Efficacy, safety and cost-effectiveness of 5-fluorouracil versus interferon α-2b as adjuvant therapy after surgery in ocular surface squamous neoplasia in a southern European tertiary hospital.

PURPOSE: To analyze the efficacy, safety and cost-effectiveness of adjuvant therapy with 5-fluorouracil (5-FU) compared to interferon α-2b (IFNα-2b) after surgery in ocular surface squamous neoplasia (OSSN). METHODS: Retrospective study that included patients diagnosed with OSSN, who underwent surgical excision followed by adjuvant therapy with IFN α-2b (Group A) or 5-FU (Group B), in a tertial referral hospital. Clinical data collected included: demographics, risk factors, appearance, size and location of the lesions, slit-lamp examination, anterior segment optical coherence tomography, iconography and histological classification of subtypes of OSSN. Costs derived from surgery and adjuvant therapy were noted. Resolution of the lesion, recurrences and adverse events were studied. Cost-effectiveness analysis was performed with the incremental cost-effectiveness index (CEI). RESULTS: 54 cases of 54 patients were included, with a mean age of 74.4 years (range 28-109). 30 were male (55.6%), and predominantly Caucasian (79.6%). The main risk factor was prolonged sun exposure (79.6%). Leukoplakic appearance (48.1%), location in bulbar conjunctiva (48.2%) and T3 (46.3%) stage were the most common clinical features. Histologically, the percentage of CIN I, CIN II, CIN III and SCC were 25.9%, 29.6%, 40.7% and 3.7%, respectively. Complete resolution was obtained in 74.1% and tolerance was overall positive. The cost was significantly higher for IFNα (1025€ ± 130.68€) compared to 5-FU (165.57€ ± 45.85 €) (p 0.001). The CEI was - 247.14€. CONCLUSIONS: Both 5-FU and IFN α-2b are effective and present a good security profile as adjuvant therapies after surgery in OSSN. Although presenting slightly more ocular complications, 5-FU can be considered more cost-effective than IFN α-2b.

Desulfovibrio desulfuricans and its derived metabolites confer resistance to FOLFOX through METTL3.

BACKGROUND: Chemoresistance is a critical factor contributing to poor prognosis in clinical patients with cancer undergoing postoperative adjuvant chemotherapy. The role of gut microbiota in mediating resistance to tumour chemotherapy remains to be investigated. METHODS: Patients with CRC were categorised into clinical benefit responders (CBR) and no clinical benefit responders (NCB) based on chemotherapy efficacy. Differential bacterial analysis using 16S rRNA sequencing revealed Desulfovibrio as a distinct microbe between the two groups. Employing a syngeneic transplantation model, we assessed the effect of Desulfovibrio on chemotherapy by measuring tumour burden, weight, and Ki-67 expression. We further explored the mechanisms underlying the compromised chemotherapeutic efficacy of Desulfovibrio using metabolomics, western blotting, colony formation, and cell apoptosis assays. FINDINGS: In comparison, Desulfovibrio was more abundant in the NCB group. In vivo experiments revealed that Desulfovibrio colonisation in the gut weakened the efficacy of FOLFOX. Treatment with Desulfovibrio desulfuricans elevates serum S-adenosylmethionine (SAM) levels. Interestingly, SAM reduced the sensitivity of CRC cells to FOLFOX, thereby promoting the growth of CRC tumours. These experiments suggest that SAM promotes the growth and metastasis of CRC by driving the expression of methyltransferase-like 3 (METTL3). INTERPRETATION: A high abundance of Desulfovibrio in the intestines indicates poor therapeutic outcomes for postoperative neoadjuvant FOLFOX chemotherapy in CRC. Desulfovibrio drives the manifestation of METTL3 in CRC, promoting resistance to FOLFOX chemotherapy by increasing the concentration of SAM. FUNDING: This study is supported by Wuxi City Social Development Science and Technology Demonstration Project (N20201005).

LncRNA GAS6-AS1 contributes to 5-fluorouracil resistance in colorectal cancer by facilitating the binding of PCBP1 with MCM3.

5-Fluorouracil (5-FU) resistance has always been a formidable obstacle in the adjuvant treatment of advanced colorectal cancer (CRC). In recent years, long non-coding RNAs have emerged as key regulators in various pathophysiological processes including 5-FU resistance. TRG is a postoperative pathological score of the chemotherapy effectiveness for CRC, of which TRG 0-1 is classified as chemotherapy sensitivity and TRG 3 as chemotherapy resistance. Here, RNA-seq combined with weighted gene correlation network analysis confirmed the close association of GAS6-AS1 with TRG. GAS6-AS1 expression was positively correlated with advanced clinicopathological features and poor prognosis in CRC. GAS6-AS1 increased the 50% inhibiting concentration of 5-FU, enhanced cell proliferation and accelerated G1/S transition, both with and without 5-FU, both in vitro and in vivo. Mechanistically, GAS6-AS1 enhanced the stability of MCM3 mRNA by recruiting PCBP1, consequently increasing MCM3 expression. Furthermore, PCBP1 and MCM3 counteracted the effects of GAS6-AS1 on 5-FU resistance. Notably, the PDX model indicated that combining chemotherapeutic drugs with GAS6-AS1 knockdown yielded superior outcomes in vivo. Together, our findings elucidate that GAS6-AS1 directly binds to PCBP1, enhancing MCM3 expression and thereby promoting 5-FU resistance. GAS6-AS1 may serve as a robust biomarker and potential therapeutic target for combination therapy in CRC.

Attenuation effect of a polysaccharide from large leaf yellow tea by activating autophagy.

Chemotherapy, the most common class of anticancer drugs, is considerably limited owing to its adverse side effects. In this study, we aimed to evaluate the protective effect and mechanism of action of large-leaf yellow tea polysaccharides (ULYTP-1, 1.29 × 104 Da) against chemotherapeutic 5-fluorouracil (5-Fu). Structural characterisation revealed that ULYTP-1 was a ß-galactopyranouronic acid. Furthermore, ULYTP-1 promoted autolysosome formation, activating autophagy and reducing the oxidative stress and inflammation caused by 5-Fu. Our in vivo study of 4 T1 tumour-bearing mice revealed that ULYTP-1 also attenuated 5-Fu toxicity through modulation of the gut microbiota. Moreover, ULYTP-1 effectively protected immune organs and the liver from 5-Fu toxicity, while promoting its tumour-inhibitory properties. The current findings provide a new strategy for optimising chemotherapy regimens in the clinic.

mFOLFIRINOX versus mFOLFOX 6 as adjuvant treatment for high-risk stage III colon cancer - the FROST trial: study protocol for a multicenter, randomized controlled, phase II trial.

BACKGROUND: High-risk stage III colon cancer has a considerably poorer prognosis than stage II and low-risk stage III colon cancers. Nevertheless, most guidelines recommend similar adjuvant treatment approaches for all these stages despite the dearth of research focusing on high-risk stage III colon cancer and the potential for improved prognosis with intensive adjuvant treatment. Given the the proven efficacy of triplet chemotherapy in metastatic colorectal cancer treatment, the goal of this study is to evaluate the oncologic efficacy and safety of mFOLFIRINOX in comparison to those of the current standard of care, mFOLFOX 6, as an adjuvant treatment for patients diagnosed with high-risk stage III colon cancer after radical resection. METHODS: This multicenter, randomized (1:1), open-label, phase II trial will assess and compare the effectiveness and toxicity of mFOLFIRINOX and mFOLFOX 6 in patients with high-risk stage III colon cancer after radical resection. The goal of the trial is to enroll 312 eligible patients, from 11 institutes, aged between 20 and 70 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, or between 70 and 75 with an ECOG performance status of 0. Patients will be randomized into two arms - Arm A, the experimental arm, and Arm B, the reference arm - and will receive 12 cycles of mFOLFIRINOX and mFOLFOX 6 every 2 weeks, respectively. The primary endpoint of this study is the 3-year disease-free survival, and secondary endpoints include the 3-year overall survival and treatment toxicity. DISCUSSION: The Frost trial would help determine the oncologic efficacy and safety of adjuvant triplet chemotherapy for high-risk stage III colon cancers and ultimately improve prognoses. TRIAL REGISTRATION: ClinicalTrials.gov NCT05179889, registered on 17 December 2021.

Villosol reverses 5-FU resistance in colorectal cancer by inhibiting the CDKN2A gene regulated TP53-PI3K/Akt signaling axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Patrinia villosa (Juss.) (PV) is the drug of choice in traditional Chinese medicine for the treatment of colorectal cancer (CRC) and has achieved reliable efficacy in clinic. Villosol is the active ingredient in PV. However, the molecular mechanism by which Villosol reverses chemoresistance in CRC remains unclear. AIM OF THE STUDY: Analysis of the molecular mechanism by which Villosol, the active ingredient of PV, reverses CRC/5-FU resistance through modulation of the CDKN2A gene was validated by network pharmacology techniques and experiments. MATERIALS AND METHODS: We identified CDKN2A as a gene associated with 5-FU resistance through gene chip analysis. Next, we conducted a series of functional analyses in cell lines, animal samples, and xenograft models to investigate the role, clinical significance, and abnormal regulatory mechanisms of CDKN2A in 5-FU resistance in CRC. In addition, we screened and obtained a raw ingredient called Villosol, which targets CDKN2A, and investigated its pharmacological effects. RESULTS: Analysis of CRC cells and animal samples showed that the upregulation of CDKN2A expression was strongly associated with 5-FU resistance. CRC cells overexpressing CDKN2A showed reduced sensitivity to 5-FU and enhanced tumor biology in vitro. Inhibition of aberrant activation of CDKN2A enhances the expression of TP53. Mechanistically, overexpression of CDKN2A activates the PI3K/Akt pathway and induces resistance to 5-FU. Villosol inhibited CDKN2A, and CRC/5-FU cells regained sensitivity to 5-FU. Villosol effectively reverses 5-FU resistance through the CDKN2A-TP53-PI3K/Akt axis. CONCLUSION: Changes in CDKN2A gene expression can be used to predict the response of CRC patients to 5-FU therapy. Additionally, inhibiting CDKN2A activation with Villosol may present a new approach to overcoming 5-FU resistance in clinical settings.

LGR5 as a Therapeutic Target of Antibody-Functionalized Biomimetic Magnetoliposomes for Colon Cancer Therapy.

Purpose: The lack of specificity of conventional chemotherapy is one of the main difficulties to be solved in cancer therapy. Biomimetic magnetoliposomes are successful chemotherapy controlled-release systems, hyperthermia, and active targeting agents by functionalization of their surface with monoclonal antibodies. The membrane receptor Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) stands out as colorectal cancer (CRC) biomarker and appears to be related to treatment resistance and the development of metastasis. The aim of this study was to assess the effectiveness and safety of LGR5-targeted biomimetic magnetoliposomes loaded with oxaliplatin (OXA) or 5-fluorouracil (5-FU) in the selective treatment of CRC and their possible application in hyperthermia. Methods: Synthesis, characterization and determination of heating capacity of magnetoliposomes transporting OXA or 5-FU (with and without LGR5 functionalization) were conducted. In vitro antitumoral activity was assayed in multiple colorectal cell lines at different times of exposition. In addition to this, cell internalization was studied by Prussian Blue staining, flow cytometry and fluorescence microscopy. In vivo acute toxicity of magnetoliposomes was performed to evaluate iron-related toxicity. Results: OXA and 5-FU loaded magnetoliposomes functionalized with LGR5 antibody showed higher cellular uptake than non-targeted nanoformulation with a reduction of the percentage of proliferation in colon cancer cell lines up to 3.2-fold of the IC50 value compared to that of free drug. The differences between non-targeted and targeted nanoformulations were more evident after short exposure times (4 and 8 hours). Interestingly, assays in the MC38 transduced cells with reduced LGR5 expression (MC38-L(-)), showed lower cell internalization of LGR5-targeted magnetoliposomes compared to non-transduced MC38 cell line. In addition, magnetoliposomes showed an in vitro favorable heating response under magnetic excitation and great iron-related biocompatibility data in vivo. Conclusion: Drug-loaded magnetoliposomes functionalized with anti-LGR5 antibodies could be a promising CRC treatment strategy for LGR5+ targeted chemotherapy, magnetic hyperthermia, and both in combination.

Impacts of hyperthermic chemotherapeutic agent on cytotoxicity, chemoresistance-related proteins and PD-L1 expression in human gastric cancer cells.

Objective: Gastric cancer with peritoneal metastasis is considered to be final stage gastric cancer. One current treatment approach for this condition is combined cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). However, the therapeutic mechanisms of HIPEC remain largely undescribed. Method: In order to assess the cellular effects of HIPEC in vitro, we treated AGS human gastric adenocarcinoma cells with or without 5-fluorouracil (5-Fu) at 37 °C or at 43 °C (hyperthermic temperature) for 1 h followed by incubation at 37 °C for 23 h. The impacts of hyperthermia/5-Fu on apoptosis, cell survival signals, oxidative stress, chemoresistance-related proteins and programmed death-ligand 1 (PD-L1) expression were measured. Results: Our results showed that hyperthermia potentiates 5-Fu-mediated cytotoxicity in AGS cells. Furthermore, the combination of 5-Fu and hyperthermia reduces levels of both phosphorylated STAT3 and STAT3, while increasing the levels of phosphorylated Akt and ERK. In addition, 5-Fu/hyperthermia enhances reactive oxygen species and suppresses superoxide dismutase 1. Chemoresistance-related proteins, such as multidrug resistance 1 and thymidylate synthase, are also suppressed by 5-Fu/hyperthermia. Interestingly, hyperthermia enhances 5-Fu-mediated induction of glycosylated PD-L1, but 5-Fu-mediated upregulation of PD-L1 surface expression is prevented by hyperthermia. Conclusion: Taken together, our findings provide insights that may aid in the development of novel therapeutic strategies and enhanced therapeutic efficacy of HIPEC.

Sodium Butyrate Inhibits the Expression of Thymidylate Synthase and Induces Cell Death in Colorectal Cancer Cells.

The most commonly used chemotherapy for colorectal cancer (CRC) is the application of 5-fluorouracil (5-FU). Inhibition of thymidylate synthase (TYMS) expression appears to be a promising strategy to overcome the decreased sensitivity to 5-FU caused by high expression of TYMS, which can be induced by 5-FU treatment. Several compounds have been shown to potentially inhibit the expression of TYMS, but it is unclear whether short-chain fatty acids (SCFAs), which are naturally produced by bacteria in the human intestine, can regulate the expression of TYMS. Sodium butyrate (NaB) is the most widely known SCFA for its beneficial effects. Therefore, we investigated the enhancing effects on inhibition of cell viability and induction of apoptosis after co-treatment of NaB with 5-FU in two CRC cell lines, HCT116 and LoVo. This study suggests that the effect of NaB in improving therapeutic sensitivity to 5-FU in CRC cells may result from a mechanism that strongly inhibits the expression of TYMS. This study also shows that NaB inhibits the migration of CRC cells and can cause cell cycle arrest in the G2/M phase. These results suggest that NaB could be developed as a potential therapeutic adjuvant to improve the therapeutic effect of 5-FU in CRC.

Visualizing External Validity: Graphical Displays to Inform the Extension of Treatment Effects from Trials to Clinical Practice.

BACKGROUND: In the presence of effect measure modification, estimates of treatment effects from randomized controlled trials may not be valid in clinical practice settings. The development and application of quantitative approaches for extending treatment effects from trials to clinical practice settings is an active area of research. METHODS: In this article, we provide researchers with a practical roadmap and four visualizations to assist in variable selection for models to extend treatment effects observed in trials to clinical practice settings and to assess model specification and performance. We apply this roadmap and visualizations to an example extending the effects of adjuvant chemotherapy (5-fluorouracil vs. plus oxaliplatin) for colon cancer from a trial population to a population of individuals treated in community oncology practices in the United States. RESULTS: The first visualization screens for potential effect measure modifiers to include in models extending trial treatment effects to clinical practice populations. The second visualization displays a measure of covariate overlap between the clinical practice populations and the trial population. The third and fourth visualizations highlight considerations for model specification and influential observations. The conceptual roadmap describes how the output from the visualizations helps interrogate the assumptions required to extend treatment effects from trials to target populations. CONCLUSIONS: The roadmap and visualizations can inform practical decisions required for quantitatively extending treatment effects from trials to clinical practice settings.

Modulatory effects of supplementation of Lentinula edodes mycelia extract and l-arginine on the therapeutic efficacy of immunogenic chemotherapy in colon cancer-bearing mice.

Some chemotherapeutic drugs can induce cancer cell death and enhance antitumor T-cell immunity in cancer-bearing hosts. Immunomodulatory reagents could augment such chemotherapy-induced effects. We previously reported that oral digestion of Lentinula edodes mycelia (L.E.M.) extract or  l-arginine supplementation can augment antitumor T-cell responses in cancer-bearing mice. In this study, the effects of L.E.M. extract with or without  l-arginine on the therapeutic efficacy of immunogenic chemotherapy by 5-fluorouracil (5-FU)/oxaliplatin (L-OHP) and/or cyclophosphamide (CP) are examined using two mouse colon cancer models. In MC38 and CT26 cancer models, therapy with 5-FU/L-OHP/CP significantly suppressed tumor growth, and supplementation with L.E.M. extract halved the tumor volumes. However, the modulatory effect of L.E.M. extract was not significant. In the CT26 cancer model, supplementation with L.E.M. extract and  l-arginine had no clear effect on tumor growth. In contrast, their addition to chemotherapy halved the tumor volumes, although the effect was not significant. There was no difference in the cytotoxicity of tumor-specific cytotoxic T cells generated from CT26-cured mice treated by chemotherapy alone versus chemotherapy combined with L.E.M. extract/ l-arginine. These results indicate that the antitumor effects of immunogenic chemotherapy were too strong to ascertain the effects of supplementation of L.E.M. extract and  l-arginine, but these reagents nonetheless have immunomodulatory effects on the therapeutic efficacy of immunogenic chemotherapy in colon cancer-bearing mice.

Nationwide Use and Outcome of Surgery for Locally Advanced Pancreatic Cancer Following Induction Chemotherapy.

BACKGROUND: Several international high-volume centers have reported good outcomes after resection of locally advanced pancreatic cancer (LAPC) following chemo(radio)therapy, but it is unclear how this translates to nationwide clinical practice and outcome. This study aims to assess the nationwide use and outcome of resection of LAPC following induction chemo(radio)therapy. PATIENTS AND METHODS: A multicenter retrospective study including all patients who underwent resection for LAPC following chemo(radio)therapy in all 16 Dutch pancreatic surgery centers (2014-2020), registered in the mandatory Dutch Pancreatic Cancer Audit. LAPC is defined as arterial involvement > 90° and/or portomesenteric venous > 270° involvement or occlusion. RESULTS: Overall, 142 patients underwent resection for LAPC, of whom 34.5% met the 2022 National Comprehensive Cancer Network criteria. FOLFIRINOX was the most commonly (93.7%) used chemotherapy [median 5 cycles (IQR 4-8)]. Venous and arterial resections were performed in 51.4% and 14.8% of patients. Most resections (73.9%) were performed in high-volume centers (i.e., ≥ 60 pancreatoduodenectomies/year). Overall median volume of LAPC resections/center was 4 (IQR 1-7). In-hospital/30-day major morbidity was 37.3% and 90-day mortality was 4.2%. Median OS from diagnosis was 26 months (95% CI 23-28) and 5-year OS 18%. Surgery in high-volume centers [HR = 0.542 (95% CI 0.318-0.923)], ypN1-2 [HR = 3.141 (95% CI 1.886-5.234)], and major morbidity [HR = 2.031 (95% CI 1.272-3.244)] were associated with OS. CONCLUSIONS: Resection of LAPC following chemo(radio)therapy is infrequently performed in the Netherlands, albeit with acceptable morbidity, mortality, and OS. Given these findings, a structured nationwide approach involving international centers of excellence would be needed to improve selection of patients with LAPC for surgical resection following induction therapy.

The moderating role of circadian gene polymorphisms in the relationship between sleep disturbance and circulating lymphocyte subsets in colorectal cancer patients.

AIM: We investigated the impact of sleep disturbance on immune status in colorectal cancer (CRC) patients with consideration of the moderating role of circadian clock gene polymorphisms. METHODS: A prospective longitudinal study design was used to collect information regarding sleep disturbance. Blood samples for immunologic assays were obtained the day before the first (baseline) and last cycles of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. Clinical sleep disturbance was compared between the two-time points using the Pittsburgh Sleep Quality Index (PSQI) global score. We analysed single-nucleotide polymorphisms in rs2278749, rs3749474, rs2291738, rs17031614, and rs2287161. The dependent variables included changes in the percentages of CD4+, CD8+, CD19+, and CD16/56+ lymphocytes between the two-time points. The results were analysed using moderated regression analysis; the p-values were adjusted using the false discovery rate. RESULTS: Among the 104 patients, no significant dyadic associations were observed between changes in lymphocyte percentages and the PSQI global score. However, the moderated regression analysis revealed five significant associations (rs2287161 with CD8+, rs2278749 and rs2291738 with CD19+, and rs17031614 with CD4+ and CD16/56+ lymphocytes). The inclusion of each interaction resulted in a significant increase (5.7-10.7%) in the variance explained by changes in lymphocyte percentage. CONCLUSION: Patients with specific circadian gene allele types may be more susceptible to immune dysregulation when experiencing sleep disturbances. Considering that sleep disturbance is a modifiable factor that can impact immune regulation, it is essential to prioritise the management of sleep disturbances in CRC patients receiving FOLFOX chemotherapy.

Comparison of different Pancreatic cancer treatments: a three-year retrospective study in the oncology center of Tangier university hospital, Morocco.

BACKGROUND: Pancreatic cancer is among the most lethal malignancies, with a 5-year overall survival (OS) of less than 10% for all stages. The present study aims to evaluate the epidemiological and clinical characteristics, as well as the results of different treatments of patients diagnosed and treated between 2019 and 2021 in the Oncology Center of Tangier, University Hospital, Morocco. METHODS: To compare the evolution of the pancreatic cancer between the different chemotherapy regimens, a retrospective study was performed using data collected over a period of 3 years. For each patient, the data were described and statistically analyzed in the dedicated operating sheet. RESULTS: 55 pancreatic cancer patients were included in this study, and the median follow up was 3 months. The mean age of patients was 59.5 ± 10.3 years (extremes 34-79) and the sex ratio male/female was 0.9. Most patients were diagnosed with adenocarcinoma (92.3%), but metastatic stage was the most frequent (56.4%). The surgery was applied to 16.36% of patients. 10.9% of patients have received adjuvant chemotherapy and 76.4% received palliative chemotherapy. Chemotherapy regimens included mainly Gemcitabine and Folfirinox. The median OS was significantly longer for patients treated with Folfirinox versus Gemcitabine (6 months versus 3 months, p-value < 0.016). The median OS for patients that received Folfirinox and Gemcitabine successively (19.7 months) was significantly longer compared to patients that received a monotherapy with either Folfirinox or Gemcitabine alone (p-value < 0.016). CONCLUSION: These findings reinforce the use of advanced methods for earlier detection of pancreatic cancer and the development of effective immunotherapies or more targeted therapies.

HuangJinShuangShen granules can improve immunity and enhance the ability of 5-fluorouracil to induce apoptosis of gastric cancer cells.

In recent years, Chinese herbal compounds have gained significant prominence in the treatment of gastric cancer. The goal of this study was to investigate the antitumor effect of HuangJinShuangShen granules (HJSS) combined with 5-fluorouracil on MFC gastric cancer mice. In this study, the MFC model with gastric cancer was successfully established. After continuous administration for 14 d, the body weight, tumor volume and weight and spleen mass of mice in each group were recorded. The levels of IFN-γ and TGF-ß1 in serum were detected by ELISA. The expression of apoptosis proteins in tumor tissues was detected by Western blotting. Compared with the model group and the 5-FU group, the combined drug group can significantly inhibit tumor growth, reduce tumor volume, promote tumor cell necrosis and increase spleen index in mice. At the same time, the combined treatment group significantly increased IFN-γ level and BAX protein expression, decreased TGF-ß1 level and decreased Bcl2, Caspase-9 and Cleaved Caspase-3 protein expressions. These findings provide evidence that HJSS can augment the suppressive impact of 5-FU on tumor growth in gastric cancer mice, potentially through the induction of tumor cell apoptosis and the restoration of immune function.

Efficacy and safety of XELOX combined with anlotinib and penpulimab vs XELOX as an adjuvant therapy for ctDNA-positive gastric and gastroesophageal junction adenocarcinoma: a protocol for a randomized, controlled, multicenter phase II clinical trial (EXPLORING study).

Background: The efficacy of current adjuvant chemotherapy for gastric adenocarcinoma/gastroesophageal junction adenocarcinoma (GA/GEJA) leaves much to be desired. ctDNA could serve as a potential marker to identify patients who are at higher risk of recurrence. Reinforcing standard adjuvant chemotherapy with immunotherapy has already been indicated to significantly improve clinical outcome, albeit such evidence is rare in GA/GEJA. Here, we intend to explore the clinical benefit of the reinforcement of adjuvant immunotherapy and antiangiogenics alongside with chemotherapy in patients who are deemed in high risk of recurrence by ctDNA analysis, which might shed light on further improvements in adjuvant therapy for GA/GEJA. Methods/Design: This study is designed as a prospective, multicenter, randomized, controlled phase II study in patients histologically or cytologically diagnosed with GA/GEJA who underwent D2 gastrectomy and achieved R0 or R1 resection. From February 2022, a total of 300 stage III patients will be enrolled and subjected according to ctDNA sequencing results, and those with positive results will subsequently be randomized 1:1 to arm A or B. Patients in arm A will receive anlotinib, penpulimab and XELOX for 6-8 cycles, maintained with anlotinib and penpulimab for up to 1 year, while patients in arm B will receive XELOX alone for 6-8 cycles. ctDNA-negative patients will be assigned to arm C, and patients who are ctDNA positive but failed in randomization will be assigned to arm D. Patients in arms C and D will receive the investigator's choice of therapy. The primary endpoint is the median disease-free survival (DFS) of arm A versus arm B determined via CT/MRI imaging. Secondary endpoints include the DFS of ctDNA positive patients versus ctDNA negative patients, the 2- and 3-year DFS rates, overall survival (OS), the impact of hallmark molecules on the treatment response, adverse events (AEs), and the impact of nutrition status or exercise on recurrence. Discussion: We expect that ctDNA would be a strong prognostic factor and ctDNA-positive patients are at higher risk of relapse than ctDNA-negative patients. The addition of anlotinib and penpulimab to XELOX, may contribute to delaying relapse in ctDNA-positive patients. Trial registration: https://www.clinicaltrials.gov, identifier NCT05494060.

Adjuvant effects of Saccharomyces cerevisiae in the treatment of experimental periodontitis in rats undergoing chemotherapy.

Surgical procedures, radiotherapy, and chemotherapy, individually or in association, are current oncological treatments. Among the most used chemotherapy drugs, 5-fluorouracil (5FU) is an antimetabolite with a broad spectrum of action. This study evaluated the effects of probiotics (PRO) as an adjuvant to the treatment of experimental periodontitis (EP) in rats immunosuppressed with 5FU.108 rats were randomly allocated to six different groups: EP; SS - systemic treatment with saline solution (SS); 5FU - systemic treatment with 5FU; 5FU+PRO - systemic treatment with 5FU, followed by the local administration of Saccharomyces cerevisiae ; 5FU+SRP - systemic treatment with 5-FU, followed by scaling and root planing (SRP); and 5FU+SRP+PRO - systemic treatment with 5FU followed by local treatments with SRP and PRO. Immunosuppression was obtained at two points: at the time of ligature installation and after 48 h. Six animals from each group were euthanized at seven, 15, and 30 d and hemimandibles were collected and processed for histopathological, histometric, and immunohistochemical analysis. Data were subjected to statistical analysis (α=5%). At 7 d, the 5FU+PRO group showed less bone resorption and better structured connective tissue compared with the EP, SS, 5FU+SRP, and 5FU+SRP+PRO groups. At 15 d, the 5FU+SRP group showed a greater intensity of the inflammatory response (p<0.05). At 30 d, the 5FU+SRP+PRO group showed better structured bone tissue and a higher percentage of bone tissue (PBT) than the EP, SS, 5FU, and 5FU+PRO groups (p<0.05). The use of Saccharomyces cerevisiae as monotherapy or as an adjuvant to periodontal therapy may have a positive effect on bone repair in immunosuppressed conditions.

Preoperative sequential short-course radiation therapy and FOLFOX chemotherapy versus long-course chemoradiotherapy for locally advanced rectal cancer: a multicenter, randomized controlled trial (SOLAR trial).

BACKGROUND: Preoperative (chemo)radiotherapy has been widely used as an effective treatment for locally advanced rectal cancer (LARC), leading to a significant reduction in pelvic recurrence rates. Because early administration of intensive chemotherapy for LARC has more advantages than adjuvant chemotherapy, total neoadjuvant therapy (TNT) has been introduced and evaluated to determine whether it can improve tumor response or treatment outcomes. This study aims to investigate whether short-course radiotherapy (SCRT) followed by intensive chemotherapy improves oncologic outcomes compared with traditional preoperative long-course chemoradiotherapy (CRT). METHODS: A multicenter randomized phase II trial involving 364 patients with LARC (cT3-4, cN+, or presence of extramural vascular invasion) will be conducted. Patients will be randomly assigned to the experimental or control arm at a ratio of 1:1. Participants in the experimental arm will receive SCRT (25 Gy in 5 fractions, daily) followed by four cycles of FOLFOX (oxaliplatin, 5-fluorouracil, and folinic acid) as a neoadjuvant treatment, and those in the control arm will receive conventional radiotherapy (45-50.4 Gy in 25-28 fractions, 5 times a week) concurrently with capecitabine or 5-fluorouracil. As a mandatory surgical procedure, total mesorectal excision will be performed 2-5 weeks from the last cycle of chemotherapy in the experimental arm and 6-8 weeks after the last day of radiotherapy in the control arm. The primary endpoint is 3-year disease-free survival, and the secondary endpoints are tumor response, overall survival, toxicities, quality of life, and cost-effectiveness. DISCUSSION: This is the first Korean randomized controlled study comparing SCRT-based TNT with traditional preoperative LC-CRT for LARC. The involvement of experienced colorectal surgeons ensures high-quality surgical resection. SCRT followed by FOLFOX chemotherapy is expected to improve disease-free survival compared with CRT, with potential advantages in tumor response, quality of life, and cost-effectiveness. TRIAL REGISTRATION: This trial is registered at Clinical Research Information under the identifier Service KCT0004874 on April 02, 2020, and at Clinicaltrial.gov under the identifier NCT05673772 on January 06, 2023.

PTEN-induced kinase 1 gene single-nucleotide variants as biomarkers in adjuvant chemotherapy for colorectal cancer: a retrospective study.

BACKGROUND: Fluoropyrimidine-based postoperative adjuvant chemotherapy is globally recommended for high-risk stage II and stage III colon cancer. However, adjuvant chemotherapy is often associated with severe adverse events and is not highly effective in preventing recurrence. Therefore, discovery of novel molecular biomarkers of postoperative adjuvant chemotherapy to identify patients at increased risk of recurrent colorectal cancer is warranted. Autophagy (including mitophagy) is activated under chemotherapy-induced stress and contributes to chemotherapy resistance. Expression of autophagy-related genes and their single-nucleotide polymorphisms are reported to be effective predictors of chemotherapy response in some cancers. Our goal was to evaluate the relationship between single-nucleotide variants of autophagy-related genes and recurrence rates in order to identify novel biomarkers that predict the effect of adjuvant chemotherapy in colorectal cancer. METHODS: We analyzed surgical or biopsy specimens from 84 patients who underwent radical surgery followed by fluoropyrimidine-based adjuvant chemotherapy at Saitama Medical University International Medical Center between January and December 2016. Using targeted enrichment sequencing, we identified single-nucleotide variants and insertions/deletions in 50 genes, including autophagy-related genes, and examined their association with colorectal cancer recurrence rates. RESULTS: We detected 560 single-nucleotide variants and insertions/deletions in the target region. The results of Fisher's exact test indicated that the recurrence rate of colorectal cancer after adjuvant chemotherapy was significantly lower in patients with the single-nucleotide variants (c.1018G > A [p < 0.005] or c.1562A > C [p < 0.01]) of the mitophagy-related gene PTEN-induced kinase 1. CONCLUSIONS: The two single-nucleotide variants of PINK1 gene may be biomarkers of non-recurrence in colorectal cancer patients who received postoperative adjuvant chemotherapy.