Gastrointestinal metastases in renal cell carcinoma: A retrospective multicenter GETUG (Groupe d'Étude des Tumeurs Uro-Génitales) study.

BACKGROUND: Among patients with renal cell carcinoma (RCC), bone and visceral metastases have a poor prognosis, while endocrine gland metastases have a more favorable prognosis. Gastrointestinal metastases (GIMs) are rare, and their prognosis is still poorly understood. OBJECTIVES: To report clinical presentations, patient characteristics, therapeutic strategies, and prognosis of GIMs from RCC. METHODS: We retrospectively collected data from RCC patients presenting GIMs, in 10 French GETUG centers, between 2000 and 2021. RESULTS: We identified 74 patients with 87 GIMs, mostly gastric or duodenal. The median age at GIM diagnosis was 69 years and 76% of patients already had other metastases. GIMs occurred after a median duration of 5.4 years (IC95%=[4.2-7.1]) and 1.9 years (IC95%=[1.2-3.8]) from RCC diagnosis and first metastasis, respectively. GIMs were symptomatic in 52 patients (70%), with anemia in 41 patients (55%) and/or gastrointestinal bleeding in 31 patients (42%). Only 22 asymptomatic patients (30%) were fortuitously diagnosed. GIM management consisted of systemic treatment only in 29 GIMs (33%), local treatment only in 23 GIMs (26%), and both local and systemic treatment in 18 GIMs (21%). For 17 GIMs (20%), there was no therapeutic modification. After diagnosis of GIM, median overall survival was 19 months. CONCLUSION: We report the largest retrospective cohort of GIMs in RCC patients. They should be suspected in case of anemia or gastrointestinal bleeding in any patient with a history of RCC. Their management varies widely depending on their location in the digestive tract and whether or not they are symptomatic.

Association of cabozantinib pharmacokinetics, progression and toxicity in metastatic renal cell carcinoma patients: results from a pharmacokinetics/pharmacodynamics study.

BACKGROUND: Cabozantinib is a tyrosine kinase inhibitor with a substantial efficacy in metastatic renal cell carcinoma, and is associated with a challenging toxicity profile leading to frequent drug discontinuations. Whereas an exposure/safety relationship was demonstrated for this drug, an exposure/efficacy relationship is still unknown. PATIENTS AND METHODS: We carried out a monocentric, observational, pharmacokinetics/pharmacodynamics (PK/PD) study in patients with metastatic renal cell carcinoma (INDS MR 5612140520). We used measured blood concentrations of cabozantinib (Cmeas) to determine the area under the curve (AUC), apparent clearance (Cl/F) and residual blood concentration (Ctrough). Best overall response according to RECIST 1.1 and relevant toxicity (adverse event grade 3-4 or grade 2 requiring dose reduction or discontinuation) were assessed according to Cmeas, Ctrough, AUC and Cl/F. RESULTS: We enrolled 76 patients, including 35 who experienced disease progression and 30 with grade 3-4 toxicity. Patients with progressive disease had a significantly lower median Ctrough (406 versus 634 ng/ml, P = 0.001), Cl/F (2 versus 2.9 l/h, P = 0.002) and AUC (16 versus 20 µg h/ml, P = 0.037) compared with patients who had disease control as best response. Patients with relevant toxicity had a significantly higher Cmeas (732 versus 531 ng/ml, P = 0.006), Ctrough (693 versus 521 ng/ml, P = 0.005) and AUC (21 versus 16 µg h/ml, P = 0.046) compared with patients who did not experience any grade relevant toxicity. Receiver operating characteristic curves obtained from our study defined a threshold for drug efficacy of 536.8 ng/ml and of 617.7 ng/ml for toxicity. CONCLUSION: We first demonstrate the PK/PD relationship for cabozantinib. Severe toxicities are associated with a higher drug exposure, whereas inefficacy is associated with a lower drug exposure. Cabozantinib plasma drug monitoring may be useful to optimize clinical practice.

Direct assay of urinary steroid glucuronides for monitoring the approach of ovulation.

The concentrations of estrone-3-glucuronide (E(1)3G) and pregnanediol-3-glucuronide (P(2)3G) in daily samples of early morning urine (EMU) were correlated with the levels of estradiol (E2), progesterone (P) and LH in respective plasma samples. Forty-six menstrual cycles were studied, in order to determine the practical usefulness of the urine assays for detecting: a) an individualized estrogen concentration threshold value, announcing the approach of ovulation. b) an individualized signal provided by P(2)3G in urine from which it can be assumed that ovulation has already occurred. The results showed that the concentration of E2 in plasma, in any day of the cycle, can be precisely inferred from the respective concentration of E(1)3G in EMU. The estimation of the plasmatic P values from those of P(2)3G in EMU had to be based on different factors according to the phase of the cycle, fact that suggests the presence of a phase-related variation in the glucuronization of P metabolites. Considering three consecutive E(1)3G urinary assay results, it was possible to identify a threshold value termed Estrogen-Peak Initiating Rise (E-PIR), which anticipated in 3.02 +/- 0.18 days the occurrence of an LH peak. The attempts to detect the occurrence of ovulation by an individualized urinary P(2)3G signal proved disappointing. The signal was detected, either before, simultaneously or after the LH peak.

Correlation between catecholamine content of the human Fallopian tube and the uterus and plasma levels of estradiol and progesterone.

The content of catecholamines in the Fallopian tube and the uterus and the plasma levels of estradiol and progesterone were studied in cycling women. During the follicular phase norepinephrine levels were 33.4+/-7.1, 50.5+/-8.0, and 145.7+/-43.6 ng. per gram of wet tissue in the external, middle, and internal segments of the Fallopian tube, respectively. During the luteal phase norepinephrine content increased significantly in the external and middle portions (219.3+/-57.0 and 206.2+/-34.3 ng. per gram) whereas it remained unchanged in the internal one (185.2+/-53.6 ng. per gram). The NE content of the external and middle segments correlated significantly with plasma progesterone levels (r = 0.76 and 0.82, respectively, whereas oviductal epincphrine levels did not show significant changes as a function of the stage of the menstrual cycle. Uterine epinephrine content decreased by 67 per cent during the luteal phase whereas norepinephrine remained unchanged.