Effects of Edge Functionalization of Nanographenes with Small Aromatic Systems.

Regulation of the physical properties of nanographenes (NGs) by edge functionalization is an active research area. We conducted a computational study of the effects of edge functionalization on the physical properties of NGs. The computed NGs were models of experimentally obtained NGs and composed of a C174 carbon framework with one to four 3,5-dimethylnaphthalene units on the edge. The effects were assessed structurally, magnetically, and electronically by the least square planarity index, harmonic oscillator model of aromaticity, nucleus-independent chemical shift, and HOMO-LUMO (H-L) gaps. Density functional theory calculations indicate that although the structures of the model NGs are not very sensitive to edge functionalization, but the magnetic and electronic properties are. The installed substituents narrowed the H-L gap and induced a redshift of the photoluminescence (PL) band by the π conjugation between NG and the substituent. These results are consistent with the extension of the absorption band and the redshift of the PL bands of the experimentally modified NGs. Furthermore, the calculations confirmed the contribution of the charge transfer character to the absorption spectra.

Computational Studies on the Structures of Nanographenes with Various Edge Functionalities.

Computational studies have often been carried out on hydrogen-terminated nanographenes (NGs). These structures are, however, far from those deduced from experimental observations, which have suggested armchair edges with two carboxy groups on the edges as dominant. We conducted computational studies on NGs consisting of C42 , C60 , C78 , C96 , C142 , and C174 carbon atoms with hydrogen, carboxy, and N-methyl imide-terminated armchair edges. DFT calculations inform distorted basal planes and similar HOMO-LUMO gaps, indicating that the edge oxidation and functionalization do not very influence the electronic structure. Comparison of observed UV-vis spectra of carboxy- and N-octadecyl chain terminated NGs with calculated spectra of model NGs informs the contribution of π-π* transitions on the basal plane to the absorptions in the visible region. A dimeric structure of NG and octadecyl-installed NG demonstrate that both the distorted basal planes and the steric contacts among the functional groups widen the surface-to-surface distance thereby allowing the invasion of solvent molecules between the surfaces. This picture is consistent with the improved solubility of edge-modified NGs.

1270 nm near-infrared light as a novel vaccine adjuvant acts on mitochondrial photoreception in intradermal vaccines.

With the development of laser technology in the 1960s, a technique was developed to inject intradermal vaccines immediately after irradiating the skin with laser light to elicit an adjuvant effect, referred to as "laser adjuvant." We have been investigating the mechanism of laser adjuvant in influenza mouse models using noninvasive continuous-wave (CW) near-infrared (NIR) light mainly at a wavelength of 1064 nm, and have shown that the production of reactive-oxygen-species (ROS) in the skin and mast cells in the skin tissue plays an important role in the laser adjuvant effect. The new wavelength of 1270 nm NIR light is characterized by its ability to elicit the same vaccine adjuvant effect as other wavelengths at a lower energy, and may be suitable for clinical applications. In this study, we investigated the physiological activity of CW1270 nm NIR light in mast cells, its biological activity on mouse skin, and the durability of the vaccine adjuvant effect in influenza vaccine mouse models. We show that irradiation of mast cells with 1270 nm NIR light produced ROS and ATP, and irradiation of isolated mitochondria also produced ATP. In mouse skin, the relative expression levels of chemokine mRNAs, such as Ccl2 and Ccl20, were increased by irradiation with 1270 and 1064 nm NIR light at minimum safe irradiance. However, the relative expression of Nfkb1 was increased at 1064 nm, but not at 1270 nm. Serum anti-influenza IgG antibody titers increased early after immunization with 1064 nm, whereas with 1270 nm, there was not only an early response of antibody production but also persistence of antibody titers over the medium- to long-term. Thus, to our knowledge, we show for the first time that 1270 nm NIR light induces ROS and ATP production in mitochondria as photoreceptors, initiating a cascade of laser adjuvant effects for intradermal vaccines. Additionally, we demonstrate that there are wavelength-specific variations in the mechanisms and effects of laser adjuvants. In conclusion, CW1270 nm NIR light is expected to be clinically applicable as a novel laser adjuvant that is equivalent or superior to 1064 nm NIR light, because it can be operated at low energy and has a wavelength-specific adjuvant effect with medium- to long-lasting antibody titer.

Metal Nanoparticles on Lipophilic Nanographenes.

Utilization of graphitic domains on nanographenes (NGs) for anchoring metal nanoparticles (NPs) can open the door for their applications in catalysis. Reported examples employ hydrophilic graphene oxides as substrates, making it difficult to coexist with organic substrates in organic solvents. The title NGs are metal NP-doped lipophilic NGs (M-NG1). Various metal cations form NPs with a diameter of a few to tens of nanometers on the basal plane. Owing to the lipophilic nature of NG1, M-NG1 is prepared by the reduction of the basal plane with sodium in THF followed by the addition of metal salts. Au-NPs on NG1 allow anchoring an organic thiol carrying an anthracene fluorophore, which is a proof of concept of composite materials utilizing the surface of NGs. The assessment of the catalytic function of Pd-NG1 reveals that chlorobenzene and bromobenzene yield a coupling product, and fluorobenzene also undergoes the reactions, demonstrating the catalytic function of Pd-NG1.

Short-term and Long-term Outcomes Following Laparoscopic Gastrectomy for Advanced Gastric Cancer Compared With Open Gastrectomy.

INTRODUCTION: To investigate the oncological feasibility and technical safety of laparoscopic gastrectomy with D2 lymphadenectomy for advanced gastric cancer. METHODS: A total of 186 advanced gastric cancer patients treated by gastrectomy with D2 lymphadenectomy were eligible for inclusion including those with invasion into the muscularis propria, subserosa, and serosa without involvement of other organs, and stages N0-2 and M0. We retrospectively compared the short-term and long-term outcomes between laparoscopic gastrectomy and open gastrectomy. RESULTS: We analyzed short-term outcomes by comparing distal with total gastrectomy results. We found no significant difference for distal gastrectomy for postoperative morbidity [laparoscopic vs. open: n=4 (4.6%) vs. n=1 (3.6%); P=1.00]. We also found no significant difference in postoperative morbidity for total gastrectomy [laparoscopic vs. open: n=2 (4.0%) vs. n=1 (4.0%); P=1.00]. No deaths occurred in any group.The entire cohort analysis revealed no statistically significant differences in overall-free or recurrence-free survival between the laparoscopic and open groups. For overall survival, there were no significant differences between open and laparoscopic groups for clinical stage II or III (P=0.29 and 0.27, respectively), and for pathologic stage II or III (P=0.88 and 0.86, respectively). For recurrence-free survival, there were no significant differences between open and laparoscopic groups for clinical stage II or III (P=0.63 and 0.60, respectively), and for pathologic stage II or III (P=0.98 and 0.72, respectively). CONCLUSION: Laparscopic gastrectomy for advanced gastric cancer compared favorably with open gastrectomy regarding short-term and long-term outcomes.

[Laparoscopic Gastrectomy for Gastric Adenocarcinoma of the Fundic Gland Type].

Case 1: A 66-year-old man underwent esophagogastroduodenoscopy(EGD), which showed a slightly elevated lesion at the greater curvature of the cardia. We diagnosed gastric adenocarcinoma(tub1, 2)as a result of the biopsy. Endoscopic submucosal dissection(ESD)was performed. The pathological examination revealed a gastric adenocarcinoma of the fundic type(GA-FG), with a tumor depth of SM2. Consequently, laparoscopic gastrectomy was additionally performed. Case 2: A 65-year-old woman underwent EGD, which revealed a slightly elevated lesion at the posterior wall of the upper body. We made a diagnosis of GA-FG as on the basis of biopsy resuit. ESD was performed. A pathological examination revealed that the tumor depth was SM2. Consequently, laparoscopic gastrectomy was additionally performed. GA-FG rarely demonstrates metastasis and recurrence. Most cases undergo ESD, few reports of surgical resection exist. We report our experience of laparoscopic gastrectomy for GA-FG.

[The Clinical Effect of Ramucirumab in the Treatment of Advanced Gastric Cancer in Our Hospital].

Ramucirumab(RAM)was approved for unresectable advanced gastric cancer in March 2015. Recent Japanese gastric cancer treatment guidelines recommended RAM plus paclitaxel(PTX)and RAM alone in the treatment of patients with advanced gastric cancer who had been previously treated with chemotherapy. In this retrospective study, we evaluated the safety and efficacy of RAM alone and PTX plus RAM in these patients. Patients who were administered RAM or PTX plus RAM between March 2015 and December 2016 were enrolled in this study. We compared the clinical outcome of RAM alone(RAM group, n=11)with that of PTX plus RAM(PTX plus RAM group, n=10). The RAM group contained more patients with poor performance status than the PTX plus RAM group. More cases of Grade 3 or 4 adverse events were found in the PTX plus RAM group than in the RAM group. The response rate was 9% in the RAM group and 30% in the PTX plus RAM group. The progression-free survival was 2 months in the RAM group and 3.75 months in the PTX plus RAM group. The overall survival was not reached in the RAM and PTX plus RAM groups. We considered that RAM and PTX plus RAM are safe and effective therapies for advanced gastric cancer patients.

[Analysis of Oxaliplatin Combination Therapy for Unresectable or Recurrent Gastric Cancer].

We analyzed 26 cases of unresectable or recurrent gastric cancer treated with oxaliplatin(OX)combination therapy between September 2014 and January 2016. The number of unresectable gastric cancer cases was 14 and there were 12 recurrent cases. The number of patients receiving S-1 plus OX(SOX), SOX plus trastuzumab(Tmab), capecitabine(Cape)plus OX(CapeOX), and CapeOX plus Tmab was 17, 1, 6, and 2, respectively. The starting dose of OX was 130mg/m2 in 12 patients and 100mg/m2 in 14. The median follow-up duration from the first treatment was 6 months(1-14). The median number of treatment cycles was 5(1-19). Dose reductions occurred in 14 cases, and treatment delay occurred in 13 cases. Grade 3 adverse events occurred in 2 cases(8%); thrombocytopenia and stomatitis occurred in 1 case. The response rate was 23%, the disease control rate was 69%, and the median relapse-free survival time was 4 months(1-14). OX combination therapy for unresectable or recurrent gastric cancer was feasible in terms of safety and might be effective for disease control.

[A Case of Goblet Cell Carcinoid of the Appendix Invading Directly into the Sigmoid Colon].

A 73-year-old man underwent a screening colonoscopy, and a depressed lesion in the sigmoid colon was detected. Biopsy revealed a Group V lesion, and he was diagnosed with sigmoid colon cancer. During surgery, there was dense adhesion of the appendix to the sigmoid colon, and sigmoidectomy combined with appendectomy was performed. However, pathological examination revealed goblet cell carcinoid of the appendix with direct invasion into the sigmoid colon. To the best of our knowledge, no similar cases have been reported in Japan. Additional surgery with lymph node dissection was recommended, but it was rejected by the patient. For adjuvant chemotherapy, a total of 8 courses of capecitabine plus oxaliplatin therapy were administered. To date, the patient is alive without recurrence 2 years postoperatively. Postoperative adjuvant chemotherapy for goblet cell carcinoid of the appendix is a useful option for cases in which additional surgery cannot be performed.

A comparison between fentanyl plus celecoxib therapy and epidural anesthesia for postoperative pain management following laparoscopic gastrectomy.

PURPOSE: To clarify the efficacy of postoperative pain management following laparoscopic gastrectomy (LG), we retrospectively compared pain assessments in patients who received fentanyl plus celecoxib with those who received epidural anesthesia. METHODS: From 2011 to 2012, 55 consecutive LG patients at our institution received 48 h of epidural anesthesia for postoperative pain management (group-E). Since September 2013, epidural anesthesia was replaced with 24 h of intravenous fentanyl and 4 days of oral celecoxib. Thirty-three consecutive LG patients who received this analgesic method (group-FC) were included in this analysis. The severity of postoperative pain as assessed by the FACES Pain Rating Scale and the frequency of rescue pain medication were retrospectively compared between the two groups. RESULTS: No significant difference in the severity of postoperative pain on postoperative day (POD) 0 or 1 was observed between the two groups. In contrast, pain was significantly lower in group-FC than group-E on PODs 2, 3, 4, and 7. The total use of rescue pain medications during the first 7 days following LG did not differ between the two groups. CONCLUSION: Pain management using 24 h of intravenous fentanyl and 4 days of oral celecoxib is comparable to epidural anesthesia following LG.

[A Case of Pseudomyxoma Peritonei Derived from Cecum Colon Cancer with Long-Term Recurrence-Free Survival].

A 29-year-old woman was diagnosed with advanced cecum colon cancer, and right hemicolectomy was performed. The pathological findings showed stage Ⅲa disease, including moderately differentiated tubular adenocarcinoma>mucinous adenocarcinoma, pT3, pN1, cM0, and Cur A resection. The patient was treated with 5-FU plus l-LV adjuvant chemotherapy. Fourteen months after surgery, bilateral ovarian metastasis and ascites were found, and another surgery was performed, revealing that the abdominal cavity was filled with a gelatinous ascites. Under the diagnosis of pseudomyxoma peritonei, resection of both ovaries, abdominal lavage, and intraperitoneal administration of CDDP were performed, followed by S-1 plus CDDP treatment. Two years after the recurrence, peritoneal re-recurrence on the vaginal fornix was detected. A total hysterectomy, partial vaginectomy, and resection of disseminated peritoneal nodules were performed. The patient received mFOLFOX6 treatment postoperatively. To date, 8 years and 9 months after her re-recurrence, the patient is alive and without signs of a third recurrence.

Laparoscopic distal gastrectomy for pyloric stenosis caused by heterotopic glands in a young female: report of a case.

A 17-year-old female was referred to our hospital with worsening dietary intake and abdominal bloating. She had epigastric fullness, but no abdominal pain. Gastrointestinal endoscopy revealed food residue and pyloric stenosis. A contrast-enhanced radiograph also showed pyloric stenosis, and gastrografin was not passed well through her pylorus. Computed tomography revealed similar findings. The biopsy results indicated hyperplasia of the gastric glands. The patient was diagnosed with a benign lesion, and underwent endoscopic balloon dilation several times. However, her stenosis worsened and we decided to perform surgery. In consideration of the cosmetic outcome, we performed laparoscopic distal gastrectomy. The postoperative course was good, and the patient was discharged on postoperative day 10. The final diagnosis was pyloric stenosis caused by heterotopic glands. No malignant lesions were found. Since gastric stenosis caused by heterotopic glands has not been reported previously, we consider this to be a very rare case.

[Adjuvant chemotherapy with capecitabine for colon cancer - a case series].

We examined the treatment condition; adverse events, especially hand-foot syndrome (HFS); and prognosis in 65 patients with colon cancer who received adjuvant chemotherapy with capecitabine. The treatment completion rate was 75.4%; however, only 15.4% of patients completed treatment without dose reduction or treatment interruption. HFS occurred in 78.5% of all cases. The 3-year relapse-free survival rate was 73.8% for all cases, 80.8% for treatment-completed cases, and 51.1% for treatment-discontinued cases; however, there were no differences in relapse-free survival rates for cases that required dose reduction or treatment interruption. We conclude that adjuvant chemotherapy with capecitabine is effective in colon cancer and that completing treatment (even with dose reduction or dose interruption) improves prognosis.

[A case of an elderly patient with recurrent GIST, which was effectively treated with low-dose imatinib mesylate].

The recommended dose of imatinib for recurrent gastrointestinal stromal tumors (GIST) is 400mg/day. However, adverse effects limit the use of the standard dose in elderly patients. We report a case of an elderly patient with recurrent GIST, where long-term control of the disease was achieved with low-dose imatinib therapy. An 86-year-old man presenting with tarry stool was admitted to the hospital; upper GI endoscopy revealed a gastric submucosal tumor of the stomach at the posterior wall of the cardia. Partial gastrectomy was performed laparoscopically. The submucosal lesion was histopathologically diagnosed as malignant GIST. Administration of imatinib was initiated 17 months after surgery because of recurrence of GIST. The initial dose of imatinib was 400mg/day, which was later adjusted to 200mg or 300 mg/day because of adverse effects. Though imatinib was withdrawn several times due to strong side effects, the disease was well controlled for 6 years after surgery.

Frequency and pattern of expression of the stem cell marker CD133 have strong prognostic effect on the surgical outcome of colorectal cancer patients.

CD133 has been reported to be a cancer stem cell marker in colorectal cancer (CRC). The aim of this study was to examine the frequency and pattern of CD133 expression by immunohistochemical methods and evaluate their correlation with clinicopathological features, including patient survival (PS) and recurrence. Tissue specimens of 151 CRC patients who underwent surgical treatment for well-differentiated/moderately differentiated adenocarcinoma and stage I-IV tumors (TNM classification) were immunostained for analyzing CD133 expression. The frequency of CD133 expression was 91.4% (138/151), and the pattern of expression was divided into membranous and cytoplasmic expression. Of the 151 patients, 136 (90.1%) showed membranous expression, whereas 44 (29.1%) showed cytoplasmic expression. Both expression patterns were seen in 42 (27.8%) patients. The frequency of CD133 overexpression (>50% of stained cells) was 27.2% (41/151); univariate analysis showed CD133 overexpression to be significantly associated with PS, but not recurrence, and multivariate analysis indicated it to be an independent prognostic factor. Multivariate analysis showed membranous overexpression (>50% of stained tumor cells on the membrane), which significantly correlated with histology and chemoresistance of recurrent and stage IV tumors, to be an independent prognostic factor for PS and recurrence. However, multivariate analysis did not indicate cytoplasmic expression, which significantly correlated with histology, lymph node metastasis, TNM stage and lymphatic invasion, as an independent prognostic factor for PS and recurrence. Our results demonstrated that evaluation of the frequency and pattern of CD133 expression is useful for predicting prognosis, recurrence, and chemosensitivity in CRC patients.

[Evaluation of low-dose FP therapy as adjuvant therapy for gastric cancer].

In the present study, we demonstrate the result of low-dose FP treatment as an adjuvant therapy for 30 patients of stage II or more progressive gastric cancer. 5-FU and CDDP were injected intravenously for 10 days from day 1 through day 5, and day 8 through 12 for 2 weeks at a dose of 250 mg/body and 10 mg/body, or for 14 days at a dose of 250 mg/m2/day and 5 mg/m2/day, respectively. Patients were excluded if they received less than 80% of the respective doses in a course of treatment by the protocol. This constituted a course of chemotherapy, which was repeated every 4 weeks. Grade 3 neutropenia was observed in one case. Other toxicities were anorexia, nausea, weight loss, diarrhea, general fatigue and elevation of serum creatinine, but they were not so severe. The two-year survival rate was 100% in cur A cases, 85% in cur B, and 0% in cur C. The median survival time of the cur C patients was 10 months. These results indicate that low-dose FP therapy is safe and recommendable for cur A and cur B patients. However, other treatment methods such as sequential chemotherapy are needed for cur C gastric cancer patients.

[Neoadjuvant chemoradiotherapy for advanced squamous cell carcinoma of thoracic esophagus].

Advanced thoracic esophageal cancer has a poor prognosis despite advances in surgery, such as three-field lymph node dissection. Multimodal therapy is needed to improve local control, resectability and survival rate. Fifteen patients with advanced squamous cell carcinoma of the thoracic esophagus were treated with neoadjuvant chemoradiotherapy (NAC) combined with concurrent radiation (30 Gy/12 f) and 3 courses of 5-FU and CDDP (CDDP 5 mg/m2/day + 5-FU 250 mg/m2/day: day 1-5: div). In the absence of unresectable disease and surgical risk, 12 patients underwent esophagectomy (Group 1) and 3 patients underwent additional chemoradiotherapy because of high surgical risk (Group 2). Side effects consisted of nausea, vomiting and myelo-suppression in 8 patients, but all patients tolerated and completed a full course of NAC. The effective rate (CR + PR) of NAC was 58.3% in Group 1 and 66.7% in Group 2. No patients showed pathological CR. Two-year survival rate was 28.1% in Group 1 (PR: 33.3%, NC: 20.0%) and 33.5% in Group 2. This protocol had acceptable toxicities but did not show survival benefit. Further trials are necessary to improve survival rate.

Immunological evaluation of peptide vaccination for patients with gastric cancer based on pre-existing cellular response to peptide.

There is no standard treatment modality for advanced gastric cancer (GC) at the present time. To develop a new treatment modality, we investigated the immunological responses of advanced GC patients (n = 13, 9 non-scirrhous and 4 scirrhous types) vaccinated with peptides to a regimen under which pre-vaccination peripheral blood mononuclear cells (PBMCs) were screened for their reactivity in vitro to each of 14 peptides on HLA-A24 or 16 peptides on -A2 allele, then only the reactive peptides (maximum: 4) were administered in vivo. This regimen was generally well tolerated, although grade I levels of fever and local skin reactions were observed in several patients. Delayed-type hypersensitivity (DTH) to the vaccinated peptides was observed in 4 patients. Increased cellular and humoral immune responses to the vaccinated peptides were observed in post-vaccination PBMCs from 4 of 8 patients and in post-vaccination sera of 8 of 10 patients tested, respectively. Prolonged survival was observed in patients showing cellular and humoral immune responses to the vaccinated peptides in the post-vaccination samples, including all 4 patients with the scirrhous type. These results encourage further development of peptide-based immunotherapy for GC patients.