TROPHY-U-01, a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors: updated safety and efficacy outcomes.

BACKGROUND: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate containing cytotoxic SN-38, the active metabolite of irinotecan. SG received accelerated US Food and Drug Administration approval for locally advanced (LA) or metastatic urothelial carcinoma (mUC) previously treated with platinum-based chemotherapy and a checkpoint inhibitor, based on cohort 1 of the TROPHY-U-01 study. Mutations in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene are associated with increased adverse events (AEs) with irinotecan-based therapies. Whether UGT1A1 status could impact SG toxicity and efficacy remains unclear. PATIENTS AND METHODS: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, phase II registrational study. Cohort 1 includes patients with LA or mUC who progressed after platinum- and checkpoint inhibitor-based therapies. SG was administered at 10 mg/kg intravenously on days 1 and 8 of 21-day cycles. The primary endpoint was objective response rate (ORR) per central review; secondary endpoints included progression-free survival, overall survival, and safety. Post hoc safety analyses were exploratory with descriptive statistics. Updated analyses include longer follow-up. RESULTS: Cohort 1 included 113 patients. At a median follow-up of 10.5 months, ORR was 28% (95% CI 20.2% to 37.6%). Median progression-free survival and overall survival were 5.4 months (95% CI 3.5-6.9 months) and 10.9 months (95% CI 8.9-13.8 months), respectively. Occurrence of grade ≥3 treatment-related AEs and treatment-related discontinuation were consistent with prior reports. UGT1A1 status was wildtype (∗1|∗1) in 40%, heterozygous (∗1|∗28) in 42%, homozygous (∗28|∗28) in 12%, and missing in 6% of patients. In patients with ∗1|∗1, ∗1|∗28, and ∗28|∗28 genotypes, any grade treatment-related AEs occurred in 93%, 94%, and 100% of patients, respectively, and were managed similarly regardless of UGT1A1 status. CONCLUSIONS: With longer follow-up, the ORR remains high in patients with heavily pretreated LA or mUC. Safety data were consistent with the known SG toxicity profile. AE incidence varied across UGT1A1 subgroups; however, discontinuation rates remained relatively low for all groups.

A carbon balance method for paper and wood products.

The approach used to track the flow of carbon sequestered in the forest through harvest, processing into products, and final disposition of products is described. The methodology is broadly flexible and applicable to forest-based carbon balance assessments. A carbon balance is computed across all forestland ownerships for the production facility of interest. The balance considers forest uptake, harvest, combustion of fuels, emissions from process steps and losses from product use, disposition and recycling. The method also allows for sensitivity and marginal assessments of a variety of real and hypothetical situations using variable assumptions. Example results for a vertically integrated pulp and paper mill are presented. Results suggest that integrated forest products facilities drawing their raw material from sustainably managed forests can achieve a net positive carbon balance over the product cycle. The amount of net carbon sequestration attributable to such facilities depends upon a number of factors. The most critical of these include net forest growth, the method for allocating the growth in forest carbon among all of those harvesting from the drain area of a given facility, and the use and disposal patterns for the paper or wood products manufactured.

[Central pontine myelinolysis induced by hyperemesis gravidarum]. / Mielinolisis central pontina inducida por hiperemesis gravídica.

An 18-year-old woman in her first pregnancy with hyperemesis gravidarum, presented dehydration, without hyponatremia. She was confused with profound disorientation, apathy, and drowsiness. She presented upbeating nistagmus on upward gaze and gate ataxia recognised as Wernicke's encephalopathy. Laboratory tests demonstrated hypokalemia, hypernatremia and aminotransferase elevation. The serum osmolality was 319 mOsm/kg and the water deficiency 2.73 l. The patient developed weakness in the four limbs, with hypotonicity, absence of tendon reflexes and showed bilateral Babinski signs. A T2 weighted sagittal cranial-magnetic resonance imaging revealed a high signal within mid-pons suggesting central pontine myelinolysis. In this case we highlight the absence of hyponatremia. Furthermore, the central pontine myelinolysis was probably secondary to hypokalemia, hypernatremia and hyperosmolality.

Mielinolisis central pontina inducida por hiperemesis gravídica. / [Central pontine myelinolysis induced by hyperemesis gravidarum]

An 18-year-old woman in her first pregnancy with hyperemesis gravidarum, presented dehydration, without hyponatremia. She was confused with profound disorientation, apathy, and drowsiness. She presented upbeating nistagmus on upward gaze and gate ataxia recognised as Wernickes encephalopathy. Laboratory tests demonstrated hypokalemia, hypernatremia and aminotransferase elevation. The serum osmolality was 319 mOsm/kg and the water deficiency 2.73 l. The patient developed weakness in the four limbs, with hypotonicity, absence of tendon reflexes and showed bilateral Babinski signs. A T2 weighted sagittal cranial-magnetic resonance imaging revealed a high signal within mid-pons suggesting central pontine myelinolysis. In this case we highlight the absence of hyponatremia. Furthermore, the central pontine myelinolysis was probably secondary to hypokalemia, hypernatremia and hyperosmolality.