Genomic Profiling of Small Intestine Cancers From a Real-World Data Set Identifies Subgroups With Actionable Alterations.

PURPOSE: Panel-based comprehensive genomic profiling (CGP) is used in clinical practice worldwide; however, large real-world data (RWD) of patients with advanced small intestine cancer have not been characterized. We investigated differences in the prevalence of clinically relevant alterations across molecularly defined or age-stratified subgroups. PATIENTS AND METHODS: This was a collaborative biomarker study of RWD from CGP testing (Foundation Medicine, Inc). Hybrid capture was conducted on at least 324 cancer-related genes and select introns from up to 31 genes frequently rearranged in cancer. Overall, 1,364 patients with advanced small intestine cancer were available for analyses and were stratified by age (≥40 years/<40 years), microsatellite instability (MSI) status, tumor mutational burden (TMB) status (high ≥10/low <10 Muts/Mb), and select gene alterations. The frequency of alterations was analyzed using a chi-square test with Yate's correction. RESULTS: Genes with frequent alterations included TP53 (59.8%), KRAS (54.8%), APC (27.7%), and CDKN2A (22.4%). Frequent genes with amplifications were MYC (6.7%), MDM2 (5.9%), GATA6 (5.5%), and CCND1 (3.4%). Patients younger than 40 years had significantly lower frequency of APC mutations than those 40 years and older (10.4% v 28.7%; P = .0008). Druggable genomic alterations were detected in 22.3% of patients: BRAF V600E (1.2%), BRCA1 (1.8%), BRCA2 (3.2%), ERBB2 amplification (3.2%), KRAS G12C (3.3%), NTRK1/2/3 fusion (0.07%), MSI-high (7.0%), and TMB-high (12.2%), with no significant differences in the frequency according to age (<40 years v ≥40 years; 22.1% v 22.3%). TMB of 10-20 Mut/Mb was observed in 4.8% of patients, and TMB ≥20 Mut/Mb was seen in 7.3% of the cohort. CONCLUSION: RWD from clinical panel testing revealed the genomic landscape in small intestine cancer by subgroup. These findings provide insights for the future development of treatments in advanced small intestine cancer.

Comparative analysis of isothiocyanates in eight cruciferous vegetables and evaluation of the hepatoprotective effects of 4-(methylsulfinyl)-3-butenyl isothiocyanate (sulforaphene) from daikon radish (Raphanus sativus L.) sprouts.

The contributions of cruciferous vegetables to human health are widely recognised, particularly at the molecular level, where their isothiocyanates play a significant role. However, compared to the well-studied isothiocyanate 4-(methylsulfinyl)butyl isothiocyanate (sulforaphane) produced from broccoli sprouts, less is known about the pharmacological effects of other isothiocyanates and the stage of vegetables preferable to obtain their benefits. We analysed the quantity and quality of isothiocyanates produced in both the sprouts and mature stages of eight cruciferous vegetables using gas chromatography-mass spectrometry (GC-MS). Additionally, we investigated the hepatoprotective effects of isothiocyanates in a mouse model of acute hepatitis induced by carbon tetrachloride (CCl4). Furthermore, we explored the detoxification enzyme-inducing activities of crude sprout extracts in normal rats. Among the eight cruciferous vegetables, daikon radish (Raphanus sativus L.) sprouts produced the highest amount of isothiocyanates, with 4-(methylsulfinyl)-3-butenyl isothiocyanate (sulforaphene) being the dominant compound. The amount of sulforaphene in daikon radish sprouts was approximately 30 times that of sulforaphane in broccoli sprouts. Sulforaphene demonstrated hepatoprotective effects similar to sulforaphane in ameliorating CCl4-induced hepatic injury in mice. A crude extract of 3-day-old daikon radish sprouts upregulated the detoxifying enzyme glutathione S-transferase (GST) in the liver, whereas the crude extract of broccoli sprouts showed limited upregulation. This study highlights that daikon radish sprouts and sulforaphene have the potential to serve as functional food materials with hepatoprotective effects. Furthermore, daikon radish sprouts may exhibit more potent hepatoprotective effects compared to broccoli sprouts.

Suppressive Effect of Shiitake Extract on Plasma Ethanol Elevation.

Alcohol is usually consumed with meals, but chronic consumption is a leading cause of alcoholic liver diseases. We investigated if shiitake extracts with a high lentinic acid content (Shiitake-H) and without lentinic acid (Shiitake-N) could suppress the elevation in plasma ethanol concentrations by accelerating ethanol metabolism and preventing ethanol absorption from the gut. Shiitake-H and Shiitake-N suppressed the elevation in concentrations of ethanol and acetaldehyde in plasma, and promoted the activities of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in the liver. However, these effects of Shiitake-H were more prominent than those of Shiitake-N. Furthermore, Shitake-H promoted ADH and ALDH activities in the stomach. We also examined the change in plasma ethanol concentration by injecting Shiitake-H or Shiitake-N into the ligated loop of the stomach or jejunum together with an ethanol solution. Shiitake-H suppressed the absorption of ethanol from the stomach and jejunum. In conclusion, Shiitake-H accelerates ethanol metabolism in the stomach and liver and inhibits ethanol absorption in the stomach and jejunum indicating that lentinic acid is a functional component in shiitake.

Effectiveness and safety of the pre-prescription of garenoxacin in comparison to moxifloxacin for low-risk febrile neutropenia in breast cancer patients undergoing adjuvant and neoadjuvant chemotherapy.

PURPOSE: The purpose of this study was to compare the efficacy of the pre-prescription of garenoxacin mesylate hydrate (GRNX) with that of moxifloxacin hydrochloride (MFLX) in the management of breast cancer patients with low-risk febrile neutropenia. METHODS: Data from female patients who had been instructed to take previously prescribed oral GRNX or MFLX for 3 days during adjuvant and neoadjuvant chemotherapy if their body temperature exceeded 38 °C were analyzed. This study compared the effectiveness between these fluoroquinolones using a propensity score matching analysis. RESULTS: The 330 patients received 1192 administrations of chemotherapy between May 2007 and April 2014 and 136 (41.2%) patients had a total of 212 (17.8%) febrile episodes. The frequencies of febrile episodes were 19.5% (113/579) and 16.2% (99/613) in the GRNX and MFLX groups, respectively. After propensity score matching, 384 episodes were matched in each group. Febrile events occurred in 80 and 56 cases in the GRNX and MFLX groups, respectively. Treatment success was identified in 80.0% (64/80) of cases in the GRNX group and 64.3% (36/56) of cases in the MFLX group (P = 0.0494). Additionally, the therapeutic use of granulocyte-colony stimulating factor was 6.3% (5/80) of cases in the GRNX group and 17.9% (10/56) of cases in the MFLX group (P = 0.0498). There were few differences in the frequency of adverse effects between the two groups. CONCLUSIONS: These results indicate that the pre-prescription of GRNX may be a more effective option for the management of low-risk febrile neutropenia during adjuvant and neoadjuvant chemotherapy for breast cancer.

Structure Determination of Novel Oxidation Products from Epicatechin: Thearubigin-Like Molecules.

Following the oxidation of epicatechin (EC), three novel compounds and two known compounds were isolated. The chemical structures of these oxidation products were determined by mass spectrometry (MS) and various nuclear magnetic resonance (NMR) experiments, and the A-ring-B-ring linkage that is characteristic of catechin was found in each molecule. Three compounds showed similar ultraviolet-visible (UV-Vis) spectra to EC, whereas two compounds showed different spectral absorption in the region between 300 and 500 nm. A similar spectrum was obtained for the thearubigin fraction prepared from a black tea infusion. This result suggests that the condensation reaction between the A-ring and B-ring is more important than reaction between B-rings for thearubigin formation.

Interaction between Tea Polyphenols and Bile Acid Inhibits Micellar Cholesterol Solubility.

The molecular mechanism by which tea polyphenols decrease the micellar solubility of cholesterol is not completely clear. To clarify this mechanism, this study investigated the interaction between tea polyphenols (catechins and oolongtheanins) and cholesterol micelles. A nuclear magnetic resonance (NMR) study was performed on a micellar solution containing taurocholic acid and epigallocatechin gallate (EGCg), and high-performance liquid chromatography (HPLC) analysis was carried out on the precipitate and the supernatant that formed when EGCg was added to a cholesterol-micelle solution. The data indicated a regiospecific interaction of EGCg with taurocholic acid. Therefore, the ability of EGCg to lower the solubility of phosphatidylcholine (PC) and cholesterol in micellar solutions can be attributed to their elimination from the micelles due to interaction between taurocholic acids and EGCg.

Synthesis of oolongtheanins and their inhibitory activity on micellar cholesterol solubility in vitro.

The synthesis of oolongtheanins (1a-d) was accomplished from EGC and/or EGCg in three steps. Oolongtheanin-3'-O-gallate (1b) showed more potent inhibitory activity on micellar cholesterol solubility than did EGCg.