consequence of poorly controlled diabetes and a familial tendency toward hyperlipidemia.

Regulation of mucociliary transport. Response of mucous cells to stimulation by amiloride applied to the frog palate in vitro.

Mucociliary transport (MCT) over the surface of isolated frog palatal epithelium was significantly inhibited by the diuretic drug amiloride (50% at 10(-5)M); this occurred when the drug was applied to the mucosal but not to the submucosal surface. The rate of ciliary beating was unchanged by treatment with amiloride (13.5 +/- 1.3 Hz, amiloride; 13.4 +/- 1.4 Hz, control). Spontaneous reversal of inhibition of MCT occurred after extended rinsing (1.5 to 3 h) with Ringer's solution; however, addition of mucus immediately restored MCT to control level. Amiloride applied to the mucosal surface stimulated 2.5 to 3 times as many cells to discharge mucus; this was correlated with an increase of 28% in apparent viscoelasticity of the mucus transport layer measured in situ (approximated by determining breaking strength of mucus using a surface tension balance). Other effects of mucosal application of amiloride included reduction of the transepithelial electrical potential by 62% and increased sodium (17%) in secreted mucus. This is the first report of a stimulatory effect by amiloride on mucous secretory cells.

A novel bioassay system for evaluating the toxicity of Bacillus thuringiensis israelensis against mosquito larvae.

A bioassay system employing acutely toxic concentrations of a spore-crystal mixture of Bacillus thuringiensis subspecies israelensis against fourth instar larvae of Aedes aegypti (L.) is described. Individual larvae are separately exposed to toxin in glass-lined miniature wells or scintillation vials. This method is free from the deaths due to predation among larvae. Such larval deaths are commonly encountered in bioassay groups of 25 larvae as currently specified in the World Health Organization guidelines. Our method offers shortened testing time, increased accuracy, and improved statistical precision.