New Metabolites Produced by Cylindrocarpon sp. SY-39 from a Driftwood.

Four novel compounds, cylindropyrone A (1), 10'-hydroxyilicicolinic acid D (3), cylindrolactones A (4) and B (5), together with known dihydroinfectopyrone (2) were isolated from the culture of Cylindrocarpon sp. SY-39 from a driftwood. Their structures were elucidated using 1D- and 2D-NMR spectroscopy. Compound 3 showed antimicrobial activity against Staphylococcus aureus with MIC value of 5.0 µg/mL.

[Use of Transdermal Fentanyl in a Hospital].

Recently, the use of transdermal fentanyl (TDF) has been increasing at our hospital owing to its convenience. Furthermore, TDF tends to be increasingly used for patients who have never used opioids. However, the appropriate criteria for indicating TDF have not been established yet. Therefore, we examined how TDF was prescribed in practice and determined its effective dosage. In 43 cases, the reasons, effects, and side effects of TDF were investigated retrospectively. Of the patients, 60% continued using TDF for 30 days. Meanwhile, approximately 25% of them terminated TDF therapy within 8 days. Of those who discontinued TDF therapy, some entirely stopped taking TDF and others chose other opioids instead because of poor pain control. Before receiving TDF therapy, 17 patients (45%) used oxycodone and 14 (37%) never used opioids. In addition, the main reason for starting TDF in opioid-naive patients was gastrointestinal condition. Between opioid-naive and opioid-using groups, no significant differences were observed in usage duration and incidence of side effects. The side effects included somnolence in 6 patients, delirium in 2 patients, and nausea and vomiting, constipation, and breathing restraint in 1 patient each. TDF was considered as an effective treatment regardless of the previous use of opioids. Nonetheless, careful deliberation is necessary because of the slow effects and difficulty with dosage adjustment.

Successful adjuvant bi-weekly gemcitabine chemotherapy for pancreatic cancer without impairing patients' quality of life.

BACKGROUND: Although adjuvant gemcitabine (GEM) chemotherapy for pancreatic cancer is standard, the quality of life (QOL) in those patients is still impaired by the standard regimen of GEM. Therefore, we studied whether mild dose-intensity adjuvant chemotherapy with bi-weekly GEM administration could provide a survival benefit with acceptable QOL to the patients with pancreatic cancer. METHODS: After a phase I trial, an adjuvant bi-weekly 1,000 mg/m2 of GEM chemotherapy was performed in 58 patients with pancreatic cancer for at least 12 courses (Group A). In contrast, 36 patients who declined the adjuvant bi-weekly GEM chemotherapy underwent traditional adjuvant 5FU-based chemotherapy (Group B). Careful periodical follow-ups for side effects of GEM and disease recurrence, and assessment of patients' QOL using the EORTC QOL questionnaire (QLQ-C30) and pancreatic cancer-specific supplemental module (QLQ-PAN26) were performed. Retrospectively, the degree of side effects, patients' QOL, compliance rate, disease-free survival (DFS), and overall survival (OS) in Group A were compared with those in Group B. RESULTS: No severe side effects (higher than Grade 2 according to the common toxicity criteria of ECOG) were observed, except for patients in Group B, who were switched to the standard GEM chemotherapy. Patients' QOL was better in Group A than B (fatigue: 48.9 ± 32.1 versus 68.1 ± 36.3, nausea and vomiting: 26.8 ± 20.4 versus 53.7 ± 32.6, diarrhea: 21.0 ± 22.6 versus 53.9 ± 38.5, difficulty gaining weight: 49.5 ± 34.4 versus 67.7 ± 40.5, P < 0.05). Compliance rates in Groups A and B were 93% and 47%. There was a significant difference in the median DFS between both groups (Group A : B =12.5 : 6.6 months, P < 0.001). The median OS of Group A was prolonged markedly compared with Group B (20.2 versus 11.9 months, P < 0.005). For OS between both groups, univariate analysis revealed no statistical difference in 69-year-old or under females, and T1-2 factors, moreover, multivariate analysis indicated three factors, such as bi-weekly adjuvant GEM chemotherapy, T2 or less, and R0. CONCLUSIONS: Adjuvant chemotherapy with bi-weekly GEM offered not only the advantage of survival benefits but the excellent compliance with acceptable QOL for postoperative pancreatic cancer patients.

Possibility of sandwiched liver surgery with molecular targeting drugs, cetuximab and bevacizumab on colon cancer liver metastases: a case report.

A 31-year-old man with sigmoid colon cancer with concomitant simultaneous multiple liver metastases had received FOLFIRI (leucovorin, fluorouracil and irinotecan) and FOLFOX6 (leucovorin, fluorouracil and oxaliplatin) after an ordinary sigmoidectomy. However, his serum carcinoembryonic antigen (CEA) level increased rapidly during the fifteen months after the operation while he was on FOLFOX6. Abdominal computed tomography revealed expanding multiple liver tumors. As the third line chemotherapy, a combination therapy of cetuximab with irinotecan was given, which markedly reduced his levels of serum CEA, and the size and number of liver tumors. He underwent lateral segmentectomy of the liver and microwave coagulation of the liver metastases in the remnant liver. Thereafter, a good quality of life with tumor dormancy was obtained for 6 months. However, his serum CEA started to rise again in the absence of liver tumors. Therefore, FOLFOX6 with bevacizumab was chosen as the fourth line chemotherapy, and the serum CEA was reduced with tumor dormancy. A good quality of life was obtained again at 3 years after the first surgery. This report indicates the effectiveness of sandwiched liver surgery with the molecular targeting drugs cetuximab and bevacizumab on multiple liver metastases of colon cancer, and suggests the possibility of a regimen consisting of bevacizumab following cetuximab.

Suppression of external quantum efficiency rolloff in organic light emitting diodes by scavenging triplet excitons.

Large external quantum efficiency rolloff at high current densities in organic light-emitting diodes (OLEDs) is frequently caused by the quenching of radiative singlet excitons by long-lived triplet excitons [singlet-triplet annihilation (STA)]. In this study, we adopted a triplet scavenging strategy to overcome the aforementioned STA issue. To construct a model system for the triplet scavenging, we selected 2,6-dicyano-1,1-diphenyl-λ5σ4-phosphinine (DCNP) as the emitter and 4,4'-bis[(N-carbazole)styryl]biphenyl (BSBCz) as the host material by considering their singlet and triplet energy levels. In this system, the DCNP's triplets are effectively scavenged by BSBCz while the DCNP's singlets are intact, resulting in the suppressed STA under electrical excitation. Therefore, OLEDs with a 1 wt.%-DCNP-doped BSBCz emitting layer demonstrated the greatly suppressed efficiency rolloff even at higher current densities. This finding favourably provides the advanced light-emitting performance for OLEDs and organic semiconductor laser diodes from the aspect of the suppressed efficiency rolloff.

Clinical Impact of the Introduction of an Early Rehabilitation Protocol on Infectious Complications in Patients after Gastrointestinal Cancer Surgery.

BACKGROUND: The clinical importance of postoperative rehabilitation for cancer patients has recently attracted much attention. However, it remains uncertain whether early rehabilitation can prevent infectious complications in patients undergoing gastrointestinal cancer surgery. METHODS: The study group consisted of 259 patients who underwent laparoscopic or open surgery for gastrointestinal cancer at our institution between December 2012 and November 2016. Our department proposed a new early rehabilitation protocol for such patients to encourage physical activity after surgery. The protocol was clinically introduced on July 21, 2015. We divided the study subjects into two groups: those who were admitted before the introduction of the new protocol and those admitted after. The frequency of infectious complications, including respiratory infections, and the length of hospital stay after surgery were compared between the two groups. RESULTS: No adverse cardiovascular event associated with the early rehabilitation protocol was experienced. After the protocol was introduced, more than 80% of patients started exercising on the first day after surgery. For patients undergoing open surgery, the frequency of infectious complications was significantly reduced with the introduction of the protocol (p<0.05). Moreover, when open surgery was performed, the protocol significantly shortened the length of hospital stay (p<0.05). CONCLUSION: Our proposed early rehabilitation protocol for patients who have undergone gastrointestinal cancer surgery was considered to be safe and feasible. The protocol may prevent infectious complications and shorten the hospital stay after such surgery.

Serum Carcinoembryonic Antigen Levels Before the First Curative Hepatectomy for Metastatic Colorectal Cancer Is a Predictor of Recurrence.

BACKGROUND/AIM: The aim of this study was to evaluate the usefulness of serum carcinoembryonic antigen (CEA) levels before the first curative hepatectomy for metastatic colorectal cancer as a predictor of recurrence. PATIENTS AND METHODS: Between 2003 and 2010, 66 patients (45 male and 21 female) who underwent a first curative hepatectomy for metastatic colorectal cancer in our hospital were evaluated retrospectively. The mean patient age was 65.2 years (range=31-80 years). A total of 28 patients had synchronous liver metastasis, and the other 38 patients developed metachronous liver metastasis. RESULTS: The 5-year relapse-free survival rate after the first hepatectomy of the 16 patients with normal serum CEA level was 61.1%, whereas that of the 50 patients with abnormal serum CEA level was 34.3% (p<0.001). Among patients whose serum CEA levels were abnormal, the 5-year relapse-free survival rate after the first hepatectomy of the 34 patients with serum CEA levels less than 50 ng/ml was 48.1%, whereas that of the 16 patients with serum CEA level equal to or greater than 50 ng/ml was 6.3% (p<0.001). All eleven patients whose serum CEA levels were at least 100 ng/ml developed recurrence within one year after hepatectomy. CONCLUSION: Serum CEA levels before the first curative hepatectomy for metastatic colorectal cancer seem to be a predictor of recurrence.

Spectroscopic characterisation of two polyketide metabolites from Cylindrocarpon sp. from driftwood.

Two new polyketides, (5R,7R,9R)-7,9-dihydroxy-5-decanolide and (4E,6R,9R)- 6,9-dihydroxydec-4-enoic acid (2), were isolated from rice cultures of Cylindrocarpon sp. SY-39 discovered during screening of driftwood at a Shonai coast area in Yamagata, Japan. The structures of 1 and 2 were determined using a variety of spectroscopic methods. Compound 2 exhibited moderate antimicrobial activity against Staphylococcus aureus NBRC 13276 and Aspergillus clavatus F 318a at a concentration of 50 µg per disk.

Successful new method of extracorporeal percutaneous endoscopic gastrostomy (E-PEG).

BACKGROUND: Although percutaneous endoscopic gastrostomy (PEG) has become popular for patients with swallowing disorders as a nutrition support or a decompressant of gastrointestine, perioperative complications associated with PEG have not decreased, especially peristomal infections. To reduce peristomal infections, we designed a new method of gastrostomy by extracorporeal approach under endoscopic observation, named as extra-corporeal PEG (E-PEG). METHODS: Experimental studies for E-PEG were performed repeatedly using pigs under general anesthesia to confirm the safety of its procedure for human use. After approval of institutional ethics review board in our university, thirty patients with prior consent participated in this study. The operation time, the incidence rate of complications and the hospital stay were compared between E-PEG and ordinary pull-method PEG groups. RESULTS: Two patients (6.7%) in E-PEG group had postoperative complications, i.e., aspiration pneumonia and surgical site infection. The operation time of E-PEG group was 5-16 (mean +/- SD: 10.3 +/- 2.96) min as compared to 14-37 (mean +/- SD: 26.9 +/- 8.39) min with pull-method PEG. The postoperative hospital day of E-PEG was within two days except for the two complicated cases. Significance differences of operation time, complication rate and postoperative hospital stay between those groups observed statistically. CONCLUSIONS: These results indicate that E-PEG was safe, tolerable and speedy when compared ordinary pull-method PEG.

Impact of delayed gastric emptying after pancreaticoduodenectomy on survival.

BACKGROUND: Delayed gastric emptying (DGE), a common postoperative complication of pancreaticoduodenectomy, is not considered a life-threatening complication. In the present study, we analyzed the risk factors for DGE and its impact on long-term prognosis. METHODS: We analyzed 383 patients who underwent pancreaticoduodenectomy between 2003 and 2010, dividing them into two groups according to DGE grade as defined by the International Study Group of Pancreatic Surgery: 243 without DGE (non-DGE group) and 140 with DGE of any grade (DGE group). RESULTS: The 5-year overall survival was 32.7% in the DGE group, and 41% in the non-DGE group (P = 0.02). Cox proportional hazards analyses showed that pancreatic cancer (compared with ampulla of Vater cancer: hazard ratio [HR] 3.4, 95% confidence interval [CI] 1.82-6.34, P < 0.001), bile duct cancer (HR 2.1, 95% CI 1.08-4.06, P = 0.03), the Union for International Cancer Control stage (compared with stages I and II: HR 2.98, 95% CI 1.66-5.35, P < 0.001; compared with stage III: HR 4.71, 95% CI 2.51-8.86, P < 0.001), and DGE grade (grade C; HR 1.6, 95% CI 1.04-2.46, P = 0.03) were independent risk factors for cancer-specific survival. CONCLUSIONS: DGE, especially grade C, negatively affects cancer-specific survival.

Study on the Validity of Pancreaticoduodenectomy in the Elderly.

AIM: Pancreaticoduodenectomy (PD) is still the only curative treatment for periampullary cancer. Confirming the outcomes of PD in elderly patients is important as the aging population continues to grow. PATIENTS AND METHODS: We analyzed 340 patients with periampullary cancer who underwent PD, dividing them into three groups by age: group A: aged 64 years or younger, n=115; group B: 65-74 years, n=144; and group C: 75 years or older, n=81. RESULTS: Group C had a significantly higher 60-day mortality of 6.3% (p=0.04), the lowest 5-year overall survival rate of 9.9% (p=0.02), and there was no impact of staging of the Union for International Cancer Control classification on overall survival of patients with pancreatic cancer. Independent prognostic factors of group C in the multivariate analysis were pancreatic cancer and reoperation. CONCLUSION: For elderly patients aged 75 years or over, caution should be exercised in selecting PD for patients with pancreatic cancer.

Pancreatic stellate cells (PSCs) express cyclooxygenase-2 (COX-2) and pancreatic cancer stimulates COX-2 in PSCs.

BACKGROUND: Cyclooxygenase 2 (COX-2), the inducible form of prostaglandin G/H synthase, is associated with several human cancers including pancreatic adenocarcinoma. Pancreatic stellate cells (PSCs) play a central role in the intense desmoplasia that surrounds pancreatic adenocarcinoma. The present study examined COX-2 expression in PSCs. PSCs isolated from normal rats, were cultured and exposed to conditioned medium (CM) from the human pancreatic cell line, PANC-1. METHODS: COX-2 expression was evaluated by immunostaining and western blotting. Proliferation of PSCs was determined by thymidine incorporation and cell counting. RESULTS: COX-2 was found to be constitutively expressed in PSCs, and COX-2 protein was up-regulated by PANC-1 CM. Moreover, the induction of COX-2 by PANC-1 CM was prevented by U0126, an extracellular signal-regulated kinase (ERK) 1/2 inhibitor suggesting that activation of ERK 1/2 is needed for stimulation of COX-2. Finally, NS398, a selective COX-2 inhibitor, reduced the growth of PSCs by PANC-1 CM, indicating that activation of COX-2 is required for cancer stimulated PSC proliferation. CONCLUSION: The results suggest that COX-2 may play an important role in the regulation of PSC proliferation in response to pancreatic cancer.

Catalytic Asymmetric Synthesis of Tertiary Alcohols and Oxetenes Bearing a Difluoromethyl Group.

The catalytic asymmetric ene reaction with difluoropyruvate as an electrophile in the presence of a dicationic palladium complex is shown. This is the reliable and practical catalytic asymmetric synthesis for various α-CF2H tertiary alcohols in high yields and enantioselectivities. The reaction with isobutene can be catalyzed efficiently under solvent-free conditions with low catalyst loading (up to S/C 2000). Furthermore, difluoropyruvate is applicable to the [2 + 2] cycloaddition reaction in high yields and enantioselectivities.

Efficacy of a half-grip technique using a fine tip LigaSure™, Dolphin Tip Sealer/Divider, on liver dissection in swine model.

BACKGROUND: Recently, a lot of energy devices in the surgical field, especially in the liver surgery, have been developed, and a fine tip LigaSure™, Dolphin Tip Sealer/Divider (DT-SD) also has been used frequently to dissect liver parenchyma as well as ultrasonically activated device (USAD). However, the utility of this instrument for liver dissection (LD) is still unknown. Moreover, to reduce bleeding during LD, a half-grip technique (HGT) was contrived. We herein report an experimental study in swine model to evaluate the feasibility and effectiveness of HGT using DT-SD for LD. METHODS: The swine model experiment was carried out under general anesthesia by veterinarians. LD was performed repeatedly by DT-SD with the HGT (Group A, n = 6), or the conventional clamp-crush technique (CCT) (Group B, n = 6), and by variable mode USAD (Group C, n = 6). The dissection length and depth (cm) as well as bleeding volume (g) were measured carefully, and the dissection area (cm(2)) and speed (cm(2)/min) were calculated precisely. Histological examinations of the dissection surfaces were also executed. Mann-Whitney's U test was used for Statistical analyses with variance at a significance level of 0.05. RESULTS: Among the three groups, the three averages of dissection lengths were unexpectedly equalized to 8.3 cm. The dissection area (cm(2)) was 9.9 ± 5.1 in Group A, 9.8 ± 4.7 in Group B, and 9.9 ± 4.5 in Group C. The mean blood loss during LD was 10.6 ± 14.8 g in Group A, 41.4 ± 39.2 g in Group B, and 34.3 ± 39.2 g in Group C. For Group A, the bleeding rate was the least, 0.9 ± 1.0 g/cm(2), and the average depth of coagulation was the thickest, 1.47 ± 0.29 mm, among the three groups (p < 0.05). The dissection speed in Group A (1.3 ± 0.3 cm(2)/min) was slower, than that in Group C (p < 0.05). CONCLUSIONS: This report indicates firstly that the HGT using DT-SD bring the least blood loss when compared with CCT or USAD. Although the HGT is feasible and useful for LD, to popularize the HGT, further clinical studies will be needed.

Transumbilical single-incision laparoscopic hepatectomy using precoagulation and clipless technique in a patient with combined hepatocellular-cholangiocarcinoma: a case report.

We report our first case of single-incision laparoscopic hepatectomy in a 43-year-old woman with a 30-mm solitary combined hepatocellular-cholangiocarcinoma. A port of single-incision laparoscopic surgery was inserted through the abdominal wall using a 2.5-cm single incision in the umbilical area. To obtain adequate operative view for the tumor in segment 6, a 5-mm flexible endoscope, roticulated instruments, and a miniloop retractor were used. After precoagulation with a 5-mm flexible microwave probe, liver resection was performed using laparoscopic ultrasonic shears, soft-coagulation devices, and a tissue-sealing knife. Subsequently, cholecystectomy was carried out for a gallbladder polyp. The procedure was successfully completed without conversion to conventional laparoscopic technique. The operation time was 180 minutes and operative blood loss was uncountable. Transumbilical single-incision laparoscopic hepatectomy using precoagulation and clipless techniques is feasible and seems to provide better cosmetic appearance in selected cases by qualified endoscopic liver surgeons.

Metastasis of breast cancer to a uterine leiomyoma.

Metastasis of breast cancer to a uterine leiomyoma is rare. We review the clinicopathological features of breast cancer metastasis to a uterine leiomyoma and discuss possible effective treatment. We describe a case of a woman who presented with abdominal discomfort after undergoing mastectomy for breast cancer. At the time of mastectomy, imaging showed osseous metastases involvement to the right kidney. The patient underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy. Microscopic examination disclosed carcinoma of breast origin localized within the leiomyoma. To date, the patient is alive and asymptomatic after treatment with anastozole and capecitabine for 11 months. Per reports in the literature, abnormal uterine bleeding or a rapidly growing leiomyoma may be symptomatic of breast cancer metastasis to a uterine leiomyoma, especially if a patient has a previous diagnosis of invasive ductal carcinoma of the breast. Palliative hysterectomy can potentially improve prognosis in patients whose cancer is restricted to a uterine leiomyoma with or without involvement of lymph nodes, and may offer relief of genital tract symptoms in patients who have widespread involvement of non-life-threatening metastases.

Streptococcal preparation OK-432 promotes fusion efficiency and enhances induction of antigen-specific CTL by fusions of dendritic cells and colorectal cancer cells.

Dendritic/tumor fusion cell (FC) vaccine is an effective approach for various types of cancer but has not yet been standardized. Antitumor activity can be modulated by different mechanisms such as dendritic cell (DC) maturation state. This study addressed optimal strategies for FC preparations to enhance Ag-specific CTL activity. We have created three types of FC preparations by alternating fusion cell partners: 1) immature DCs fused with autologous colorectal carcinoma cells (Imm-FCs); 2) Imm-FCs followed by stimulation with penicillin-inactivated Streptococcus pyogenes (OK-432) (Imm-FCs/OK); and 3) OK-432-stimulated DCs directly fused to autologous colorectal carcinoma cells (OK-FCs). Both OK-FCs and Imm-FCs/OK coexpressed the CEA, MUC1, and significantly higher levels of CD86, CD83, and IL-12 than those obtained with Imm-FCs. Short-term culture of fusion cell preparations promoted the fusion efficiency. Interestingly, OK-FCs were more efficient in stimulating CD4(+) and CD8(+) T cells capable of high levels of IFN-gamma production and cytolysis of autologous tumor or semiallogeneic targets. Moreover, OK-FCs are more effective inducer of CTL activation compared with Imm-FCs/OK on a per fusion cell basis. The pentameric assay confirmed that CEA- and MUC1-specific CTL was induced simultaneously by OK-FCs at high frequency. Furthermore, the cryopreserved OK-FCs retained stimulatory capacity for inducing antitumor immunity. These results suggest that OK-432 promotes fusion efficiency and induction of Ag-specific CTL by fusion cells. We conclude that DCs fused after stimulation by OK-432 may have the potential applicability to the field of antitumor immunotherapy and may provide a platform for adoptive immunotherapy in the clinical setting.

Three-Port laparoscopic partial hepatectomy using an ultrasonically activated device (USAD).

BACKGROUND/PURPOSE: We provide an initial report of the indications and procedure for three-port laparoscopic partial hepatectomy. METHODS: Three-port laparoscopic partial hepatectomy was performed in nine patients (age, 49 to 73 years) at our department. Eight patients (seven men and one woman) had hepatocellular carcinoma (HCC); six of these patients had liver cirrhosis (LC) and two had chronic hepatitis (CH). The ninth patient, a woman had a single metastatic liver tumor from colon cancer. The tumors were located in regons S(2), S(3), S(4), S(5), S(6), and S(8). Preoperative liver function assessment revealed Child-Pugh classification A or B. All the tumors were located superficially, and their diameter averaged approximately 3 cm. Hepatectomy was performed laparoscopically, using an ultrasonically activated device (USAD) with or without microwave coagulation therapy (MCT). RESULTS: The operative time was 50 to 168 min, and the intraoperative blood loss ranged from 32 to 158 g. The postoperative hospital stay was 5 to 17 days. No recurrences, including local relapse, were observed. CONCLUSIONS: Three-port laparoscopic partial hepatectomy is safe and feasible for patients with Child-Pugh liver function classification A or B if the tumor is located superficially and is less than 3 cm in diameter.

Pancreatic cancer stimulates pancreatic stellate cell proliferation and TIMP-1 production through the MAP kinase pathway.

Pancreatic adenocarcinoma is characterized by an intense desmoplastic reaction that surrounds the tumor. Pancreatic stellate cells (PSCs) are thought to be responsible for production of this extracellular matrix. When activated, PSCs have a myofibroblast phenotype and produce not only components of the extracellular matrix including collagen, fibronectin, and laminin, but also matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs). Since PSCs are found in the stroma surrounding human pancreatic adenocarcinoma, we postulate that pancreatic cancer could impact PSC proliferation and TIMP-1 production. Rat PSCs were isolated and cultured. Isolated PSCs were exposed to PANC-1 conditioned medium (CM) and proliferation, activation of the mitogen-activated protein (MAP) kinase pathway, and TIMP-1 gene induction were determined. Exposure to PANC-1 CM increased PSC DNA synthesis, cell number, and TIMP-1 mRNA (real-time PCR) as well as activating the extracellular-regulated kinase (ERK) 1/2. Inhibition of ERK 1/2 phosphorylation (U0126) prevented the increases in growth and TIMP-1 expression. PANC-1 CM stimulates PSC proliferation and TIMP-1 through the MAP kinase (ERK 1/2) pathway.