Morphological Transformation and Surface Engineering of Glycovesicles Driven by Bioinspired Hydrogen Bonds of Nucleobases.

Glycopolymer-based supramolecular glycoassemblies with signal-driven cascade morphological deformation and accessible surface engineering toward bioinspired functional glycomaterials have attracted much attention due to their diverse applications in fundamental and practical scenarios. Herein, we achieved the cascade morphological transformation and surface engineering of a nucleobase-containing polymeric glycovesicle through exploiting the bioinspired complementary multiple hydrogen bonds of complementary nucleobases. First, the synthesized thymine-containing glycopolymers (PGal30-b-PTAm249) are capable of self-assembling into well-defined glycovesicles. Several kinds of amphiphilic adenine-containing block copolymers with neutral, positive, and negative charges were synthesized to engineer the glycovesicles through the multiple hydrogen bonds between adenine and thymine. A cascade of morphological transformations from vesicles to ruptured vesicles with tails, to worm-like micelles, and finally to spherical micelles were observed via continuously adding the adenine-containing polymer into the thymine-containing glycovesicles. Furthermore, the surface charge properties of these glyconano-objects can be facilely regulated through incorporating various adenine-containing polymers. This work demonstrates the potential application of a unique bioinspired approach to precisely engineer the morphology and surface properties of glycovesicles for boosting their biological applications.

The emerging emetogenicity of trifluridine/tipiracil (TAS­102) from patient self-reporting: a multicenter, prospective, observational study.

BACKGROUND: Trifluridine/tipiracil (TAS-102) is an oral anticancer drug with adequate efficacy in unresectable colorectal cancer, but frequently also induces chemotherapy-induced nausea and vomiting (CINV). To investigate the occurrence of CINV and antiemetic therapy in patients with colorectal cancer treated with TAS-102 (JASCC-CINV 2001). METHODS: We conducted a multicenter, prospective, observational study in patients with colorectal cancer who received TAS-102 without dose reduction for the first time. Primary endpoint was the incidence of vomiting during the overall period. Secondary endpoints were the incidence of nausea, significant nausea, anorexia, other adverse events (constipation, diarrhea, insomnia, fatigue, dysgeusia) and patient satisfaction. Patient diaries were used for primary and secondary endpoints. All adverse events were subjectively assessed using PRO-CTCAE ver 1.0. and CTCAE ver 5.0. RESULTS: Data from 100 of the 119 enrolled patients were analyzed. The incidence of vomiting, nausea, and significant nausea was 13%, 67%, and 36%, respectively. The incidence of vomiting in patients with and without prophylactic antiemetic therapy were 20.8% and 10.5%, respectively. Prophylactic antiemetics were given to 24% of patients, of whom 70% received D2 antagonists. Multivariate Cox proportional hazards analysis showed that experience of CINV in previous treatment tended to be associated with vomiting (hazard ratio [HR]: 7.13, 95% confidence interval [CI]: 0.87-58.5, P = 0.07), whereas prophylactic antiemetic administration was not (HR: 1.61, 95 CI: 0.50-5.21, P = 0.43). With regard to patient satisfaction, the proportion of patients who were "very satisfied," "satisfied," "slightly satisfied" or "somewhat satisfied" was 81.8%. CONCLUSIONS: The low incidence of vomiting and high patient satisfaction suggest that TAS-102 does not require the use of uniform prophylactic antiemetic treatments. However, patients with the experience of CINV in previous treatment might require prophylactic antiemetic treatment.

Ultrafast and Multichannel Generation of the Triplet State in DNA-Intercalated Gilvocarcin V for an Enhanced Photoaddition Reaction.

Gilvocarcin V (GV) is a natural antibiotic exhibiting excellent antitumor activities and remarkably low toxicity in near-ultraviolet or visible light-dependent treatment. Notwithstanding, the [2 + 2] cycloaddition reaction between GV and thymine has been proven to be the key for its function in photodynamic therapy, and crucial mechanistic details about such a reaction are poorly understood. In this study, the electronic relaxation pathways and photoaddition reaction are characterized by femto- to nanosecond time-resolved spectroscopy combined with quantum chemical calculation. Our results reveal that ultrafast intersystem crossing (<3 ps) leads to the population of a local triplet excited state in DNA-intercalated GV. Such a state can further induce the formation of a biradical state, which is identified as the important reactive precursor for photoaddition between GV and thymine. The overall photoaddition quantum efficiency is determined to be 11.57 ± 1.0%. These results are essential to the elucidation of the DNA photoaddition mechanism of C-aryl glycoside-based artificial photocytotoxic agents and could help further development of those medicines.

Protocol of a phase II study investigating the efficacy and safety of trifluridine/tipiracil plus ramucirumab as a third-line or later treatment for advanced gastric cancer.

In Japan, systemic chemotherapy is the standard treatment for unresectable, advanced, or recurrent gastric cancer. However, numerous patients with gastric cancer do not receive late-line treatment because of the rapid progression of gastric cancer. Additionally, late-line treatments, such as nivolumab, trifluridine tipiracil (FTD/TPI), or irinotecan, have limited effects on improving clinical symptoms and delaying the onset of symptoms associated with cancer progression. Recently, a combination of FTD/TPI and ramucirumab was reported to have a high response rate in late-line treatment; however, owing to patient selection bias and a high rate of hematologic toxicity in that previous study, this regimen may not be feasible in real-world clinical applications. Our objective is to conduct a single-arm phase II study to assess the safety and efficacy of FTD/TPI plus ramucirumab combination therapy for gastric cancer after third-line treatment under real-world clinical conditions. This study will recruit 32 patients according to eligibility criteria and administer FTD/TPI (35 mg/m2) and intravenous ramucirumab (8 mg/kg). The primary endpoint will be the time to treatment failure. The secondary endpoints will include the overall survival time, progression-free survival time, overall response rate, disease control rate, relative dose intensity, and incidence of adverse events. The results will add new insights for improving the late-line treatment of advanced gastric cancer.

Programming sp3 Quantum Defects along Carbon Nanotubes with Halogenated DNA.

Atomic defect color centers in solid-state systems hold immense potential to advance various quantum technologies. However, the fabrication of high-quality, densely packed defects presents a significant challenge. Herein we introduce a DNA-programmable photochemical approach for creating organic color-center quantum defects on semiconducting single-walled carbon nanotubes (SWCNTs). Key to this precision defect chemistry is the strategic substitution of thymine with halogenated uracil in DNA strands that are orderly wrapped around the nanotube. Photochemical activation of the reactive uracil initiates the formation of sp3 defects along the nanotube as deep exciton traps, with a pronounced photoluminescence shift from the nanotube band gap emission (by 191 meV for (6,5)-SWCNTs). Furthermore, by altering the DNA spacers, we achieve systematic control over the defect placements along the nanotube. This method, bridging advanced molecular chemistry with quantum materials science, marks a crucial step in crafting quantum defects for critical applications in quantum information science, imaging, and sensing.

Loop nucleobases-dependent folding of G-quadruplex in normal and cancer cell-mimicking KCl microenvironments.

In this study, the folding of G-quadruplex (G4) from the telomeric DNA sequences having loop nucleobases of different chemical natures, numbers, and arrangements in 10 mM and 100 mM KCl salt conditions mimicking the cancerous and normal KCl salt microenvironments have been investigated. The data suggest that the structure and stability of the G4 are highly dependent on the KCl salt concentration. In general, the conformational flexibility of the folded G4 is higher in KCl salt relevant to cancer than in the normal case for any loop arrangements with the same number of nucleobases. The stability of the G4 decreases with the increase in the number of loop nucleobases for both salt conditions. However, the decrease in the stability of G4 having adenine in the loop region is significantly higher than the case of thymine, particularly more prominent in the KCl salt relevant to the cancer. The topology of the folded G4 and its stability also depend delicately on the permutation of the nucleobases in the loop and the salt concentrations for a particular sequence. The findings indicate that the structure and stability of G4 are noticeably different in KCl salt relevant to physiological and cancer conditions.

Impact of KRASG12 mutations on survival with trifluridine/tipiracil plus bevacizumab in patients with refractory metastatic colorectal cancer: post hoc analysis of the phase III SUNLIGHT trial.

BACKGROUND: In metastatic colorectal cancer (mCRC), KRAS mutations are often associated with poorer survival; however, the prognostic impact of specific point mutations is unclear. In the phase III SUNLIGHT trial, trifluridine/tipiracil (FTD/TPI) plus bevacizumab significantly improved overall survival (OS) versus FTD/TPI alone. We assessed the impact of KRASG12 mutational status on OS in SUNLIGHT. PATIENTS AND METHODS: In the global, open-label, randomized, phase III SUNLIGHT trial, adults with mCRC who had received no more than two prior chemotherapy regimens were randomized 1 : 1 to receive FTD/TPI alone or FTD/TPI plus bevacizumab. In this post hoc analysis, OS was assessed according to the presence or absence of a KRASG12 mutation in the overall population and in patients with RAS-mutated tumors. RESULTS: Overall, 450 patients were analyzed, including 302 patients in the RAS mutation subgroup (214 with a KRASG12 mutation and 88 with a non-KRASG12RAS mutation). In the overall population, similar OS outcomes were observed in patients with and without a KRASG12 mutation [median 8.3 and 9.2 months, respectively; hazard ratio (HR) 1.09, 95% confidence interval (CI) 0.87-1.4]. Similar OS outcomes were also observed in the subgroup analysis of patients with a KRASG12 mutation versus those with a non-KRASG12RAS mutation (HR 1.03, 95% CI 0.76-1.4). FTD/TPI plus bevacizumab improved OS compared with FTD/TPI alone irrespective of KRASG12 mutational status. Among patients with a KRASG12 mutation, the median OS was 9.4 months with FTD/TPI plus bevacizumab versus 7.2 months with FTD/TPI alone (HR 0.67, 95% CI 0.48-0.93), and in patients without a KRASG12 mutation, the median OS was 11.3 versus 7.1 months, respectively (HR 0.59, 95% CI 0.43-0.81). CONCLUSIONS: The presence of a KRASG12 mutation had no detrimental effect on OS among patients treated in SUNLIGHT. The benefit of FTD/TPI plus bevacizumab over FTD/TPI alone was confirmed independently of KRASG12 status.

Efficacy of Chemotherapy Rechallenge Versus Regorafenib or Trifluridine/Tipiracil in Third-Line Setting of Metastatic Colorectal Cancer: A Multicenter Retrospective Comparative Study.

PURPOSE: Metastatic colorectal cancer (mCRC) is a significant global health burden. This retrospective study compared the effectiveness of trifluridine/tipiracil (FTD/TPI), regorafenib, and chemotherapy rechallenge for third-line mCRC treatment. MATERIALS AND METHODS: We reviewed the medical records of 132 patients with mCRC treated with regorafenib, FTD/TPI, or a rechallenge with the initial chemotherapy regimen in a third-line setting from four different institutions. The primary end point was progression-free survival (PFS). Secondary end points were objective response rate and overall survival (OS) across the three treatment approaches. RESULTS: Twenty-nine patients received chemotherapy rechallenge, and 103 received FTD/TPI or regorafenib. Patients' characteristics were comparable, except for a lower number of left-sided primaries and KRAS wild-type tumors in the FTD/TPI-regorafenib group. The median PFS for the entire group was 3.0 months, and the median OS was 13.7 months. Chemotherapy rechallenge has resulted in a median PFS of 3.1 months and a median OS of 21.2 months, compared with 2.9 months (PFS) and 12.6 months (OS) for the FTD/TPI-regorafenib group. Multivariate analyses identified male sex and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 as independent prognostic factors for better PFS, whereas chemotherapy rechallenge, localized stage at diagnosis, and an ECOG PS of 0-1 were significant prognostic factors for better OS. CONCLUSION: This study suggests that chemotherapy rechallenge may provide a survival benefit in the third-line treatment of mCRC. However, patient characteristics, such as sex and ECOG PS, should also be considered in treatment decisions. Further prospective studies are required to confirm our findings.

A Phase II Study of FOLFIRI Plus Ziv-Aflibercept After Trifluridine/Tipiracil Plus Bevacizumab in Patients with Metastatic Colorectal Cancer: WJOG 11018G.

BACKGROUND: Non-inferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) to irinotecan/fluoropyrimidine plus BEV in metastatic colorectal cancer was investigated in the phase III TRUSTY study, and we conducted a phase II study of FOLFIRI (5-FU+leucovorin+irinotecan) plus zib-aflibercept (AFL) after FTD/TPI plus BEV. However, the TRUSTY study failed during the recruitment of our patients. OBJECTIVE: We present the findings of a phase II study on the efficacy of FOLFIRI plus zib-aflibercept (AFL) after FTD/TPI plus BEV, including clinical results with plasma biomarker analyses. METHODS: This was a multicenter, single-arm, phase II study in patients with metastatic colorectal cancer refractory or intolerant to oxaliplatin, fluoropyrimidine, BEV, and FTD/TPI. The primary endpoint was progression-free survival. Fifteen plasma angiogenesis-associated biomarkers were analyzed using a Luminex® multiplex assay U-kit. RESULTS: Between January 2020 and May 2022, 26 patients (median age, 68 years) from 15 sites were enrolled. The median progression-free survival was 4.9 months (85% confidence interval, 3.4 month-not estimated). The overall response and disease control rates were 8% and 62%, respectively. The median levels of vascular endothelial growth factor-A and placental growth factor, both targets of AFL, were below the measurable limit of 30 pg/mL and 16 pg/mL, respectively. Patients were divided into two groups at the median levels of baseline biomarkers. The progression-free survival did not differ between high and low expressers of placental growth factor (p = 0.7), while it tended to be shorter in those with high levels of osteopontin (p = 0.05), angiopoietin-2 (p = 0.07), and tissue inhibitor of matrix metalloproteinases-1 (p = 0.1). CONCLUSIONS: This study did not meet the primary endpoint. Hence, FOLFIRI plus AFL should not be used after FTD/TPI plus BEV for metastatic colorectal cancer. Further studies are needed to determine factors not targeted by AFL that may affect the efficacy of the treatment. CLINICAL TRIAL REGISTRATION: jRCTs041190100.

The Importance of Anharmonicity and Solvent Effects on the OH Radical Attack on Nucleobases.

Previous theoretical investigations of the reactions between an OH radical and a nucleobase have stated the most important pathways to be the C5-C6 addition for pyrimidines and the C8 addition for purines. Furthermore, the abstraction of a methyl hydrogen from thymine has also been proven an important pathway. The conclusions were based solely on gas-phase calculations and harmonic vibrational frequencies. In this paper, we supplement the calculations by applying solvent corrections through the polarizable continuum model (PCM) solvent model and applying anharmonicity in order to determine the importance of anharmonicity and solvent effects. Density functional theory (DFT) at the ωB97-D/6-311++G(2df,2pd) level with the Eckart tunneling correction is used. The total reaction rate constants are found to be 1.48 ×10-13 cm3 molecules-1s-1 for adenine, 1.02 ×10-11 cm3 molecules-1s-1 for guanine, 5.52 ×10-13 cm3 molecules-1s-1 for thymine, 1.47 ×10-13 cm3 molecules-1s-1 for cytosine and 7.59 ×10-14 cm3 molecules-1s-1 for uracil. These rates are found to be approximately two orders of magnitude larger than experimental values. We find that the tendencies observed for preferred pathways for reactions calculated in a solvent are comparable to the preferred pathways for reactions calculated in gas phase. We conclude that applying a solvent has a larger impact on more parameters compared to the inclusion of anharmonicity. For some reactions the inclusion of anharmonicity has no effect, whereas for others it does impact the energetics.

Genomic and Epigenomic Changes in the Progeny of Cold-Stressed Arabidopsis thaliana Plants.

Plants are continuously exposed to various environmental stresses. Because they can not escape stress, they have to develop mechanisms of remembering stress exposures somatically and passing it to the progeny. We studied the Arabidopsis thaliana ecotype Columbia plants exposed to cold stress for 25 continuous generations. Our study revealed that multigenerational exposure to cold stress resulted in the changes in the genome and epigenome (DNA methylation) across generations. Main changes in the progeny were due to the high frequency of genetic mutations rather than epigenetic changes; the difference was primarily in single nucleotide substitutions and deletions. The progeny of cold-stressed plants exhibited the higher rate of missense non-synonymous mutations as compared to the progeny of control plants. At the same time, epigenetic changes were more common in the CHG (C = cytosine, H = cytosine, adenine or thymine, G = guanine) and CHH contexts and favored hypomethylation. There was an increase in the frequency of C to T (thymine) transitions at the CHH positions in the progeny of cold stressed plants; because this type of mutations is often due to the deamination of the methylated cytosines, it can be hypothesized that environment-induced changes in methylation contribute to mutagenesis and may be to microevolution processes and that RNA-dependent DNA methylation plays a crucial role. Our work supports the existence of heritable stress response in plants and demonstrates that genetic changes prevail.

Label-free fluorescence detection of mercury ions based on thymine-mercury-thymine structure and CRISPR-Cas12a.

In this work, we developed a novel label-free fluorescent sensor for the highly sensitive detection of mercury ions (Hg2+) based on the coordination chemistry of thymine-Hg2+-thymine (T-Hg2+-T) structures and the properties of CRISPR-Cas12a systems. Most notably, two T-rich sequences (a blocker and an activator) were designed to form stable double-stranded structures in the presence of Hg2+ via the T-Hg2+-T base pairing. The formation of T-T mismatched double-stranded DNA between the blocker and the activator prevented the cleavage of G-rich sequences by Cas12a, allowing them to fold into G-quadruplex-thioflavin T complexes, resulting in significantly enhanced fluorescence. Under the optimized conditions, the developed sensor showed an excellent response for Hg2+ detection in the linear range of 0.05 to 200 nM with a detection limit of 23 pM. Moreover, this fluorescent sensor exhibited excellent selectivity and was successfully used for the detection of Hg2+ in real samples of Zhujiang river water and tangerine peel, demonstrating its potential in environmental monitoring and food safety applications.

Efficacy and safety of trifluridine/tipiracil (TAS-102) in patients with metastatic colorectal cancer: a systematic review and meta-analysis

Objectives The purpose of this meta-analysis is to evaluate the efficacy and safety of TAS-102 in treating metastatic colorectal cancer (mCRC) using the most recent data available. Methods The literature on the efficacy and safety of TAS-102 versus placebo and/or best supportive care (BSC) in mCRC was obtained through a systematic search of PubMed, Embase, and Web of Science databases through January 2023. Identify the included literature and extract pertinent data, such as the overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), disease control rate (DCR), incidence of adverse events (AEs) and serious adverse events (SAEs). Results There were eight eligible articles that included 2903 patients (1964 TAS-102 versus 939 Placebo and/or BSC). In this meta-analysis, TAS-102 treatment resulted in longer OS, PFS, TTF, and higher DCR in patients with mCRC versus placebo and/or BSC. TAS-102 improved OS and PFS in subgroup analyses of mCRC patients with KRAS wild-type and KRAS mutant-type. In addition, TAS-102 did not increase the incidence of serious adverse events. Conclusion TAS-102 can enhance the prognosis of mCRC patients whose standard therapy has failed, regardless of KRAS mutation status, and its safety is acceptable (AU)

Highly Sensitive Detection of T790 M with a Three-Level Characteristic Current by Thymine-Hg(II)-Thymine in the α-Hemolysin Nanopore.

Sensitive detection of resistance mutation T790 M is of great significance for early diagnosis and prognostic monitoring of non-small-cell lung cancer (NSCLC). In this paper, we showed a highly sensitive detection strategy for T790 M using a three-level characteristic current signal pattern in an α-hemolysin nanopore. A probe was designed that formed a C-T mismatched base pair with wild-type/P and a T-T mismatched with the T790M/P. The T790M/P produced a unique three-level characteristic current signal in the presence of mercury ions(II): first, T790M-Hg2+-P entering the vestibule of α-HL under the transmembrane potential and overhang of probe occupying the ß-barrel, then probe unzipping from the T790M/P, T790 M temporally residing inside the nanocavity due to the interaction with Hg(II), and finally T790 M passing through the ß-barrel. The blocking current distribution was concentrated with a small relative standard deviation of about 3%, and the signal peaks of T790 M and wild-type can be completely separated with a high separation resolution of more than 2.5, which achieved the highly sensitive detection of T790 M down to 0.001 pM (confidence level P 95%) with a linear range from 0.001 pM to 1 nM in human serum samples. This highly sensitive recognition strategy enables the detection of low abundance T790 M and provides a method for prognostic monitoring in NSCLC patients.

Parenting behaviors, inhibitory control, and aggression: Moderation by serotonin receptor 2A haplotypes.

Despite the well-established relationship between parenting and child aggression, the mechanisms by which children incur this risk and whether genetic sources contribute to the heterogeneity in their vulnerability are not entirely clear. This study utilized a longitudinal sample of adolescents (n = 1,047, 50.2% females, Mage = 13.32 ± 0.48 years at Time 1) to examine the effects of positive and negative parenting on aggression, as mediated by inhibitory control and moderated by the serotonin receptor 2A (5-HTR2A) haplotype. Mediation analysis revealed that inhibitory control indirectly mediated the link between both positive and negative parenting and overt aggression but not relational aggression. Further, the indirect effect of negative parenting on overt aggression via inhibitory control was moderated by the 5-HTR2A haplotype. Compared to adolescents carrying zero copies of Thymine-Thymine haplotype, those with one copy of Thymine-Thymine haplotype had better inhibitory control when experiencing less negative parenting, which buffers the risk for overt aggression. However, the mediating role of inhibitory control did not hold in the positive parenting model. These findings elucidate the manner by which adolescents with different genetic predispositions develop aggressive behaviors in the context of family and suggest different etiology of overt and relational aggression. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A phase II study of guadecitabine combined with irinotecan vs regorafenib or TAS-102 in irinotecan-refractory metastatic colorectal cancer patients.

DNA methyltransferase inhibitors (DNMTi) have demonstrated benefit in reversing resistance to systemic therapies for several cancer types. In a phase II trial of guadecitabine and irinotecan compared to regorafenib or TAS-102 in pts with advanced mCRC refractory to irinotecan. Patients with mCRC refractory to irinotecan were randomized 2:1 to guadecitabine and irinotecan (Arm A) vs standard of care regorafenib or TAS-102 (Arm B) on a 28-day cycle. Between January 15, 2016 and October 24, 2018, 104 pts were randomized at four international sites, with 96 pts undergoing treatment, 62 in Arm A and 34 in Arm B. Median overall survival was 7.15 months for Arm A and 7.66 months for Arm B (HR 0.93, 95% CI: 0.58-1.47, P = .75). The Kaplan-Meier rates of progression free survival at 4 months were 32% in Arm A and 26% in Arm B. Common ≥Grade 3 treatment related adverse events in Arm A were neutropenia (42%), anemia (18%), diarrhea (11%), compared to Arm B pts with neutropenia (12%), anemia (12%). Guadecitabine and irinotecan had similar OS compared to standard of care TAS-102 or regorafenib, with evidence of target modulation. Clinical trial information: NCT01896856.

Comparative Efficacy and Safety of Standard and Biweekly Trifluridine/Tipiracil Regimen in Patients With Colorectal Cancer.

BACKGROUND/AIM: Trifluridine/tipiracil (FTD/TPI) is used to treat metastatic colorectal cancer (mCRC). Since the standard regimen of FTD/TPI features a complex dosing schedule and frequently results in severe hematological toxicities, a simplified regimen has emerged, in which FTD/TPI is orally administered biweekly. However, the survival benefits and potential adverse events associated with the biweekly FTD/TPI regimen have not been fully evaluated in previous reports. Therefore, in this study, the differences in efficacy and safety between the standard and biweekly FTD/TPI regimens were retrospectively investigated in patients with mCRC. PATIENTS AND METHODS: Data from 90 patients who received FTD/TPI for mCRC were extracted from the electronic medical records at the Osaka University Hospital. According to the inclusion and exclusion criteria, 85 of the 90 patients were enrolled in the study. We compared patient characteristics, overall survival (OS), progression-free survival (PFS), and adverse events between the standard (n=56) and biweekly groups (n=29). RESULTS: The biweekly group exhibited prolonged OS and PFS compared to patients in the standard group. Multivariate analysis for OS and PFS demonstrated that the biweekly regimen was the only significant factor that affected OS, and not PFS (HR=0.561, p=0.049). Kaplan-Meier analysis indicated that neutropenia (grade ≥3) in the biweekly group was significantly prolonged compared to the standard group (p=0.012). However, there were no significant differences in adverse events between the two groups (p>0.999). CONCLUSION: The biweekly FTD/TPI regimen, compared to the standard regimen, should enhance both OS and PFS in patients with mCRC without escalating any adverse event.

Exploratory Biomarker Analysis Using Plasma Angiogenesis-Related Factors and Cell-Free DNA in the TRUSTY Study: A Randomized, Phase II/III Study of Trifluridine/Tipiracil Plus Bevacizumab as Second-Line Treatment for Metastatic Colorectal Cancer.

BACKGROUND: The TRUSTY study evaluated the efficacy of second-line trifluridine/tipiracil (FTD/TPI) plus bevacizumab in metastatic colorectal cancer (mCRC). OBJECTIVE: This exploratory biomarker analysis of TRUSTY investigated the relationship between baseline plasma concentrations of angiogenesis-related factors and cell-free DNA (cfDNA), and the efficacy of FTD/TPI plus bevacizumab in patients with mCRC. PATIENTS AND METHODS: The disease control rate (DCR) and progression-free survival (PFS) were compared between baseline plasma samples of patients with high and low plasma concentrations (based on the median value) of angiogenesis-related factors. Correlations between cfDNA concentrations and PFS were assessed. RESULTS: Baseline characteristics (n = 65) were as follows: male/female, 35/30; median age, 64 (range 25-84) years; and RAS status wild-type/mutant, 29/36. Patients in the hepatocyte growth factor (HGF)-low and interleukin (IL)-8-low groups had a significantly higher DCR (risk ratio [95% confidence intervals {CIs}]) than patients in the HGF-high (1.83 [1.12-2.98]) and IL-8-high (1.70 [1.02-2.82]) groups. PFS (hazard ratio {HR} [95% CI]) was significantly longer in patients in the HGF-low (0.33 [0.14-0.79]), IL-8-low (0.31 [0.14-0.70]), IL-6-low (0.19 [0.07-0.50]), osteopontin-low (0.39 [0.17-0.88]), thrombospondin-2-low (0.42 [0.18-0.98]), and tissue inhibitor of metalloproteinase-1-low (0.26 [0.10-0.67]) groups versus those having corresponding high plasma concentrations of these angiogenesis-related factors. No correlation was observed between cfDNA concentration and PFS. CONCLUSION: Low baseline plasma concentrations of HGF and IL-8 may predict better DCR and PFS in patients with mCRC receiving FTD/TPI plus bevacizumab, however further studies are warranted. CLINICAL TRIAL REGISTRATION NUMBER: jRCTs031180122.

Electron interaction with DNA constituents in aqueous phase.

Electron driven chemistry of biomolecules in aqueous phase presents the realistic picture to study molecular processes. In this study we have investigated the interactions of electrons with the DNA constituents in their aqueous phase in order to obtain the quantities useful for DNA damage assessment. We have computed the inelastic mean free path (IMFP), mass stopping power (MSP) and absorbed dose (D) for the DNA constituents (Adenine, Cytosine, Guanine, Thymine and Uracil) in the aqueous medium from ionisation threshold to 5000 eV. We have modified complex optical potential formalism to include band gap of the systems to calculate inelastic cross sections which are used to estimate these entities. This is the maiden attempt to report these important quantities for the aqueous DNA constituents. We have compared our results with available data in gas and other phase and have observed explicable accord for IMFP and MSP. Since these are the first results of absorbed dose (D) for these compounds, we have explored present results vis-a-vis dose absorption in water.

Long-Term Progression-Free Survival of a Pre-Treated Patient with Metastatic Colorectal Cancer Receiving Trifluridine/Tipiracil.

Trifluridine/tipiracil is approved for the use in later or last-line setting in previously treated metastatic colorectal cancer (mCRC) patients who progressed on standard anti-tumor drugs including 5-fluorouracil (5-FU), irinotecan, oxaliplatin, anti-VEGF and anti-EGFR antibodies, or who are not considered candidates for those standard therapies. In this report, we describe a 67-year-old male patient with KRAS-mutated mCRC and metachronous liver and lung metastasis who failed prior 5-FU- and irinotecan-containing regimens, but then showed long-term disease control for 31 months on single-agent trifluridine/tipiracil given as second-line treatment. According to our experience, trifluridine/tipiracil is a feasible and effective treatment option in earlier but not necessarily last-line therapy in mCRC patients who are not considered candidates for doublet or triplet chemotherapy. Besides its efficacy, it is associated with maintained quality of life and a manageable toxicity profile. Considering increasing age of mCRC patients and their wish for maintaining an independent lifestyle, further research on the use of trifluridine/tipiracil in earlier lines of systemic mCRC therapy is warranted.