Mannitol versus furosemide in patients with thoracic malignancies who received cisplatin-based chemotherapy using short hydration: A randomized phase II trial.

BACKGROUND: Mannitol is exclusively recommended in the National Comprehensive Cancer Network guidelines for diuresis in cisplatin (CDDP)-based chemotherapy. The utility of furosemide, a widely used and convenient diuretic, thus requires clarification. METHODS: This is a prospective, single-centered, open-label, noninferiority phase II study. Patients with thoracic malignancies who planned to receive CDDP-based chemotherapy were randomly assigned to receive either mannitol (arm A) or furosemide (arm B). The primary end point was set as the proportion of patients who experienced any grade of "creatinine (Cr) increased" based on the upper limit of the normal range (ULN) during the first cycle as assessed by Common Terminology Criteria for Adverse Events Version 4.0. Secondary end points were Cr increased based on the baseline value during the first cycle, Cr increased after the completion of CDDP, and the proportion of patients with phlebitis. RESULTS: Between April 2018 and March 2022, 115 patients were enrolled and 106 were analyzed. Any grade of Cr increased based on the ULN during the first cycle was 17.3% (arm A) and 24.1% (arm B), respectively (p = 0.34). Therefore, the primary end point was not met. After completion of chemotherapy, any grade of Cr increased was observed in 23.1% (arm A) and 31.5% (arm B), respectively. However, the actual serum Cr level and Cr clearance during the courses were not different between the arms. Phlebitis occurred more frequently in arm A (28.8%) than arm B (16.7%). CONCLUSIONS: Mannitol should remain the standard diuresis in CDDP-based chemotherapy assessed by conventional CTCAE grading, but furosemide can be room for consideration when assessed by actual serum Cr level and Cr clearance.

Mutational landscape of multiple primary lung cancers and its correlation with non-intrinsic risk factors.

Multiple primary lung cancers (MPLCs) harbour various genetic profiles among the tumours, even from individuals with same non-intrinsic risk factors. Paired mutational analyses were performed to obtain a census of mutational events in MPLC and assess their relationship with non-intrinsic risk factors. Thirty-eight surgical specimens from 17 patients diagnosed as MPLC were used. Extracted DNAs were sequenced for somatic mutations in 409 cancer-associated genes from a comprehensive cancer panel. We statistically analysed the correlation between each driver mutation frequency and non-intrinsic risk factors using Fisher's exact test, and whether genetic mutations occurred concomitantly or randomly in MPLC using an exact test. Comprehensive genetic analyses suggested different mutation profiles in tumours within the same individuals, with some exceptions. EGFR, KRAS, TP53, or PARP1 mutations were concomitantly detected in some MPLC cases. EGFR mutations were significantly more frequent in never or light smokers and females. Concomitant EGFR or KRAS mutations in MPLCs were significantly more frequent than expected by chance (P = .0023 and .0049, respectively) suggesting a more prominent role of non-intrinsic risk factors in EGFR and KRAS mutations than other mutations, which occurred more randomly. Concomitant EGFR or KRAS mutations were particularly prominent in never or light smokers and males.

Histopathological factors affecting the extraction of high quality genomic DNA from tissue sections for next-generation sequencing.

To enable the widespread application of genomic medicine, the extraction of genomic DNA from thin sections of archived formalin-fixed and paraffin-embedded (FFPE) tissue blocks for next-generation sequencing (NGS) is often necessary. However, there are currently no guidelines available on which specific regions of the microtome sections to use for macrodissection with respect to the histopathological factors observed under microscopic examination. The aim of this study was to clarify the relationship between histopathological factors and DNA quality, and to standardize the macrodissection method for more efficient implementation of NGS. FFPE tissue specimens of 218 patients from the Biomarker Research for Anti-EGFR Monoclonal Antibodies by Comprehensive Cancer Genomics study were used to investigate the relationship between 15 histopathological factors and the quantitative ratio of double-stranded DNA (dsDNA) to total nucleic acids, as well as the ∆ crossing point value of each tissue specimen. Multivariate logistic regression analysis revealed that specimen storage of ≥3 years was negatively associated with dsDNA quality (P=0.0007, OR: 4.30, 95% CI: 1.85-10.04). In contrast, the presence of a mucus pool was positively associated with dsDNA quality (P=0.0308, OR: 0.23, 95% CI: 0.06-0.87). Metastatic tumors and longer specimen storage periods were significantly associated with lower ∆Cp values (P=0.0007, OR: 4.43, 95% CI: 1.87-10.49; and P=0.0003, OR: 5.51, 95% CI: 2.18-13.95, respectively). Therefore, macrodissection should not be performed on specimens exhibiting histopathological factors associated with poor DNA quality. In particular, the use of tissue blocks with a storage period of <3 years allows the extraction of genomic DNA suitable for NGS.

Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study.

BACKGROUND: Patients with BRAFV600E-mutated metastatic colorectal cancer (mCRC) have a poorer prognosis as well as resistance to anti-EGFR antibodies. However, it is unclear whether BRAF mutations other than BRAFV600E (BRAFnon-V600E mutations) contribute to anti-EGFR antibody resistance. METHODS: This study was composed of exploratory and inference cohorts. Candidate biomarkers identified by whole exome sequencing from super-responders and nonresponders in the exploratory cohort were validated by targeted resequencing for patients who received anti-EGFR antibody in the inference cohort. RESULTS: In the exploratory cohort, 31 candidate biomarkers, including KRAS/NRAS/BRAF mutations, were identified. Targeted resequencing of 150 patients in the inference cohort revealed 40 patients with RAS (26.7%), 9 patients with BRAFV600E (6.0%), and 7 patients with BRAFnon-V600E mutations (4.7%), respectively. The response rates in RAS, BRAFV600E, and BRAFnon-V600E were lower than those in RAS/BRAF wild-type (2.5%, 0%, and 0% vs 31.9%). The median PFS in BRAFnon-V600E mutations was 2.4 months, similar to that in RAS or BRAFV600E mutations (2.1 and 1.6 months) but significantly worse than that in wild-type RAS/BRAF (5.9 months). CONCLUSIONS: Although BRAFnon-V600E mutations identified were a rare and unestablished molecular subtype, certain BRAFnon-V600E mutations might contribute to a lesser benefit of anti-EGFR monoclonal antibody treatment.

Synthesis and biological evaluation of novel allophenylnorstatine-based HIV-1 protease inhibitors incorporating high affinity P2-ligands.

A series of stereochemically defined cyclic ethers as P2-ligands were incorporated in an allophenylnorstatine-based isostere to provide a new series of HIV-1 protease inhibitors. Inhibitors 3b and 3c, containing conformationally constrained cyclic ethers, displayed impressive enzymatic and antiviral properties and represent promising lead compounds for further optimization.

[Allergic reaction against an emulsifier, HCO-60, contained in multamin and enocitabine].

We report two cases of an allergic reaction to HCO-60, which is used as an emulsifien for Multamin and enocitabine. A 55-year-old woman with M 4 Eo developed a high fever, urticaria and erythema after induction chemotherapy. After stopping the administration of Multamin, her fever and eruptions subsided. A 51-year-old woman with L 2 developed erythema and hypotension 30 minutes after the third administration of Multamin. When the patient was given enocitabine, she developed anaphylactic shock. During chemotherapy in patients with leukemia, it is important to distinguish the allergic reaction against Multamin-containing HCO-60 from infection and allergies to other drugs.

Differential gene expression profiles and identification of the genes relevant to clinicopathologic factors in colorectal cancer selected by cDNA array method in combination with principal component analysis.

The clinical outcome of patients with colorectal cancer frequently varies even if they are at the same clinicopathologic stage. Alternative superior tumor markers of colorectal cancer are needed for prediction of clinical outcome. To clarify the regulatory factors in colorectal cancers, we examined differential expression profiles using cDNA macroarray technique with surgically resected specimens obtained from the patients with colorectal cancer. The gene profiles by an average-linkage hierarchical clustering analysis were found to be almost separable into two groups: tumor group and normal mucosa group. The relationship between several clinicopathologic factors and cancer related genes were investigated by using statistical analyses including principal component analysis (PCA). c-myc-binding protein MM-1, and c-jun proto-oncogene were identified as possible markers of tumor histology and clinical prognosis and early growth response protein 1 (EGR1) was selected to play an important role in progression of clinical stage. We conclude that, with PCA method, we successfully selected the genes relevant to clinicopathologic factors using limited population of clinical samples.