Background/Aim: Bevacizumab-based chemotherapy is the standard treatment for metastatic colorectal cancer (mCRC) but has several specific adverse events. The cumulative bevacizumab dose (CBD) increases with longterm treatment as it is often used beyond the first disease progression, based on existing evidence. However, the association between CBD and the frequency and severity of adverse events in mCRC patients who received bevacizumab for long-term treatment remains unclear. Patients and Methods: Among the mCRC patients who received bevacizumab-based chemotherapy between March 2007 and December 2017 at the University of Tsukuba Hospital, those who continued treatment for more than 2 years were eligible for the study. The onset and worsening of proteinuria, hypertension, bleeding, and thromboembolic events were assessed to determine their relationship with CBD. Results: Of the 109 patients who received bevacizumab-based chemotherapy, 24 were included in the study. Grade 3 proteinuria was observed in 21 (88%) and 9 (38%) patients. The severity of proteinuria markedly increased after administering >100 mg/kg of CBD and progressed to grade 3 at concentrations exceeding 200 mg/kg. Thromboembolic events were observed in three (13%) patients, and two of them developed acute myocardial infarction after receiving a CBD of >300 mg/kg. Grade 2 or higher hypertension and grade 1 bleeding were observed in 9 (38%) patients and in 6 (25%) patients, respectively, regardless of the CBD. Conclusion: Proteinuria and thromboembolic events occurred and worsened in mCRC patients when the bevacizumab dose exceeded the threshold dose.Colorectal cancer is the third leading cause of cancer-related deaths worldwide and the second leading cause of cancerrelated deaths in Japan (1). For metastatic colorectal cancer (mCRC), bevacizumab, an angiogenesis inhibitor, is used as the standard treatment in fluoropyrimidine combination with oxaliplatin or irinotecan-based doublet chemotherapy, which is generally administered at 2.5 mg/kg/week (2). The median progression-free survival time with first-line chemotherapy, including bevacizumab, is 8-15 months (2-4). In addition, the significance of continuing bevacizumab treatment even after disease progression has been proven in a previous randomized phase III trial; bevacizumab is frequently used as a second-line treatment after failure of bevacizumab-based first-line therapies (5-7). Although the long-term administration of bevacizumab has shown a survival benefit, the increased incidence and severity of bevacizumab-related adverse events (AEs) remain a concern.Bevacizumab-related AEs included proteinuria, hypertension, arterial or venous thrombosis, bleeding, gastrointestinal perforation, and delayed wound healing (2). Several studies have investigated the association between bevacizumab treatment duration and bevacizumab-related AEs. The severity of proteinuria and cardiovascular events increases with longterm use of bevacizumab (8). A similar relationship has been shown between the risk of protein...
Let M be a complex manifold. Then we prove that for any family 3 c O ( M ) the equicontinuity domain E ( 3 ) and the Montel domain B ( 3 ) of 3 satisfy the strong disk property in M. k'eyword.c: Equicontinuity domain; Montel domain; normality domain; disk property A M S Classification Categories: 32E10, 32A17, 32F15
Choudary–Dimca [CD ] proved that Dimca hypersurfaces are diffeomorphic to ℝ2n and some of the hypersurfaces with dimension 3 are isomorphic to the plane and the embeddings are equivalent to linear embeddings. However, neither an isomorphism nor a trivializing polynomial automorphism was given explicitly. The purpose of the present paper is to give these explicitly.
(Jpn. J. Soil Sci.Plant Nutr., 77, 257–263, 2006) The symptom of blighted leaves was observed for the melon plants grown on an isolated soil bed after steam sterilization (SS) in a greenhouse in Kochi Prefecture, Japan. To clarify the causes of this symptom, soil and plant analyses were conducted in the first experiment. Manganese concentrations in the leaves with the symptom were higher than 1,000 mg kg−1and exchangeable Mn in the soil was higher than 30 mg kg−1, which indicated the observed symptom was due to Mn excess. In the second experiment, formation of Mn oxide‐dissolving substances after SS was examined for several organic amendments, because large amounts of palm chips had been supplied to the soil before SS in the first experiment. As a treatment similar to SS, palm chips, bark compost, and cattle feces manure were autoclaved. The water extracts were collected before and after the autoclave treatment and the Mn oxide‐dissolving capacities of the extracts were evaluated. The Mn oxide‐dissolving capacity of the water extracts after SS was remarkably higher than before SS, and the value was highest in palm chips, and followed by bark compost, and cattle feces manure. Fractionation and HPLC analysis of the water extracts after SS revealed that the main substance behind Mn oxide reduction in palm tips was arabinose and that in bark manure was malic acid. Further, Mn oxide‐dissolving capacities of the water extracts were almost completely explained by the amounts of arabinose or malic acid found in these materials. From these results, it was considered that reducing substances such as arabinose were released by SS from the palm chips which had been applied in large quantity before SS and these reducing substances dissolved the soil Mn oxides and increased the amounts of available Mn, which led to the occurrence of Mn toxicity to the plants.
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