Synthesis, Optical Properties, and In Vivo Biodistribution Performance of Polymethine Cyanine Fluorophores.

Near-infrared (NIR) cyanine dyes showed enhanced properties for biomedical imaging. A systematic modification within the cyanine skeleton has been made through a facile design and synthetic route for optimal bioimaging. Herein, we report the synthesis of 11 NIR cyanine fluorophores and an investigation of their physicochemical properties, optical characteristics, photostability, and in vivo performance. All synthesized fluorophores absorb and emit within 610-817 nm in various solvents. These dyes also showed high molar extinction coefficients ranging from 27,000 to 270,000 cm-1 M-1, quantum yields 0.01 to 0.33, and molecular brightness 208-79,664 cm-1 M-1 in the tested solvents. Photostability data demonstrate that all tested fluorophores 28, 18, 20, 19, 25, and 24 are more photostable than the FDA-approved indocyanine green. In the biodistribution study, most compounds showed tissue-specific targeting to selectively accumulate in the adrenal glands, lymph nodes, or gallbladder while excreted to the hepatobiliary clearance route. Among the tested, compound 23 showed the best targetability to the bone marrow and lymph nodes. Since the safety of cyanine fluorophores is well established, rationally designed cyanine fluorophores established in the current study will expand an inventory of contrast agents for NIR imaging of not only normal tissues but also cancerous regions originating from these organs/tissues.

Dual near-infrared II laser modulates the cellular redox state of T cells and augments the efficacy of cancer immunotherapy.

Immunotherapy, including immune checkpoint inhibitors, has revolutionized cancer treatment, but only a minor fraction of patients shows durable responses. A new approach to overcome this limitation is yet to be identified. Recently, we have shown that photobiomodulation (PBM) with near-infrared (NIR) light in the NIR-II window reduces oxidative stress and supports the proliferation of CD8+ T cells, suggesting that PBM with NIR-II light could augment anti-cancer immunity. Here, we report a novel approach to support tumor-infiltrating CD8+ T cells upon PBM with NIR-II laser with high tissue penetration depth. Brief treatments of a murine model of breast cancer with dual 1064 and 1270 nm lasers reduced the expression of the programmed cell death protein 1 (PD-1) in CD8+ T cells in a syngeneic mouse model of breast cancer. The direct effect of the NIR-II laser treatment on T cells was confirmed by the enhanced tumor growth delay by the adoptive transfer of laser-treated CD8+ T cells ex vivo against a model tumor antigen. We further demonstrated that specific NIR-II laser parameters augmented the effect of the immune checkpoint inhibitor on tumor growth. PBM with NIR-II light augments the efficacy of cancer immunotherapy by supporting CD8+ T cells. Unlike the current immunotherapy with risks of undesirable drug-drug interactions and severe adverse events, the laser is safe and low-cost. It can be broadly combined with other therapy without modification to achieve clinical significance. In addition, our study established a path to develop a novel laser-based therapy to treat cancer effectively.

Clinical Relevance of Tissue and Serum Human Epidermal Growth Factor Receptor 2 Expression in Patients With Esophageal Squamous Cell Carcinoma.

BACKGROUND: Serum and tissue human epidermal growth factor receptor 2 (HER2) levels were evaluated in resected esophageal squamous cell carcinoma (SCC) specimens to assess the relationship between HER2 expression and long-term prognosis. METHODS: We included 95 patients who underwent esophagectomy for esophageal SCC. The serum HER2-extracellular domain (sHER2-ECD) levels were measured using an ELISA kit. A time-dependent receiver operating characteristics curve for censored survival outcomes was constructed to estimate the optimal cut-off value of sHER2-ECD (set at 4211 pg/mL). Immunohistochemical (IHC) staining was performed for HER2, and specimens were classified based on low (0 or 1+) or high HER2-IHC expression (2+ or 3+). RESULTS: Patients with low sHER2-ECD levels showed poorly differentiated tumors, nodal involvement, and larger tumor size more frequently compared to patients with high sHER2-ECD levels. There were no differences in clinicopathological features based on HER2-IHC expression. Between patients with high and low HER2-IHC expression, the former group showed significantly higher sHER2-ECD levels. Patients with high sHER2-ECD levels had significantly favorable relapse-free survival (RFS) and overall survival (OS) compared to those with low sHER2-ECD levels. Conversely, patients with high HER2-IHC expression had significantly poorer RFS than did patients with low HER2-IHC expression, although no difference was observed in OS. Additionally, patients with high sHER2-ECD levels and low HER2-IHC expression had the highest OS and RFS among the patients studied. CONCLUSIONS: The correlation among sHER2-ECD levels, HER2-IHC expression, and prognosis was demonstrated. Prospective studies are required to validate the impact of serum and tissue HER2 expression in esophageal SCC prognosis.

Correlation Between Immunoinflammatory Measures and Periostin Expression in Esophageal Squamous Cell Carcinoma: A Single-Center, Retrospective Cohort Study.

BACKGROUND: Immunoinflammatory measures such as the neutrophil-lymphocyte ratio (NLR), the platelet-lymphocyte ratio (PLR), and the C-reactive protein (CRP)-albumin ratio (CAR) are useful prognostic measures in various malignancies. However, no study has investigated the correlation of these measures with microenvironmental inflammation. Periostin (POSTN), a small extracellular matrix protein, strongly associates with cancer microenvironmental inflammation. The current study investigated the correlation of NLR, PLR, and CAR with periostin expression in esophageal squamous cell carcinoma (ESCC). METHODS: The study retrospectively evaluated preoperative NLR, PLR, and CAR hematologically and POSTN immunohistochemically in 171 patients. The correlation of immunoinflammatory measures, POSTN expression, and survival outcomes was measured. RESULTS: The study showed a significant correlation of POSTN-positive expression with poor overall survival (OS) (P < 0.0001) and recurrence-free survival (RFS) (P = 0.03). The POSTN-positive group had higher PLR (189.6 ± 8 vs. 159.3 ± 12; P = 0.04) and CAR (0.36 ± 0.06 vs. 0.14 ± 0.09; P < 0.05) than the POSTN-negative group, whereas NLR did not differ between the two groups (3.27 ± 0.19 vs. 2.65 ± 0.28; P = 0.07). The uni- and multivariate analyses showed that POSTN-positive expression (hazard ratio [HR], 1.595; 95% confidence interval [CI], 0.770-3.031; P = 0.03), CAR (HR, 1.663; 95% CI, 1.016-2.764; P = 0.03), gender (HR, 2.303; 95% CI, 1.067-6.019; P = 0.03), and tumor depth (HR, 1.957; 95% CI, 1.122-3.526; P = 0.01) were independent prognostic factors. CONCLUSIONS: Because POSTN-positive expression strongly correlates with immunoinflammatory measures, especially PLR and CAR, it is an independent prognostic factor in ESCC.

Postoperative pneumonia causes the loss of skeletal muscle volume and poor prognosis in patients undergoing esophagectomy for esophageal cancer.

PURPOSES: This retrospective study investigated the effect of postoperative pneumonia on the loss of skeletal muscle volume after esophagectomy for esophageal cancer. METHODS: A total of 123 patients who had undergone esophagectomy for esophageal cancer and had (30 patients) or did not have (93 patients) postoperative pneumonia were included in the analysis. The association of clinicopathological characteristics with loss of skeletal muscle volume and long-term survival were evaluated in patients with or without postoperative pneumonia. RESULTS: There were no differences in the psoas muscle volume index (PI), lymphocyte count, serum albumin level, or prognostic nutritional index between the two groups both preoperatively and at 6 months after surgery. The decrease in PI at 6 months after surgery was significant in patients with postoperative pneumonia (- 9.9 ± 2.5%) but not in those without pneumonia (- 2.6 ± 1.6%). Patients with postoperative pneumonia had a significantly increased frequency of asymptomatic pneumonia at 6 months after surgery compared with those who did not have postoperative pneumonia (36.7% vs. 19.4%). Overall survival was significantly poorer in patients with postoperative pneumonia than in those without pneumonia (p < 0.05). CONCLUSIONS: Postoperative pneumonia was associated with the loss of skeletal muscle volume and asymptomatic pneumonia within 6 months of surgery as well as poorer overall survival.

Impact of postoperative infectious complications on adjuvant chemotherapy administration after gastrectomy for advanced gastric cancer.

BACKGROUND: The aim of this study was to investigate the impact of postoperative infectious complications on adjuvant chemotherapy administration in patients with gastric cancer. METHODS: A retrospective review of 308 patients who underwent curative resection for gastric cancer was performed. Patients were divided into two groups based on the presence (90 patients, 29.2%) or absence (218 patients, 70.8%) of postoperative infectious complications to analyze clinicopathological characteristics, treatment factors and survival. RESULTS: Fewer patients with postoperative infectious complication received adjuvant chemotherapy compared to those without postoperative infectious complication. The proportion of patients who started treatment within 6 weeks after surgery was significantly lower in patients with postoperative infectious complication. The treatment completion rate was significantly lower in patients with postoperative infectious complication. The number of treatment cycles and relative dose intensity was significantly lower in patients with postoperative infectious complication. In univariate analysis, only postoperative infectious complication was significantly associated with continuation of adjuvant chemotherapy. Multivariate analysis demonstrated tumor depth, nodal involvement, postoperative infectious complication and adjuvant chemotherapy were significantly associated with overall survival. CONCLUSION: Postoperative infectious complications are significantly associated with the delay of adjuvant chemotherapy and predict adverse clinical outcome in patients with gastric cancer.

Bilateral Approach for Thoracoscopic Esophagectomy in a Patient with Esophageal Cancer and Solitary Posterior Thoracic Para-aortic Lymph Node Metastasis.

We report a successful dissection of metastatic posterior thoracic para-aortic lymph node (No. 112aoP) via bilateral thoracoscopic surgery. With the anesthetized patient (a 73-year-old Japanese woman) in the prone position, two working ports were inserted for the left-side approach, and artificial pneumothorax was created. Thoracoscopic examination revealed a swollen LN posterior to the descending aorta. Fat and metastatic LNs posterior to the aorta were dissected from the aortic arch level to the diaphragm while preserving intercostal arteries. For the right-side approach, two working ports were inserted and a routine thoracoscopic esophagec-tomy was performed. Gastric conduit reconstruction was achieved laparoscopically. Operation time for the left thoracic procedure: 54 min; estimated blood loss: almost none. No recurrence was detected 24 months post-operatively. There are several surgical options for approaching No. 112aoP, including transhiatal, left thora-cotomy, and thoracoscopy. Although a wide dissection of the posterior thoracic para-aortic area has not been reported, it may be feasible and safe if the artery of Adamkiewicz and intercostal arteries are preserved. A min-imally invasive bilateral thoracoscopic approach for a thoracoscopic esophagectomy is safe and useful for esophageal cancer patients with solitary No. 112aoP metastasis.

Differences Between Laparoscopic and Open Gastrectomy on the Impact of Postoperative Infectious Complications on Prognosis.

BACKGROUND/AIM: The aim of this study was to evaluate the impact of laparoscopic gastrectomy (LG) for gastric cancer on long-term survival in patients with postoperative infectious complications (PIC). PATIENTS AND METHODS: A total of 608 patients who underwent gastrectomy were classified into two groups based on the surgical approach: LG (385 patients) and open gastrectomy (OG: 211 patients). Long-term survival after gastrectomy was compared between patients with and without PIC in both LG and OG groups. RESULTS: Although the patients with PIC in OG group tended to have worse overall survival (OS) than those without PIC, the OS was not significantly different between the patients with and without PIC in LG group. Although multivariate analysis demonstrated that nodal involvement and PIC were significantly associated with OS in OG group, age and tumor depth, and not PIC, were associated with OS in LG group. CONCLUSION: PIC were negative predictors of clinical outcomes in patients with gastric cancer, particularly those who underwent OG, and long-term prognosis may be impacted less by PIC in patients undergoing LG.

A Novel Systemic Inflammatory Score Combined With Immunoinflammatory Markers Accurately Reflects Prognosis in Patients With Esophageal Cancer.

AIM: To establish a novel systemic inflammatory score (SIS) combined with neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein/albumin ratio (CAR) and to validate its prognostic value and relation with serum cytokine levels in patients who underwent esophagectomy for esophageal cancer (EC). PATIENTS AND METHODS: Preoperative NLR, PLR, and CAR were evaluated in 102 patients undergoing esophageal resection for EC from 2009 to 2014. Receiver operating characteristic (ROC) curves censored for 5-year survival were plotted to determine the cutoff values of each measure. Each measure was scored 1 if it was above the cutoff value (NLR >3.12, PLR >230, and CAR >0.085) and scored 0 if it was below that. The SIS was defined as the sum of these values and was divided into the two groups: High SIS (SIS=2-3) and low SIS (SIS=0-1). Univariate and multivariate analyses were used to determine the prognostic significance. The area under the ROCs (AUROC) was compared to verify the discriminative power of survival prediction. In addition, we analyzed the relationship between SIS and perioperative serum interleukin (IL)-6 and IL-10 levels. RESULTS: In the clinicopathological findings, only tumor depth was significantly related to SIS (p=0.004). At 0.732, the AUROC of SIS was the highest (NLR=0.618, PLR=0.545), and CAR=0.712). The high-SIS group had a significantly poorer prognosis than the low-SIS group (p=0.011). SIS was identified as an independent prognostic factor in the multivariate analysis (hazard ratio=1.96, 95% confidence intervaI=1.11-3.41, p=0.020). The preoperative serum interleukin-6 level was significantly low (p=0.046) and postoperative serum interleukin-10 level was significantly high in the high-SIS group (p=0.047). CONCLUSION: SIS was a superior predictor of prognosis compared with existing immunoinflammatory markers and closely reflected the fluctuation of peripheral inflammatory cytokines in patients with EC.

Ultrabright and Serum-Stable Squaraine Dyes.

Highly stable symmetric and asymmetric squaraine fluorophores have been synthesized featuring an internal salt bridge between a quaternary ammonium cation and the central oxycyclobutenolate ring of the chromophore. Some of our newly synthesized symmetric and asymmetric compounds display increased molar absorptivity, quantum yield in serum, and thermal/photochemical stability over previously reported squaraine-based dyes. Consequently, both classes show great promise in resurfacing the normal environment-labile squaraine dyes as novel imaging agents and scaffolds for fluorescence sensing. Furthermore, incorporating a covalent attachment point away from the conjugated system allows for biological tagging applications without disturbing the optimum optical characteristics of the newly designed fluorophore.

Impact of Antiplatelet and Anticoagulant Therapies on Platelet-related Prognostic Markers in Patients With Esophageal Cancer.

BACKGROUND/AIM: In recent years, platelet-related markers were recognized as useful prognostic factors in various malignancies. We investigated the relationship between platelet-related prognostic markers and anti-platelet or anti-coagulant therapies for survival outcomes in esophageal squamous cell carcinoma. PATIENTS AND METHODS: Preoperative platelet-related prognostic markers were evaluated from peripheral blood testing and statistical analyses were performed to evaluate the prognostic value of these markers and reveal the effects of antiplatelets and/or anticoagulants regarding their prognostic relevance. RESULTS: In all 176 patients, preoperative platelet-to-lymphocyte ratio (PLR) was not found to be a predictor of overall survival (OS). However, in patients without antiplatelet or anticoagulant therapies, PLR was significantly associated with a poor OS (p=0.03). Although platelet large cell ratio (P-LCR) was not associated with the prognosis in patients with antiplatelet and/or anticoagulant therapies, higher P-LCR was associated with a poor prognosis in patients without antiplatelet or anticoagulant therapies (p<0.0001). CONCLUSION: Researching detailed antiplatelet and anticoagulant therapies could reinforce the prognostic value of platelet-related prognostic markers in ESCC.

Highly reliable, targeted photothermal cancer therapy combined with thermal dosimetry using a near-infrared absorbent.

Photothermal therapy (PTT) using a photo-absorbent in the near-infrared (NIR) region is an effective methodology for local cancer treatment. Before PTT using a NIR absorbent is executed, the operator generally determines the two parameters of fluence rate and irradiation time. However, even if the irradiation parameters are unchanged, the therapeutic effect of PTT is often different for individual tumors. Hence, we examined the therapeutic effect of PTT using a NIR absorbent (ICG lactosome) while changing two parameters (fluence rate and irradiation time) in various combinations. As a result, there was no robust correlation between those parameters and the therapeutic effect. Compared to those parameters, we found that a more reliable determinant was maintenance of the tumor temperature above 43 °C during NIR irradiation. To reconfirm the significance of the determinant, we developed a new system that can regulate the temperature at the NIR irradiation site at a constant level. By using the new system, we verified the treatment outcomes for tumors in which the NIR absorbent had accumulated. All of the tumors that had been kept at 43 °C during NIR irradiation were cured, while none of the tumors that had been kept at a temperature below 41 °C were cured. In conclusion, PTT using a NIR absorbent with thermal dosimetry is a highly reliable treatment for cancer.

Predictive value of immuno-inflammatory and nutritional measures modulated by neoadjuvant chemotherapy on the response of neoadjuvant chemotherapy and long-term outcomes in patients with esophageal cancer.

It has been reported that immuno-inflammatory and nutritional parameters are associated with long-term survival in various malignancies. However, little is known regarding the associations between alterations of these parameters during neoadjuvant chemotherapy (NAC) and the response to NAC in patients with esophageal cancer. The present study examined the clinical significance of alterations in these parameters during NAC in terms of the response to NAC and the long-term outcomes in patients with esophageal cancer. Various systemic immuno-inflammatory and nutritional measures including the systemic neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), C-reactive protein (CRP)-to-albumin ratio (CAR) and psoas muscle index (PMI) were examined before and after NAC. Statistical analyses were performed to determine the significance of immuno-inflammatory and nutritional parameters prior to NAC and alterations during NAC regarding the response to NAC and long-term outcomes. The NLR, PMI, neutrophil count and platelet count declined significantly following NAC, whereas no alterations in PLR, CAR, lymphocyte counts, CRP levels and albumin concentration were observed. The decreases in NLR and neutrophil counts following NAC were strongly associated with a favorable overall survival (P=0.006). In conclusion, decreases in NLR and neutrophil counts following NAC were clinically significant predictors of the response to NAC and of survival in esophageal cancer, respectively.

Role of Albumin in Accumulation and Persistence of Tumor-Seeking Cyanine Dyes.

Some heptamethine cyanine dyes accumulate in solid tumors in vivo and persist there for several days. The reasons why they accumulate and persist in tumors were incompletely defined, but explanations based on uptake into cancer cells via organic anion transporting polypeptides (OATPs) have been widely discussed. All cyanine-based "tumor-seeking dyes" have a chloride centrally placed on the heptamethine bridge (a "meso-chloride"). We were intrigued and perplexed by the correlation between this particular functional group and tumor uptake, so the following study was designed. It features four dyes (1-Cl, 1-Ph, 5-Cl, and 5-Ph) with complementary properties. Dye 1-Cl is otherwise known as MHI-148, and 1-Ph is a close analog wherein the meso-chloride has been replaced by a phenyl group. Data presented here shows that both 1-Cl and 1-Ph form noncovalent adducts with albumin, but only 1-Cl can form a covalent one. Both dyes 5-Cl and 5-Ph have a methylene (CH2) unit replaced by a dimethylammonium functionality (N+Me2). Data presented here shows that both these dyes 5 do not form tight noncovalent adducts with albumin, and only 5-Cl can form a covalent one (though much more slowly than 1-Cl). In tissue culture experiments, uptake of dyes 1 is more impacted by the albumin in the media than by the pan-OATP uptake inhibitor (BSP) that has been used to connect uptake of tumor-seeking dyes in vivo with the OATPs. Uptake of 1-Cl in media containing fluorescein-labeled albumin gave a high degree of colocalization of intracellular fluorescence. No evidence was found for the involvement of OATPs in uptake of the dyes into cells in media containing albumin. In an in vivo tumor model, only the two dyes that can form albumin adducts (1-Cl and 5-Cl) gave intratumor fluorescence that persisted long enough to be clearly discerned over the background (∼4 h); this fluorescence was still observed at 48 h. Tumors could be imaged with a higher contrast if 5-Cl is used instead of 1-Cl, because 5-Cl is cleared more rapidly from healthy tissues. Overall, the evidence is consistent with in vitro and in vivo results and indicates that the two dyes in the test series that accumulate in tumors and persist there (1-Cl and 5-Cl, true tumor-seeking dyes) do so as covalent albumin adducts trapped in tumor tissue via uptake by some cancer cells and via the enhanced permeability and retention (EPR) effect.

Mixed adenoneuroendocrine carcinoma with loss of HER2 positivity after trastuzumab-based chemotherapy for HER2-positive gastric cancer: a case report.

BACKGROUND: Trastuzumab (T-mab)-based chemotherapy is a standard regimen for human epithelial growth factor 2 (HER2)-positive gastric cancer. However, some patients have demonstrated a change in HER2 status after T-mab-based treatment of breast cancer. We report a rare case of mixed adenoneuroendocrine carcinoma with loss of HER2 positivity after T-mab-based chemotherapy for HER2-positive gastric cancer. CASE PRESENTATION: A 60-year-old man presented with a mass of the upper abdomen, which was diagnosed as adenocarcinoma with a HER2 score of 3+ by endoscopic biopsy. He received seven cycles of combination chemotherapy with capecitabine, cisplatin, and T-mab. Subsequently, he underwent open total gastrectomy, distal pancreatosplenectomy, and extended left hepatic lobectomy as a conversion surgery. The surgically resected specimen demonstrated both adenocarcinoma and neuroendocrine components; therefore, it was diagnosed as HER2-negative mixed adenoneuroendocrine carcinoma. Although the patient received additional chemotherapy, multiple liver metastases appeared at 3 months postoperatively and he died at 6 months postoperatively because of the rapidly progressing metastatic tumor. CONCLUSIONS: We encountered a rare case of rapidly progressive mixed adenoneuroendocrine carcinoma that was negative for HER2 expression after T-mab treatment combined with chemotherapy.

Efficacy of artificial pneumothorax under two-lung ventilation in video-assisted thoracoscopic surgery for esophageal cancer.

BACKGROUND: One-lung ventilation (OLV) is the standard and widely applied ventilation approach used in video-assisted thoracoscopic surgery for esophageal cancer (VATS-e). To address the disadvantages of OLV with respect to difficulties in intubation and induction, as well as the risk of respiratory complications, two-lung ventilation (TLV) with artificial pneumothorax has been introduced for use in VATS-e. However, no studies have yet compared TLV and OLV with postoperative infection and inflammation in the prone position over time postoperatively. Here, we investigated the efficacy of TLV in patients undergoing VATS-e in the prone position. METHODS: Between April 2010 and December 2016, 119 patients underwent VATS-e under OLV or TLV with carbon dioxide insufflation. Clinical characteristics, surgical outcomes, and postoperative outcomes, including oxygenation and systemic inflammatory responses, were compared between patients who underwent OLV and those who underwent TLV. RESULTS: Clinical characteristics other than pT stage were comparable between groups. The TLV group had shorter thoracic operation time than the OLV group. No patients underwent conversion to open thoracotomy. The PaO2/FiO2 ratios of the TLV group on postoperative day (POD) 5 and on POD7 were significantly higher than those of the OLV group. C-reactive protein levels on POD7 were lower in the TLV group than in the OLV group. There were no significant differences with respect to postoperative complications between the OLV and TLV groups. In the TLV group, the white blood cell count on POD7 was significantly lower than that in the OLV group; body temperature showed a similar trend immediately after surgery and on POD1. CONCLUSIONS: In this study, we demonstrated that, compared with OLV, TLV in the prone position provides better oxygenation and reduced inflammation in the postoperative course. Accordingly, TLV might be more useful than OLV for ventilation during esophageal cancer surgery.

Risk factors for nonalcoholic fatty liver disease after gastrectomy for gastric cancer.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) refers to hepatic steatosis caused by something other than alcoholic liver injury, and often occurs after gastrointestinal surgeries such as pancreatoduodenectomy and gastrectomy. This study aimed to identify the risk factors for NAFLD after gastrectomy for gastric cancer. METHODS: A total of 721 patients who underwent gastrectomy for gastric cancer and plane abdominal computed tomography (CT) preoperatively and 1 year after surgery were included in this study. NAFLD was defined as having a mean hepatic CT attenuation value of < 40 Hounsfield units. We retrospectively examined the relationship between the onset of NAFLD and clinicopathological findings to identify the risk factors associated with the development of NAFLD after gastrectomy. RESULTS: The incidence of postoperative NAFLD was 4.85% (35/721). The univariate analysis identified the following factors as being significantly associated with the incidence of NAFLD: age, preoperative BMI ≥ 25 kg/m2, tumor depth of pT3 ≤, lymph node metastasis grade of pN2 ≤, cholecystectomy, D2 lymphadenectomy, adjuvant chemotherapy, high preoperative cholinesterase serum level, and low grade of preoperative FIB-4 index. Adjuvant chemotherapy (p < 0.001) and high preoperative cholinesterase serum level (p = 0.021) were identified as independent risk factors for NAFLD 1 year after gastrectomy. CONCLUSION: Our study showed that adjuvant chemotherapy with S-1 and high level of serum cholinesterase were considered as the risk factors for NAFLD occurring after gastrectomy for gastric cancer.

Impact of perioperative high mobility group box chromosomal protein 1 expression on long-term outcomes in patients with esophageal squamous cell carcinoma.

BACKGROUND AND AIM: High mobility group box chromosomal protein-1 (HMGB-1) is a potential late mediator of sepsis and a possible risk factor for postoperative pulmonary complications after esophagectomy. This study aimed to determine the relationship between HMGB-1 and clinicopathological factors and long-term prognosis after esophagectomy for esophageal cancer. METHODS: We measured perioperative serum HMGB-1 levels using ELISA and HMGB-1 protein by immunohistochemistry expression in resected specimens. RESULTS: Postoperative serum HMGB-1 levels were significantly higher than preoperative levels. Preoperative serum HMGB-1 levels were significantly higher in patients with more intraoperative bleeding, longer intensive care unit stays, and postoperative pneumonia. Postoperative serum HMGB-1 levels were significantly higher in older patients and those with longer operation time and more intraoperative bleeding. There were significant differences in long-term outcomes according to postoperative but not preoperative serum HMGB-1 levels. Multivariate analysis demonstrated that advanced pathological stage, postoperative pulmonary complications, and higher postoperative serum HMGB-1 levels were independently associated with relapse-free survival and overall survival. Preoperative serum HMGB-1 levels were significantly higher in patients with high HMGB-1 expression than those with low HMGB-1 expression by immunohistochemistry, whereas such statistical differences were not observed in postoperative serum HMGB-1. There were no differences in relapse-free survival and overall survival according to HMGB-1 expression by immunohistochemistry. Serum HMGB-1 levels were significantly increased after esophagectomy for esophageal cancer. CONCLUSION: Elevated postoperative serum HMGB-1, which was associated not only with poor long-term but also short-term outcomes such as postoperative complications, might serve as a potential marker for prognosis in esophageal cancer.

Renal Clearable Theranostic Nanoplatforms for Gastrointestinal Stromal Tumors.

Advances in molecular imaging modalities have accelerated the diagnosis and treatment of human diseases. However, tumors less than 1 cm in size still remain difficult to localize by conventional means because of the difficulty in specific targeting/delivery to the tumor site. Furthermore, high nonspecific uptake in the major organs and persistent background retention results in low tumor-to-background ratio. The targeting and therapy of gastrointestinal stromal tumors (GIST) using nonsticky and renal clearable theranostic nanoparticles (a.k.a. H-Dots) are demonstrated. H-Dots not only target GIST for image-guided surgery, but also tailor the fate of anticancer drugs such as imatinib (IM) to the tumor site resulting in efficient treatment of unresectable GIST. In addition, H-Dots can monitor targetability, pharmacokinetics, and drug delivery, while also showing therapeutic efficacy in GIST-bearing xenograft mice following surgical resection. More importantly, IM loaded H-Dots exhibit lower uptake into the immune system, improved tumor selectivity, and increased tumor suppression compared to free IM, which accumulates in the spleen/liver. Precisely designed H-Dots can be used as a promising theranostic nanoplatform that can potentially reduce the side effects of conventional chemotherapies.

Efficacy of xanthine oxidase inhibitor for chronic kidney disease patients with hyperuricemia.

BACKGROUND: Hyperuricemia is a known risk factor for end-stage renal disease. Although xanthine oxidase (XO) inhibitors are expected to protect the kidney function, evidence to this end is insufficient at present. METHODS: This study was a multi-center, open-labeled, randomized study conducted in Mie Prefecture in Japan. Patients were included if they were between 20 and 80 years old and had a serum uric acid (sUA) level ≥ 7.0 mg/dl with or without gout, estimated glomerular filtration rate (eGFR) of 15-60 ml/min/1.73 m2, and urinary protein creatinine ratio (uPCR) of 0.15-3.5 g/gCr. Patients were randomly assigned to a Topiroxostat or Febuxostat group, and the treatment target for the sUA level was < 6.0 mg/dl. The primary outcome was the change in the uPCR after 24 weeks. RESULTS: The change in the median uPCR after 24 weeks was not statistically significant after treatment in the Topiroxostat or Febuxostat group (0.05 g/gCr and - 0.04 g/gCr, respectively). However, the sUA levels decreased significantly in both groups (Topiroxostat group: 8.6 ± 1.1 at baseline to 6.0 ± 1.1 mg/dl at 24 weeks, Febuxostat group: 8.4 ± 1.1 mg/dl at baseline to 5.9 ± 1.3 mg/dl at 24 weeks). No significant change in the eGFR after 24 weeks was noted in either the Topiroxostat or Febuxostat group (- 0.04 ± 4.59 ml/min/1.73 m2 and 0.31 ± 4.70 ml/min/1.73 m2, respectively). CONCLUSIONS: In this study, XO inhibitors did not significantly reduce the uPCR in chronic kidney disease stage 3 and 4 patients with hyperuricemia.