Impact of primary resistance to front-line targeted therapy in metastatic renal cell carcinoma on subsequent immune-checkpoint-inhibition.

INTRODUCTION: Synergistic effects have been discussed for tyrosine kinase (TKI) and immune checkpoint inhibitors (ICI). Primary resistance to TKI might disturb subsequent ICI effectiveness. The objective was to investigate, if primary resistance to 1st line TKI monotherapy predicts response to ICI in subsequent therapy lines and impacts overall survival (OS) in advanced renal cell carcinoma (aRCC). MATERIALS AND METHODS: Retrospectively, aRCC patients which received front-line TKI from 2016 to 2019 were analyzed for the outcomes primary resistance (1LR), response to sequential ICI therapy, progression free survival (PFS) and overall survival (OS). Kaplan-Meier-estimates, Cox proportional hazards and logistic regression were used. RESULTS: Primary resistance to front-line TKI was observed in 27 (53%) of 51 patients. Groups with disease control (DC) and 1st line TKI resistance (1LR) were not different at baseline with regard to clinicopathological features. Median duration on 1st line therapy was significantly shorter in the 1LR (5.1 months) than in the DC (14.7 months) group (p = 0.01). Sequential therapy was started in 21 (75%) and 12 (52%) patients of 1LR and DC groups using nivolumab in 16 (76%) vs. 11 (92%) cases (p > 0.05). Logistic regression revealed that 1LR status, neutrophil-to-lymphocyte ratio < 3, IMDC favorable prognosis and clear cell histology had no significant impact on responsiveness to ICI in subsequent therapy lines. Cox proportional hazards demonstrated no significant association of 1LR status with PFS and OS in patients who received subsequent ICI treatment. CONCLUSION: Primary TKI resistance of aRCC was neither significantly associated with responsiveness to ICI during sequential therapy nor with PFS and OS. This adds the evidence for ICI based sequential therapy in primary TKI resistant aRCC.

Comparison of quantitative echocardiography with endomyocardial biopsy to define myocardial rejection in pediatric patients after cardiac transplantation.

Endomyocardial biopsy is the gold standard for determining rejection; however, no echocardiographic indexes have been widely accepted as indicators of rejection. The stress-velocity relation of corrected velocity of circumferential fiber shortening to wall stress is a preload independent index of contractility that incorporates afterload and has been shown to distinguish a decreased velocity caused by excess afterload from that caused by decreased contractility. Wall stress has not been previously reported as a determinant of rejection. We report a prospective double-blind study of pediatric cardiac transplant patients comparing biopsy and quantitative systolic echocardiographic data. Thirty-two pediatric patients underwent 67 biopsies. At the time of catheterization, an echocardiographic evaluation was performed. Standard measurements of systolic function were collected and left ventricular (LV) fractional shortening, LV volume, LV mass, velocity of circumferential fiber shortening, and estimated end-systolic wall stress were calculated. In evaluating echocardiographic data of patients with and without biopsy-proven rejection, we were unable to identify any significant correlation between any systolic echocardiographic parameter and rejection. We conclude that: (1) the stress-velocity relation does not detect myocardial rejection; and (2) neither LV fractional shortening, LV volume, nor LV mass detect rejection; and (3) central venous pressure influence wall stress values significantly.

Acute tryptophan depletion and increased food intake and irritability in bulimia nervosa.

OBJECTIVE: Data suggest that serotonin activity is reduced in women at normal weight who have bulimia nervosa. The authors tested whether acute perturbations in serotonin activity could alter short-term eating behavior and mood. METHOD: They examined the effect of acute tryptophan depletion in 10 women with and 10 women without bulimia nervosa. RESULTS: Women with bulimia nervosa exhibited an increase in caloric intake and mood irritability after acute tryptophan depletion. CONCLUSIONS: These results indicate that women with bulimia nervosa have an exaggerated or pathological response to transient alterations in serotonin activity.

Differences in weight gain between restrictor and bulimic anorectics.

After admission for weight restoration, restrictor anorectics (n = 17) gained significantly less weight than bulimic anorectics (n = 17) in a 30-day period. However, these groups had similar caloric intake. Severity of illness was found to be a predictor of rate of weight gain for restrictor anorectics, but not for bulimic anorectics.

Twenty-four-hour food intake in patients with anorexia nervosa and in healthy control subjects.

Ad libitum feeding over 24 hours was assessed in underweight restrictor anorectic (RAN) women (n = 8) and matched healthy control subjects (n = 9) in a relatively naturalistic laboratory setting. RAN consumed 828 +/- 210 kcal/day (20 +/- 6 kcal/kg/day); controls ingested 2274 +/- 564 kcal/day (41 +/- 13 kcal/kg/day). Expressed as macronutrient consumption, RAN, compared to healthy controls, ate less fat (13% vs 31%), more carbohydrate (73% vs 57%), and similar amounts of protein (14% vs 12%). RAN initiated fewer eating episodes than controls (4 vs 7). This study quantitatively confirms the growing body of evidence suggesting that RAN avoid fat-containing foods. Such persistent fat avoidance may significantly contribute to the difficulty RAN experience in gaining and maintaining body weight.

Prenatal sonographic detection of intra-abdominal extralobar pulmonary sequestration: report of three cases and literature review.

Three cases of intra-abdominal extralobar pulmonary sequestration detected antenatally by ultrasound are reported. One case was associated with a large left diaphragmatic hernia. Sonographically, all the cases were found in the left supra-renal region presenting as a well-defined echogenic mass with cystic hypoechoic areas. The condition should be considered in the differential diagnosis of all antenatally detected upper abdominal echogenic masses, particularly when associated with a diaphragmatic hernia. Postnatal ultrasound-guided fine needle aspiration biopsy in one case yielded respiratory type epithelium and this procedure could provide a reasonably confident diagnosis of the lesion.

The association of in vitro arachidonic acid responsiveness and plasma thromboxane levels with early platelet deposition on the luminal surface of small-diameter grafts.

The response of canine platelets to arachidonic acid (AA) stimulation was studied as a predictor of thrombotic potential. Fifty mongrel dogs underwent in vitro platelet aggregation studies with adenosine diphosphate (ADP), collagen, and AA used as inducing agents. Thirty-two dogs were selected on the basis of their response to AA stimulation. Platelet aggregation in response to AA stimulation occurred in 16 (responders) and 16 showed no aggregatory response (nonresponders). The animals were divided into four groups. Group I received no antiplatelet agents (control); group II received U-63,557A, a specific thromboxane synthetase inhibitor (TSI); group III received aspirin; and group IV received aspirin and TSI. Polytetrafluoroethylene grafts were implanted in the carotid and femoral arteries of the dogs in all four groups. Plasma thromboxane (TxB2) levels were drawn before drug treatment and 4 weeks after surgery. Platelet deposition on the luminal surface of the implanted grafts was studied in vivo with a technique that uses both 111In-labeled platelets and 99mTc-labeled red blood cells and was expressed as percentage of indium excess (%IE). Group I (control) dogs whose platelets aggregated in response to AA stimulation had significantly higher 24-hour platelet deposition (%IE) on the luminal surface of implanted grafts (p less than 0.02), lower 4-week graft patency (p less than 0.002), and higher plasma TxB2 levels (p less than 0.01) than those dogs whose platelets did not aggregate. In contrast to the results of AA stimulation, neither ADP nor collagen responsiveness was discriminatory for the thrombotic potential of canine arteries as measured by 24-hour platelet deposition (%IE), 4-week graft patency, or plasma TxB2 levels.(ABSTRACT TRUNCATED AT 250 WORDS)