Impact of Perioperative Immunonutrition on Postoperative Outcomes for Patients Undergoing Head and Neck or Gastrointestinal Cancer Surgeries: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: To clarify whether perioperative immunonutrition is effective in adult patients with or without malnutrition undergoing elective surgery for head and neck (HAN) or gastrointestinal (GI) cancers. BACKGROUND: It is important to avoid postoperative complications in patients with cancer as they can compromise clinical outcomes. There is no consensus on the efficacy of perioperative immunonutrition in patients with or without malnutrition undergoing HAN or GI cancer surgery. MATERIALS AND METHODS: We searched MEDLINE (PubMed), MEDLINE (OVID), EMBASE, Cochrane Central Register of Controlled Trials, Web of Science Core Selection, and Emcare from 1981 to 2022 using search terms related to immunonutrition and HAN or GI cancer. We included randomized controlled trials. Intervention was defined as immunonutritional therapy including arginine, n-3 omega fatty acids, or glutamine during the perioperative period. The control was defined as standard nutritional therapy. The primary outcomes were total postoperative and infectious complications, defined as events with a Clavien-Dindo classification grade ≥ II that occurred within 30 days after surgery. RESULTS: Of the 4825 patients from 48 included studies, 19 had upper GI cancer, 9 had lower, and 8 had mixed cancer, whereas 12 had HAN cancers. Immunonutrition reduced the total postoperative complications (relative risk ratio: 0.78; 95% CI, 0.66-0.93; certainty of evidence: high) and infectious complications (relative risk ratio: 0.71; 95% CI, 0.61-0.82; certainty of evidence: high) compared with standard nutritional therapy. CONCLUSIONS: Nutritional intervention with perioperative immunonutrition in patients with HAN and GI cancers significantly reduced total postoperative complications and infectious complications.

Association of High LAT1 Expression with Poor Prognosis and Recurrence in Colorectal Cancer Patients Treated with Oxaliplatin-Based Adjuvant Chemotherapy.

The mammalian target of rapamycin (mTOR) is often activated in several cancers. We focused on two mTOR regulatory mechanisms: oxaliplatin-induced mTOR signaling and L-type amino acid transporter 1 (LAT1)-induced mTOR activation. High LAT1 expression in several cancers is associated with mTOR activation and resistance to chemotherapy. However, the significance of LAT1 has not yet been elucidated in colorectal cancer (CRC) patients treated with post-operative adjuvant chemotherapy. Immunohistochemistry was conducted to examine the significance of membrane LAT1 expression in 98 CRC patients who received adjuvant chemotherapy, including oxaliplatin. In vitro analysis was performed using CRC cell lines to determine the effects of LAT1 suppression on proliferation, oxaliplatin sensitivity, and mTOR signaling. LAT1 expression was associated with cancer aggressiveness and poor prognosis in 98 CRC patients treated with adjuvant chemotherapy. We found that positive LAT1 expression correlated with shorter survival in 43 patients treated with the capecitabine-plus-oxaliplatin (CAPOX) regimen. LAT1 suppression in CRC cells inhibited the proliferation potency and oxaliplatin-induced activation of mTOR signaling, and improved oxaliplatin sensitivity. LAT1 evaluation before adjuvant treatment may therefore be a sensitive marker for oxaliplatin-based regimens. Moreover, LAT1 may be a promising target for patients with refractory CRC.

High L-Type Amino Acid Transporter 1 Levels Are Associated with Chemotherapeutic Resistance in Gastric Cancer Patients.

INTRODUCTION: We investigated whether the expression of L-type amino acid transporter 1 (LAT-1) in clinical gastric cancer (GC) patients could predict patient therapeutic response to postoperative adjuvant chemotherapy. METHODS: Immunohistochemistry was used to investigate LAT-1, CD98, and phosphorylated-mammalian target of rapamycin (p-mTOR) expression in 111 GC patients. To clarify whether LAT-1 influences the therapeutic effects of chemotherapy, the correlation between disease-free survival rates and LAT-1 was determined in 2 groups: 59 patients who did not undergo postoperative adjuvant chemotherapy and 52 patients who did undergo postoperative adjuvant chemotherapy. RESULTS: LAT-1 was significantly correlated with CD98 and p-mTOR expressions. We did not find any statistically significant correlation between LAT-1 and recurrence in the nontreated group. In contrast, a significant association was found between LAT-1 expression and disease-free survival in the chemotherapy group. Moreover, multivariate regression analysis demonstrated that LAT-1 was an independent predictor of disease-free survival in the postoperative adjuvant chemotherapy group (p = 0.012). CONCLUSION: Our findings demonstrate that LAT-1 is a useful predictive marker for a successful postoperative adjuvant chemotherapy treatment.

Planned Esophagectomy after Neoadjuvant Hyperthermo-Chemoradiotherapy using Weekly Low-Dose Docetaxel and Hyperthermia for Advanced Esophageal Carcinomas.

BACKGROUND/AIMS: The optimal treatment for locally advanced esophageal carcinoma has not yet been determined. We report results of neoadjuvant hyperthermo-chemoradiotherapy (HCRT) using weekly low-dose docetaxel followed by surgery in patients with advanced esophageal squamous cell carcinoma. METHODOLOGY: Twenty-four patients were enrolled. 7 patients were considered to have inoperable tumors or rejected surgery after HCRT, and the remaining 17 patients had an esophagectomy. Clinical responses, HCRT toxicity and survival after surgery were evaluated. RESULTS: In the 24 patients, the response rate was 41.7%. The pathological complete response (pCR) rate was 17.6% in the 17 patients. HCRT toxicity grade 2 occurred in six patients (25.0%: esophagitis, 4; leukopenia, 6; neutropenia, 4) and grade 3 (pneumonia) in 3 patients (12.5%). The 3- and 5-year survival rates were 56.3% and 50.0%, respectively. When the patients were divided into a pCR group and a pathological partial response (pPR) group, the 3-year survival rates were 66.7% and 42.9% and the 5-year survival rates were 66.7% and 42.9%, respectively (log-rank P = .5842). CONCLUSIONS: Esophagectomy after docetaxel HCRT may have potential for prolonging survival in patients with locally advanced esophageal cancer. A larger randomized, controlled study will be required to confirm the benefit of esophagectomy after HCRT.

Study on accelerated evaluation system for release profiles of covered-rod type silicone formulation using indomethacin as a model drug.

The purpose of this study was to establish a method allowing rapid evaluation in vitro of the profiles of drug release from covered-rod type silicone formulation (CR silicone formulation), which releases drug for a prolonged period of time. Three CR silicone formulations containing indomethacin (IDM) with different release profiles were used in this study. The release of IDM was accelerated in a mixture of methanol and water (MeOH/water) compared with in phosphate-buffered saline (PBS) added by Tween 20 (PBS-based solvent). The velocity of IDM release varied depending on the composition of the MeOH/water. The change in release velocity was dependent on the solubility of IDM and the permeability of IDM through the silicone membrane. In all the tested formulations, the release rates of IDM estimated in 90% (v/v) MeOH/water were equally 14.6 times faster than those estimated in PBS-based solvent. Release of IDM from the cross-sections and lateral side evaluated by a bi-directional elution cell were accelerated in the MeOH/water in a similar degree. By introducing a common factor to shorten the time axis in all formulations, a fairly good agreement was observed between the two release profiles obtained in the accelerated MeOH/water system and the usual PBS-based solvent system. These results indicate that MeOH/water system enables to reduce the period for evaluation of profiles of drug release from CR silicone formulations in reflecting their release characteristics in usual PBS-based solvent system.

New drug delivery system for water-soluble drugs using silicone and its usefulness for local treatment: application of GCV-silicone to GCV/HSV-tk gene therapy for brain tumor.

Controlled release of a water-soluble low-molecular-weight drug from silicone and its usefulness as a local therapeutic drug were studied. For application to ganciclovir/helpes simplex virus thymidine kinase (GCV/HSV-tk) suicide gene therapy for brain tumor, two kinds of GCV-containing silicone formulations were prepared for evaluation. In vitro, GCV release from matrix-type formulation consisting of a single matrix was characterized by Fickian diffusion, while covered-rod-type formulation, in which the side surface of the outer layer was covered with 100% silicone, exhibited a near-zero-order release pattern. In an in vivo study using a rat 9L glioblastoma model, administration of GCV-silicone formulation into brain tumor yielded sustained intracerebral GCV concentration for 4 days after administration, with excellent antitumor effect equal to or better than that of daily intraperitoneal administration of aqueous solution of GCV, at a dose less than 1/100 of the total dose of solution for intraperitoneal administration. Furthermore, GCV was undetectable in blood, suggesting that decrease in systemic adverse reactions can be expected with intracerebral administration of GCV-silicone formulation.