Management of elderly patients with unresectable pancreatic cancer.

Systemic chemotherapy plays important role in pancreatic cancer not only for palliative treatment of unresectable disease, but also for neoadjuvant and adjuvant treatment of resectable disease. Most clinical trials of systemic chemotherapy have been conducted in non-elderly patients, and the results cannot always be extrapolated to elderly patients because of the uniqueness of this population. The number of elderly patients with pancreatic cancer has increased in an aging society; therefore, there is an urgent need to develop specific treatments for elderly patients with pancreatic cancer. Gemcitabine or S-1 monotherapy is generally considered appropriate even for vulnerable elderly patients. FOLFIRINOX is considered inapplicable based on its safety profile. Gemcitabine plus nab-paclitaxel and nanoliposomal irinotecan with fluorouracil plus folinic acid can be administered to elderly patients, because the phase III trials have shown the efficacy and safety for patients including those who were 75 years or older. However, the feasibility of these therapies for elderly patients is still under debate since the number of elderly populations was relatively small in these studies. To determine the indication for these regimens in the elderly, the background of each patient should be considered. Geriatric assessment such as the Geriatric 8 and the Geriatric Nutritional Risk Index can identify vulnerabilities and are therefore recommended in daily clinical practice as well as in clinical studies of elderly patients. It is expected that geriatric assessment will elucidate the eligibility criteria for those regimens in elderly individuals. Randomized clinical trials are ongoing to establish a standard treatment in the vulnerable elderly with advanced pancreatic cancer, who cannot tolerate the same regimen as in the non-elderly patients.

Visualization of the seasonal shift of a variety of airborne pollens in western Tokyo.

Airborne pollens cause pollinosis and have the potential to affect microphysics in clouds; however, the number of monitored species has been very limited due to technical difficulties for the morphotype identification. In this study, we applied an eDNA approach to the airborne pollen communities in the suburbs of the Tokyo metropolitan area in Japan, within a mixed urban, rural, and mountain landscape, revealing pollen seasonality of various taxa (a total of 78 families across the period) in the spring season (February to May). Those taxa distinctly shifted in the season, especially in the beginning of February and the middle of April. Air temperature shift was an obvious key factor to affect the airborne pollen community, while the influence of other meteorological factors, such as wind speed, humidity, and precipitation, was not clear. Taxonomic classification of major Amplicon Sequence Variants (ASVs) indicates multiple pollen sources, including natural forest, planted forest, roadside, park lands, and horticultural activities. Most major ASV belongs to Japanese cedar (Cryptomeria japonica), which is the most notable allergen that causes pollinosis in Japan, peaking in mid-February to March. Backward trajectory analysis of air masses suggests that the Japanese cedar and other Cupressaceae plantation forests in the western mountains were a significant source of airborne pollen communities detected at our sampling site. Other major plant pollen sources, including Japanese zelkova (Zelkova serrata) and ginkgo (Ginkgo biloba), emanated from the nearby parks or roadside regions. This study's approach enables us to visualize the phenology of multiple pollen, including timing and duration. Long-term monitoring of this type would provide additional insight into understanding the role of climate change on pollen transmission and links to flowering events.

Forecasting the seasonal pollen index by using a hidden Markov model combining meteorological and biological factors.

The seasonal pollen index (SPI) is a continuing concern within the fields of aerobiology, ecology, botany, and epidemiology. The SPI of anemophilous trees, which varies substantially from year to year, reflects the flowering intensity. This intensity is regulated by two factors: weather conditions during flower formation and the inner resource for assimilation. A deterministic approach has to date been employed for predicting SPI, in which the forecast is made entirely by parameters. However, given the complexity of the masting mechanism (which has intrinsic stochastic properties), few attempts have been made to apply a stochastic model that considers the inter-annual SPI variation as a stochastic process. We propose a hidden Markov model that can integrate the stochastic process of mast flowering and the meteorological conditions influencing flower formation to predict the annual birch pollen concentration. In experiments conducted, the model was trained and validated by using data in Hokkaido, Japan covering 22 years. In the model, the hidden Markov sequence was assigned to represent the recurrence of mast years via a transition matrix, and the observation sequences were designated as meteorological conditions in the previous summer, which are governed by hidden states with emission distribution. The proposed model achieved accuracies of 83.3% in the training period and 75.0% in the test period. Thus, the proposed model can provide an alternative perspective toward the SPI forecast and probabilistic information of pollen levels as a useful reference for allergy stakeholders.

Randomized, phase II trial of sequential hepatic arterial infusion chemotherapy and sorafenib versus sorafenib alone as initial therapy for advanced hepatocellular carcinoma: SCOOP-2 trial.

BACKGROUND: The efficacy of hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC) remains unclear. We conducted a multi-center randomized phase II study comparing a sequential HAIC-sorafenib regimen versus sorafenib alone as an initial therapy for HCC. METHODS: Patients were randomly assigned (ratio, 1:1) to receive sequential HAIC with cisplatin followed by sorafenib (HAIC group, n = 35) or sorafenib alone (sorafenib group, n = 33) as an initial therapy. The primary endpoint was the one-year survival rate. Secondary endpoint included overall survival (OS), the 2-year survival rate, the time-to-progression (TTP), the objective response rate (ORR), the disease control rate (DCR), and safety. RESULTS: For the primary endpoint, the one-year survival rates were 46% in the HAIC group and 58% in the sorafenib group. The median OS period was 10.0 months (95% CI, 7.0-18.8) in the HAIC group and 15.2 months (95% CI, 8.2-19.7) in the sorafenib group (hazard ratio [HR], 1.08; 95% CI, 0.63 to 1.86, P = 0.78). The median TTP, ORR and DCR in the HAIC group were 2.8 months (95% CI, 1.7-5.5), 14.3, and 45.7%, respectively, while those in the sorafenib group were 3.9 months (95% CI, 2.3-6.8), 9.1, and 45.5%, respectively. No unexpected adverse events related to HAIC or sorafenib were observed in either group. CONCLUSIONS: Sequential HAIC with cisplatin and sorafenib does not improve the survival benefit, compared with sorafenib alone, when used as an initial therapy for advanced HCC. However, this study was underpowered in regard to its primary and secondary endpoints, so the results should be interpreted with caution. TRIAL REGISTRATION: UMIN ID 000006147 , registration data: August 11, 2011.

Randomized controlled trial of hyperbaric oxygen therapy in adhesive postoperative small bowel obstruction.

BACKGROUND: Hyperbaric oxygen (HBO) therapy is a controversial treatment for adhesive postoperative small bowel obstruction (ASBO), with only a few retrospective studies reported. The aim of this study was to assess the clinical impact of HBO therapy in the treatment of ASBO. METHODS: Patients with ASBO were randomly assigned to no-HBO (standard arm) or HBO (intervention arm). Patients of the intervention arm were treated once daily at a pressure of 2.0 atm absolute and received 100% oxygen. The primary endpoint was the success rate of medical treatment. This study was registered at the UMIN Clinical Trial Registry as UMIN000010399. RESULTS: The no-HBO group included 40 patients, and the HBO group included 33 patients. Patient characteristics, time to oral intake, and length of hospital stay were similar between the two groups. No significant differences were noted between the no-HBO and HBO groups in the need for long intestinal tube decompression (20.0 versus 18.2%, respectively, p = 1.000) and the need for operative intervention (10.0 versus 18.2%, respectively, p = 0.332). The overall success rate of medical treatment was 72.5% in the no-HBO group and 78.8% in the HBO group (p = 0.594). CONCLUSIONS: In this randomized controlled trial, HBO for ASBO has no additional effect in medical treatment.

Modified response evaluation criteria in solid tumors is superior to response evaluation criteria in solid tumors for assessment of responses to sorafenib in patients with advanced hepatocellular carcinoma.

BACKGROUND: Modified response evaluation criteria in solid tumors (mRECIST) and RECIST are used to assess the effect of treatment with targeted agents for hepatocellular carcinoma (HCC). The aim of this study was to determine which set of criteria is superior in patients with advanced HCC treated with sorafenib. METHODS: A multicenter retrospective study to assess the tumor response and patient prognosis of 191 patients with HCC who had been treated with sorafenib from May 2009 through December 2011. We analyzed tumor responses as shown by contrast-enhanced computed tomography scan images according to RECIST 1.1 and mRECIST and compared the findings. RESULTS: The median duration of follow-up was 9.7 months and median overall survival was 10.8 months. Twenty-five patients (13.1 %) were assessed as responders by mRECIST and 15 (7.8 %) by RECIST 1.1. There was a significant difference in overall survival (OS) between responders and non-responders according to mRECIST (P = 0.0117), but no significant difference in OS between responders and non-responders according to RECIST 1.1 (P = 0.0722). Sixteen patients (8.4 %) had no measurable enhanced target lesions that could be assessed as required by mRECIST; however, these patients could be assessed by RECIST 1.1. According to RECIST 1.1, eight of them had stable disease (SD) and eight had progressive disease (PD). There was a significant difference in OS between these SD and PD patients (P = 0.0312). CONCLUSIONS: Patients treated with sorafenib for HCC should be evaluated by mRECIST; RECIST 1.1 is preferable only for assessment of patients with lesions that are non-measurable according to mRESIST.

Involvement of acyl-CoA synthetase genes in n-alkane assimilation and fatty acid utilization in yeast Yarrowia lipolytica.

Here, we investigated the roles of YAL1 (FAA1) and FAT1 encoding acyl-CoA synthetases (ACSs) and three additional orthologs of ACS genes FAT2-FAT4 of the yeast Yarrowia lipolytica in the assimilation or utilization of n-alkanes and fatty acids. ACS deletion mutants were generated to characterize their function. The FAT1 deletion mutant exhibited decreased growth on n-alkanes of 10-18 carbons, whereas the FAA1 mutant showed growth reduction on n-alkane of 16 carbons. However, FAT2-FAT4 deletion mutants did not show any growth defects, suggesting that FAT1 and FAA1 are involved in the activation of fatty acids produced during the metabolism of n-alkanes. In contrast, deletions of FAA1 and FAT1-FAT4 conferred no defect in growth on fatty acids. The wild-type strain grew in the presence of cerulenin, an inhibitor of fatty acid synthesis, by utilizing exogenously added fatty acid or fatty acid derived from n-alkane when oleic acid or n-alkane of 18 carbons was supplemented. However, the FAA1 deletion mutant did not grow, indicating a critical role for FAA1 in the utilization of fatty acids. Fluorescent microscopic observation and biochemical analyses suggested that Fat1p is present in the peroxisome and Faa1p is localized in the cytosol and to membranes.

Effect of phosphorous ion implantation on the mechanical properties and bioactivity of hydroxyapatite.

Hydroxyapatite (HA) has ability of bone-like apatite formation, which consists with chemical interaction between the surface of HA and ions included in body fluid. Thus, proper surface modification might enhance the function. In the present study, the effect of phosphorous ion implantation on mechanical properties and bioactivity of HA was investigated. In order to clarify the effect of ion implantation dose, ion dose of 1 × 10(12), 1 × 10(13) and 1 × 10(14) ions/cm(2) were selected. Mechanical properties and bioactivity were evaluated in 4-point bending tests and immersion test in simulated body fluid. Bending strength was reduced due to ion implantation. The amount of decreasing strength was similar regardless of ion implantation dose. Bone-like apatite formation was slightly delayed with ion implantation, however, improvement in interfacial strength between bone-like apatite layer and the base HA was indicated. From the results, the possibility of phosphorous ion implantation for enhancement of bioactivity of HA was proved.

Neoadjuvant oxaliplatin and capecitabine and bevacizumab without radiotherapy for poor-risk rectal cancer: N-SOG 03 Phase II trial.

OBJECTIVE: This Phase II trial was designed to evaluate the safety and efficacy of neoadjuvant oxaliplatin and capecitabine and bevacizumab without radiotherapy in patients with poor-risk rectal cancer. METHODS: Patients with magnetic resonance imaging-defined poor-risk rectal cancer received neoadjuvant oxaliplatin and capecitabine and bevacizumab followed by total mesorectal excision or more extensive surgery. RESULTS: Between February 2010 and December 2011, 32 patients were enrolled in this study. The completion rate of the scheduled chemotherapy was 91%. Reasons for withdrawal were refusal to continue therapy in two patients and disease progression in one, with two of these three patients not undergoing surgery. Among the 29 patients who completed the scheduled chemotherapy, one refused surgery within 8 weeks after the completion of chemotherapy, which was the period stipulated by the protocol, and another had rectal perforation, requiring urgent laparotomy. As a result, the completion rate of this experimental treatment was 84%. Of the 30 patients who underwent surgery, the R0 resection rate was 90% and a postoperative complication occurred in 43%. A pathological complete response was observed in 13% and good tumor regression was exhibited in 37%. CONCLUSIONS: Neoadjuvant oxaliplatin and capecitabine plus bevacizumab for poor-risk rectal cancer caused a high rate of anastomotic leakage and experienced a case with perforation during chemotherapy, both of which were bevacizumab-related toxicity. Although the short-term results with the completion rate of 84.4% and the pathological complete response rate of 13.3% were satisfactory, we have to reconsider the necessity of bevacizumab in neoadjuvant chemotherapy (UMIN number, 000003507).

Transcriptional repression by glycerol of genes involved in the assimilation of n-alkanes and fatty acids in yeast Yarrowia lipolytica.

The yeast Yarrowia lipolytica assimilates n-alkanes or fatty acids as carbon sources. Transcriptional activation by n-alkanes of ALK1 encoding a cytochrome P450 responsible for the terminal hydroxylation has been well studied so far, but its regulation by other carbon sources is poorly understood. Here, we analyzed the transcriptional regulation of ALK1 by glycerol. Glycerol is a preferable carbon source compared to glucose for Y. lipolytica. The n-decane-induced transcript levels of ALK1 as well as the reporter gene under the control of ALK1 promoter were significantly decreased in the simultaneous presence of glycerol, but not of glucose. Similarly, the expression of PAT1 encoding acetoacetyl-CoA thiolase involved in ß-oxidation was induced by n-decane or oleic acid, but its transcript level was decreased when glycerol was supplemented. These results indicate that glycerol represses the transcription of the genes involved in the metabolism of hydrophobic carbon sources in Y. lipolytica. Repression of ALK1 transcription by glycerol was not observed in the deletion mutant of GUT1 encoding glycerol kinase, implying that the phosphorylation of glycerol is required for the glycerol repression.

Hypervascular hepatocellular carcinoma: correlation between biologic features and signal intensity on gadoxetic acid-enhanced MR images.

PURPOSE: To analyze the correlation among biologic features, tumor marker production, and signal intensity at gadoxetic acid-enhanced MR imaging in hepatocellular carcinomas (HCCs). MATERIALS AND METHODS: Institutional ethics committee approval and informed consent were obtained for this retrospective study. From April 2008 to September 2011, 180 surgically resected HCCs in 180 patients (age, 65.0 years ± 10.3 [range, 34-83 years]; 138 men, 42 women) were classified as either hypointense (n = 158) or hyperintense (n = 22) compared with the signal intensity of the background liver on hepatobiliary phase gadoxetic acid-enhanced MR images. Pathologic features were analyzed and a fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) production were compared by means of serum analysis and immunohistochemical staining. Recurrence and survival rates were also evaluated. The Mann-Whitney and Pearson correlation tests were used for statistical analysis. RESULTS: The grade of differentiation was higher (P = .028) and portal vein invasion was less frequent in hyperintense HCCs (13.6%) than in hypointense HCCs (36.7%) (P = .039). The serum levels of AFP, Lens culinaris agglutinin reactive fraction of AFP, and PIVKA-II were lower in hyperintense than in hypointense HCCs (P = .003, .004, and .026, respectively). Immunohistochemical AFP and PIVKA-II expression were lower in hyperintense than in hypointense HCCs (both P < .001). The recurrence rate was lower in hyperintense than in hypointense HCCs (P = .039). CONCLUSION: The results suggest that hyperintense HCCs on gadoxetic acid-enhanced MR images are less aggressive than hypointense HCCs. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120226/-/DC1.

[Influence of body surface area on efficacy and safety of sorafenib in advanced hepatocellular carcinoma].

UNLABELLED: Some clinical studies confirmed the efficacy and safety of sorafenib in advanced hepatocellular carcinoma(HCC), for which the standard initial dose is 400 mg twice daily. However, it is unclear whether this dosage is tolerable for patients with a low body surface area(BSA). We retrospectively analyzed the difference in efficacy and safety of sorafenib between patients with low BSA and high BSA. METHOD: From July 2009 to June 2010, 64 patients with Child-Pugh grade A cirrhosis receiving sorafenib at 4 institutions were enrolled, and divided into two groups(BSA<1. 6m2 and ≥1. 6m2). RESULTS: In BSA<1. 6m2 and BSA≥1. 6m2 groups, grade 3-4 adverse events were observed in 64. 3% and 55. 3% of patients, respectively, and subsequent discontinuation was 38. 5% and 24. 2%, respectively indicating poor compliance in the former group. The disease control rate was 33. 3% and 37. 8%, the median time-to-radiological progression(TTRP)was 2. 1 months and 3. 6 months(p=0. 003), and median survival time was 6. 6 months and 11. 2 months in low BSA and high BSA groups(p=0. 10), respectively. Multi-variate analysis showed that poor prognostic factors for TTRP were ECOG performance status of ≥1 and BSA<1. 6m2. CONCLUSION: Standard dosage seems intolerable for patients with low BSA, and results in poor prognosis.

Selective induction hyperthermia following transcatheter arterial embolization with a mixture of nano-sized magnetic particles (ferucarbotran) and embolic materials: feasibility study in rabbits.

PURPOSE: To evaluate the possibility of selective hyperthermia following transcatheter arterial embolization (TAE) with ferucarbotran using a newly developed inductive heating (IH) device. MATERIALS AND METHODS: Twelve Japanese white rabbits were separated into four groups: those treated with TAE using a mixture of ferucarbotran and lipiodol (F-L group); those treated with ferucarbotran and gelatin sponge powder; those treated with saline and lipiodol; and a control group. These four groups received IH. Nine rabbits with renal VX2 carcinoma were separated into three groups: IH after TAE (IH-TAE tumor), TAE without IH (TAE tumor), and no treatment (control tumor). The temperature of the tumor was kept at 45 degrees C for 20 min. The therapeutic effect was pathologically evaluated by TUNEL staining. RESULTS: In the heating rates of the kidney, the F-L group showed significantly greater values than the group in which iron was not used. In the IH-TAE tumor group, tumors could be selectively heated. In TUNEL staining, the IH-TAE tumor and TAE tumor groups showed significantly greater values of apoptosis rate than in the control tumor group. CONCLUSION: IH following TAE with a mixture of ferucarbotran and lipiodol was capable of inducing selective hyperthermia with our device. However, further investigation is needed to confirm its safety and effectiveness in the treatment of malignant neoplasms in humans.

In vitro screening of exogenous factors for human neural stem/progenitor cell proliferation using measurement of total ATP content in viable cells.

One of the newest and most promising methods for treating intractable neuronal diseases and injures is the transplantation of ex vivo-expanded human neural stem/progenitor cells (NSPCs). Human NSPCs are selectively expanded as free-floating neurospheres in serum-free culture medium containing fibroblast growth factor 2 (FGF2) and/or epidermal growth factor (EGF); however, the culture conditions still need to be optimized for performance and cost before the method is used clinically. Here, to improve the NSPC culture method for clinical use, we used an ATP assay to screen the effects of various reagents on human NSPC proliferation. Human NSPCs responded to EGF, FGF2, and leukemia inhibitory factor (LIF) in a dose-dependent manner, and the minimum concentrations eliciting maximum effects were 10 ng/ml EGF, 10 ng/ ml FGF2, and 5 ng/ml LIF. EGF and LIF were stable in culture medium without NSPCs, although FGF2 was degraded. In the presence of human NSPCs, however, FGF2 and LIF were both degraded very rapidly, to below the estimated minimum concentration on day 3, but EGF remained above the minimum concentration for 5 days. Adding supplemental doses of each growth factor during the incubation promoted human NSPC proliferation. Among other supplements, insulin and transferrin promoted human NSPC growth, but progesterone, putrescine, selenite, D-glucose, and lactate were not effective and were cytotoxic at higher concentrations. Supplementing with conditioned medium from human NSPCs significantly increased human NSPC proliferation, but using a high percentage of the medium had a negative effect. These findings suggest that human NSPC culture is regulated by a balance in the culture medium between decreasing growth factor levels and increasing positive or negative factors derived from the NSPCs. Thus, in designing culture conditions for human NSPCs, it is useful to take the individual properties of each factor into consideration.