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Recent publications provided controversial results indicating that perioperative heparin bridging anticoagulation (HBA) increased the bleeding risk without decreasing the thromboembolic risk in patients undergoing minor surgery. To investigate if this is also the case in high-risk patients undergoing major abdominal malignancy surgery, we retrospectively collected data of 3268 patients over a 10-year period. After the interruption of preoperative antithrombotic agents, HBA was initiated with a prophylactic-dose of unfractionated heparin in 133 patients (HBA group), and 62 patients did not receive HBA (non-HBA group). The incidence of exogenous blood transfusion (EBT) and thromboembolic events (TEEs) within 30 days after surgery were compared between the HBA and non-HBA groups. The results showed that the incidence of EBT and TEEs was similar between the two groups (23.3 vs 19.4 %; P = 0.535) and (4.1 vs 3.2 %; P = 0.821), respectively. The amount of intraoperative bleeding and the length of postoperative hospital stay were also similar [median (quantile 1-3); 192 (71-498) vs 228 ml (100-685); P = 0.422] and [12 (9-19) vs 14.5 days (10-21); P = 0.052], respectively. These findings may suggest it is unlikely that prophylactic-dose HBA affects bleeding and thromboembolic risks in patients undergoing major abdominal malignancy surgery.

Purpose: In the present study, we aimed to describe the surgical results of single-port laparoscopic stoma creation in our institution., Methods: We examined the safety of the surgical procedure and short-term results in 10 consecutive patients who underwent single-port laparoscopic stoma creation at our hospital between April 2011 and July 2013., Results: The median age of the patients was 60.5 (range, 31-75) years. Five patients were men, and 5 were women. There were 5 cases of colorectal cancer, 2 each of extramammary Paget's disease and uterine cancer, and one of perineal neurofibroma. Eight surgeries were performed for bowel obstruction or stenosis, and two surgeries were performed for other reasons. The median operative time was 59.5 (range, 40-91) min, blood loss volume was 0 (range, 0-10) mL, postoperative duration before commencement of oral intake was 2.5 (range, 1-4) days, and duration of postoperative hospital stay was 11(range, 5-19) days. No short-term complications were noted after the surgery., Conclusion: Single-port laparoscopic stoma creation appears to be feasible in terms of safety and short-term surgical results, and may improve the quality of life of patients requiring fecal diversion.

Recent studies have identified myeloid-derived suppressor cells (MDSCs) that are potent suppressors of tumor immunity and therefore a significant impediment to cancer immunotherapy. It has been reported that MDSCs are generated by malignant diseases or inflammation. However, no systematic studies in patients have been described. In order to clinically characterize MDSCs, we tested PBMCs from patients with various types of cancer including cholangiocellular, hepatocellular and pancreatic carcinoma, esophageal, gastric and colorectal cancer, breast cancer and thyroid cancer, and GIST, and those from normal volunteers using flow cytometry analysis. A significant increase was seen in the percentages of MDSCs in PBMCs from patients compared with normal volunteers. Among these patients, MDSC level was higher in patients with cancer of the digestive system and patients with breast cancer compared with normal volunteers. MDSC level was significantly and inversely correlated to stimulation indices (SI) of PHA-blastogenesis of lymphocytes and serum concentration of total protein, and positively correlated to neutrophil count. MDSC percentage in patients with gastric and colorectal cancer was also significantly correlated to neutrophil count and inversely correlated with lymphocyte count, and showed highly significant correlation to neutrophil/lymphocyte rate (NLR). In patients with breast cancer, MDSC levels in preoperative patients was significantly increased compared to normal volunteers and significantly decreased in postoperative patients. Thus, it is clear that MDSCs are increased in patients with cancer and closely related to suppression of cell-mediated immune responses. These data also suggest that they are related to chronic inflammation and that their levels are increased further in the terminal stages of patients whose nutritional status is impaired as observed in hypoproteinemia. MDSC levels have also been shown to decrease after removal of tumors in patients with breast cancer.

Purpose: Little research has been done on supportive needs of cancer patients in acute hospitals in Japan. This study aims to comprehensively assess the unmet supportive needs of hospitalized cancer patients, as well as literacy and utilization of appropriate professional care., Methods: All cancer patients (aged 20 to 80 years) who were hospitalized in a university hospital in Tokyo during the designated 3-day period between September 1 and October 31, 2007 were recruited for participation in the study. The M.D. Anderson Symptom Inventory, Brief Cancer-Related Worry Inventory, and Hospital Anxiety and Depression Scale were administered. Patients' knowledge and use of relevant services were evaluated. The results were compared with those of non-cancer patients in the same treatment settings., Results: A total of 125 cancer patients and 59 non-cancer patients were enrolled. Cancer patients and non-cancer patients equally suffered from physical symptoms (15-26% had severe appetite loss, 18-19% had severe dry mouth, and 16-22% had severe pain); however, psychological distress of cancer patients exceeded that of non-cancer patients (28.0% vs 8.5%; p ≤ 0.05). Severe psychological distress was associated with severe worry about future prospects or interpersonal and social issues and presence of two or more severe symptoms. Two thirds of the patients with severe psychological distress knew about the psychiatric division, but only one third actually sought treatment., Conclusions: Needs related to psychological issues were more prevalent among cancer patients than among non-cancer patients, despite a similar level of physical distress. Special attention should be paid to cancer patients who worry over future prospects or interpersonal and social issues, and those who have two or more severe symptoms.

The highest barriers for non-viral vectors to an efficient in vivo gene transfection would be (1) non-specific interaction with biological molecules, and (2) large size of the DNA complex particles. Protective coating of the DNA/polyethyleneimine (PEI) complexes by hyaluronic acid (HA) effectively diminished the adverse interactions with biological molecules. Here we found HA also protected the DNA/PEI complexes against aggregation and inactivation through lyophilization-and-rehydration procedures. It allows us to prepare the concentrated very small DNA complex particles (<70 nm) suspension by preparing the complexes at highly diluted conditions, followed by lyophilized-and-rehydrated to a small volume. In vivo gene expression efficiency of the small complex was examined with mice subcutaneously inoculated with B16 melanoma cells. These formulations showed high reporter-gene expression level in tumor after intravenous injection into tumor-bearing mice. Small complex was then made of the plasmid encoding GM-CSF gene, and injected into the mice bearing subcutaneous solid B16 tumor. After intravenous injection, it induced apparent tumor growth suppression in 50% of the mice. Notably, significant therapeutic effect was detected in the mice that received intratumoral injection, and 75% of the mice were completely cured with disappearance of tumor., (2010 Elsevier Ltd. All rights reserved.)

A long-term goal of cancer diagnosis is to develop tumor-imaging techniques that have sufficient specificity and sensitivity. To achieve this goal, minimizing the background signal originating from nontarget tissues is crucial. Here we achieve highly specific in vivo cancer visualization by using a newly designed targeted 'activatable' fluorescent imaging probe. This agent is activated after cellular internalization by sensing the pH change in the lysosome. Novel acidic pH-activatable probes based on the boron-dipyrromethene fluorophore were synthesized and then conjugated to a cancer-targeting monoclonal antibody. As proof of concept, ex vivo and in vivo imaging of human epidermal growth factor receptor type 2-positive lung cancer cells in mice was performed. The probe was highly specific for tumors with minimal background signal. Furthermore, because the acidic pH in lysosomes is maintained by the energy-consuming proton pump, only viable cancer cells were successfully visualized. The design concept can be widely adapted to cancer-specific, cell surface-targeting molecules that result in cellular internalization.

Purpose: Epidermal growth factor receptors (EGFR) play an important role in tumorigenesis and, therefore, have become targets for new molecular therapies. Here, we use a "cocktail" of optically labeled monoclonal antibodies directed against EGFR-1 (HER1) and EGFR-2 (HER2) to distinguish tumors by their cell surface expression profiles., Experimental Design: In vivo imaging experiments were done in tumor-bearing mice following s.c. injection of A431 (overexpressing HER1), NIH3T3/HER2+ (overexpressing HER2), and Balb3T3/DsRed (non-expression control) cell lines. After tumor establishment, a cocktail of optically labeled antibodies: Cy5.5-labeled cetuximab (anti-HER1) and Cy7-labeled trastuzumab (anti-HER2) was i.v. injected. In vivo and ex vivo fluorescence imaging was done. For comparison with radionuclide imaging, experiments were undertaken using (111)Indium-labeled antibodies. Additionally, a "blinded" diagnostic study was done for mice bearing one tumor type., Results: In vivo spectral fluorescent molecular imaging of 14 mice with three tumor types clearly differentiated tumors using the cocktail of optically labeled antibodies both in vivo and ex vivo. Twenty-four hours after injection, A431 and NIH3T3/HER2+ tumors were detected distinctly by their peak on Cy5.5 and Cy7 spectral images, respectively; radionuclide imaging was unable to clearly distinguish tumors at this time point. In blinded single tumor experiments, investigators were able to correctly diagnose a total of 40 tumors., Conclusion: An in vivo imaging technique using an antibody cocktail simultaneously differentiated two tumors expressing distinct EGFRs and enabled an accurate characterization of each subtype.

Goal: Although the importance of the palliative care team (PCT) to university hospitals is widely accepted, the issues of palliative care at the national level have not been clarified. We conducted a nationwide survey of the current status of PCTs in all (123) Japanese university hospitals., Materials and Methods: In 2003, 2004 and 2005, the authors conducted a self-reporting cross-sectional survey. Questionnaires were mailed to nursing directors and selected PCT members of all Japanese university hospitals., Results: Of 123 hospitals in 2005, 99 (80%) returned the questionnaire; 33% used PCTs, and 11% used certified PCTs. Our findings include: annual number of patients treated by PCTs (83/70 +/- 64, mean/median +/- SD), daily number of patients treated by PCTs (12/11 +/- 14), and days of PCT care per patient (30/30 +/- 22). Certified PCTs treated more patients per year (p = 0.004) and more patients per day (p < 0.001) compared to noncertified PCTs. Over the 3-year period, the number of hospitals utilizing PCTs only slightly increased (2003: 27%, 2004: 29%, 2005: 33%), as did those using certified PCTs (2003: 3%, 2004: 9%, 2005: 11%). In 2005, the reasons for noncertification of PCTs included "lack of physicians who specialize in palliative care (82%)" and "lack of nurses who specialize in palliative care (56%).", Conclusions: The entire system of palliative care in Japanese university hospitals is currently insufficient. The lack of physicians and nurses who specialize in palliative care is a significant barrier, and therefore, the initiation of a formal training system for these health care professionals is a high priority issue.

Beta-galactosidase is a widely used reporter enzyme, but although several substrates are available for in vitro detection, its application for in vivo optical imaging remains a challenge. To obtain a probe suitable for in vivo use, we modified our previously developed activatable fluorescence probe, TG-betaGal (J. Am. Chem. Soc. 2005, 127, 4888-4894), on the basis of photochemical and photophysical experiments. The new probe, AM-TG-betaGal, provides a dramatic fluorescence enhancement upon reaction with beta-galactosidase, and further hydrolysis of the ester moiety by ubiquitous intracellular esterases affords a hydrophilic product that is well retained within the cells without loss of fluorescence. We used a mouse tumor model to assess the practical utility of AM-TG-betaGal, after confirming that tumors in the model could be labeled with an avidin-beta-galactosidase conjugate. This conjugate was administered to the mice in vivo, followed by AM-TG-betaGal, and subsequent ex vivo fluorescence imaging clearly visualized intraperitoneal tumors as small as 200 microm. This strategy has potential clinical application, for example, in video-assisted laparoscopic tumor resection.

In vivo optical imaging to enhance the detection of cancer during endoscopy or surgery requires a targeted fluorescent probe with high emission efficiency and high signal-to-background ratio. One strategy to accurately detect cancers is to have the fluorophore internalize within the cancer cells permitting nonbound fluorophores to be washed away or absorbed. The choice of fluorophores for this task must be carefully considered. For depth of penetration, near-infrared probes are ordinarily preferred but suffer from relatively low quantum efficiency. Although green fluorescent protein has been widely used to image tumors on internal organs in mice, green fluorescent probes are better suited for imaging the superficial tissues because of the short penetration distance of green light in tissue and the highly efficient production of signal. While the fluorescence properties of green fluorophores are well-known in vitro, less attention has been paid to their fluorescence once they are internalized within cells. In this study, the emission efficiency after cellular internalization of four common green fluorophores conjugated to avidin (Av-fluorescein, Av-Oregon green, Av-BODIPY-FL, and Av-rhodamine green) were compared after each conjugate was incubated with SHIN3 ovarian cancer cells. Using the lectin binding receptor system, the avidin-fluorophore conjugates were endocytosed, and their fluorescence was evaluated with fluorescence microscopy and flow cytometry. While fluorescein demonstrated the highest signal outside the cell, among the four fluorophores, internalized Av-rhodamine green emitted the most light from SHIN3 ovarian cancer cells both in vitro and in vivo. The internalized Av-rhodamine green complex appeared to localize to the endoplasmic vesicles. Thus, among the four common green fluorescent dyes, rhodamine green is the brightest green fluorescence probe after cellular internalization. This information could have implications for the design of tumor-targeted fluorescent probes that rely on cellular internalization for cancer detection.

In order to identify the risks, methods and locations of suicide among Japanese cancer patients, we followed up 23,979 cancer patients aged 15 years and older, who were newly diagnosed at one medical center between 1978-94. Suicide risk was evaluated by comparing the observed number (O) with the expected number (E), which was calculated from the suicide mortality rate among Osaka residents. By the end of 1994, there were 48 suicide death among 109,374 person-years of follow-up. Suicide risk was significantly increased within the first five years following cancer diagnosis (male: O/E=1.62, 95% confidence interval (CI)=1.03-2.43, female: O/E=2.13, 95% CI=1.22-3.47), and decreased to unity after five years had elapsed following the cancer diagnosis. Patients in their fifties (O/E=1.93, 95% CI=1.48-4.37), diagnosed between 1978-85 (O/E=1.93, 95% CI=1.19-2.95), having remote metastasis at their initial diagnosis (O/E=4.66, 95% CI=2.12-8.84), the site being in the female genital organs (O/E=3.58, 95% CI=1.54-7.06) or in the male genital organs (O/E= 5.86, 95% CI=1.58-15.05), had a significantly higher suicide risk within five years following cancer diagnosis. The highest suicide mortality was observed between the third and fifth months after cancer diagnosis (O/E=4.35, 95% CI=1.87-8.58); most of these suicides (7/8) occurred soon after discharge from hospital. Among the 39 patients who committed suicide within five years after their diagnosis, the most common method among those who took their lives while in hospital was by jumping to their death (10/16), and that among those who committed suicide in other locations was by hanging (14/23). These findings indicate that Japanese patients with cancer run the highest risk of suicide soon after having been discharged from hospital. Clinicians should assess cancer patients' psychological distress and potential risk of suicide before approving discharge from hospital.

A new fluorinated pyrimidine, TAC-278, was studied for its safety, anti-tumor activity and pharmacokinetics in patients with solid tumors of various types. Single oral administration was done in 43 patients with dose range of 50 to 1200 mg. These single administrations caused no side effects but nausea in only one patient daily given 900 mg. Repeated oral dose tolerance was assessed in 79 patients in daily doses of 100 to 1800 mg. Side effects were reported by 26 (33.3%) of the 79 patients. Major side effects were mild gastrointestinal symptoms. The maximum tolerated dose was considered to be 1200 mg/day, over which CNS symptoms as dose limiting factor for TAC-278 developed in some patients. As to the therapeutic effect, minor response was obtained in 2 of the 24 evaluable patients. Concentration of 5-FU in body fluid and tumor tissues were high following oral administration of TAC-278, but the disappearance was relatively rapid. Excretion of TAC-278 occurred predominantly in urine.

CAM is a derivative compound of mycophenolic acid produced by Penicillium brevicompactum, and is a new oral Purine antagonistic anticancer agent. The Phase I study was carried out cooperatively in ten hospitals. The results are as follows: The administration method was single administration and the starting dose was 200 mg/m2 (1n). The dose level was escalated according to varied Fibonacci formula. The number of total cases was thirty-one: three cases at 1n level, four at 2n, six at 3.3n, six at 7n and seven at 9n. Side effects were observed in five of thirteen cases over 7n dose levels, such as nausea, vomiting, anorexia and diarrhea. Leukopenia was developed in only one case at 7n dose level. Other side effects such as anemia, thrombocytopenia, and disturbances of liver function and renal function were not observed. It was estimated from above results that a dose limiting factor of CAM is nausea and vomiting. A subtoxic dose was 7n (1,400 mg/m2) and a maximum tolerated dose was 9n (1,800 mg/m2) which corresponded to 2,200-3,000 mg as a single administration.

A Phase II Study of (2''R)-4'-O-tetrahydropyranyladriamycin (THP) in patients with various solid tumors was carried out by 44 cooperative study institutions. Seven hundred fifty-six patients administered the drug intravenously were entered into this study. Of these, 499 patients were evaluated for objective responses. THP was given mainly at a dose of 40 to 60 mg/body every 3 to 4 weeks or 20 to 30 mg/body once a week. Response rates were 18.8% for head and neck cancer, 13.1% for stomach cancer, 21.4% for breast cancer, 22.2% for bladder cancer, 30% for renal pelvic and urinary tract tumor, 26.8% for ovarian cancer and 24.2% for uterine cancer. Overall response rate was 15.4% including 10 complete responses and 67 partial responses. Adverse reactions were similar to those previously reported in the phase I study, including gastrointestinal toxicities and myelosuppression. Alopecia and stomatitis, which are major side effects of other anthracyclines, were rather mild. Incidence of ECG changes was 2.8% and no congestive heart failure was observed.

A phase I trial of a new anthracycline derivative, 4'-O-tetrahydropyranyldoxorubicin (THP), was conducted in 54 patients with various advanced solid tumors and malignant lymphomas. Starting dose was 5 mg/m2 i.v. and dose escalations were made by a modified Fibonacci search scheme. There were 40 evaluable courses. The dose-limiting toxic effect was leukopenia which was dose-related and reversible. The maximum tolerated dose for a single i.v. injection was estimated to be 55 mg/m2. The median nadir day for leukopenia was day 12 with recovery occurring 13 days (median) after reaching the nadir. Thrombocytopenia was less commonly observed than leukopenia. Other toxic effects were mild gastrointestinal disturbances, fever and general malaise. Ventricular extrasystole was observed in a case of pancreatic cancer who received 5 mg/m2 of the drug. There were no cases with alopecia, or with hepatic or renal dysfunction. With regard to objective tumor response, CR was observed in 2 cases with NHL, and MR in 2 cases with lung cancer, and 1 case each with breast cancer and NHL. Response occurred at a dose of more than 35 mg/m2. The recommended dose schedule for phase II trial is 35-45 mg/m2 by single i.v. injection at 3-4-week intervals.

A phase I study of a new fluorinated pyrimidine, 1-hexylcarbamoyl-5-fluorouracil (HCFU), was performed by a multi-institutional clinical study group using a total of 111 patients with histologically proven malignancies. The characteristic toxic effects were a transient hot sensation and pollakiuria, which occurred 15-120 minutes after oral administration of the drug, continued for 30 minutes to 4 hours, and subsided spontaneously. Gastrointestinal disturbances such as nausea, vomiting, diarrhea, and anorexia, which are common with 5-FU administration, also occurred with HCFU but did so less frequently. The maximum tolerated dose for a single oral administration was estimated to be between 12 and 15 mg/kg and the optimal daily dose for continuous administration was considered to be between 9 and 18 mg/kg, with divided daily administration. Fifty-seven patients received 5-19 mg/kg/day of HCFU for > 4 weeks, including 31 patients with > 60 days' treatment. Cumulative doses were from 9.5 to 166.2 g, with a mean of 26.3 g. Hematopoietic toxicity was slight and hepatic toxicity was questionable. No renal or other cumulative toxicity was observed. In ten of the 57 patients, favorable clinical effects were seen: an active decrease in the size of the solid tumor (three patients), the disappearance of ascites (six), and the improvement of intestinal obstruction due to peritoneal carcinomatosis (one).

The pharmacokinetic properties of THP and ADM were comparatively studied in the same patients with various cancers. The concentration of ADM in either plasma or blood cells was higher than that of THP from 5 minutes to 24 hours after administration. The metabolites of ADM such as aglycones were detected in plasma until 3 hours after administration, but these were never detected in blood cells. By contrast, the metabolites of THP were detected until 24 hours after administration. These results suggested that THP was metabolized in tissues and excreted into urine and that the rate of metabolism and excretion of THP was faster than that of ADM. Distribution volumes (V1, V2, and V3) of THP were larger than those of ADM. The above results strongly suggested that THP would be easily transferred into the tissues, but that in the case of slower transferring tissues with lower K13 values, ADM rather than THP would be easily transferred to the tissues. These pharmacokinetic properties suggested that the toxicity of THP might be diminished compared with that of ADM.

A phase II study of a new fluoropyrimidine antitumor agent, carmofur (HCFU) fine granules, was performed in 24 institutions. The eligibility of patients and the criteria of response evaluation were based on the "Japanese Criteria for Evaluation of Clinical Effects of Cancer Chemotherapy on Solid Tumors." Out of 119 patients entered in the study, 65 patients were evaluable: 63 patients among them had measurable or evaluable lesions. Positive responses better than PR (Partial Response) were obtained in five (17.9%) out of 28 patients with gastric cancer, four (36.4%) out of 11 patients with colorectal cancer and five (45.5%) out of 11 patients with breast cancer. The total positive response rate was 22.2%. Optimal doses for the clinical use were ranged from 9 to 18mg/kg, and the median duration of PR was 19.6 weeks. In addition to the similar gastrointestinal toxicities observed in other fluoropyrimidines, hot sensation, pollakiuria and frequent defecation were seen in 12.4%, 10.1% and 3.4% of patients, respectively.

Phase I study of a new antitumor antibiotic, neothramycin which belongs to anthramycins was performed by a cooperative study group involving 15 major institutions. A total of 63 cases including 42 various solid tumors and 21 hematologic tumors refractory to standard treatments underwent the study during June 1979 to June 1981. Doses of single injection were escalated from an initial dose of 2 mg/m2 estimated by one twentieth of LD10 in mice up to 60 mg/m2. The most frequent and severest toxicity was nausea and vomiting seen in about the half of patients being administered dosages ranged from 24 mg/m2 to 40 mg/m2, and 3 out of 4 patients received dosages exceeding 50 mg/m2 required clinical managements; moreover, 1 out of 2 patients administered 60 mg/m2 was ranked as grade 4 of the criterion of toxicities in WHO handbook. Other clinical toxicities such as skin rash, hepatotoxicity or nephrotoxicity observed in the minority of the patients were reversible. Furthermore, hematologic toxicity was extremely mild and appeared not to be dose dependent. One patient with chronic myelogeneous leukemia had a hematological improvement and the other with esophageal cancer had a partial response. The result indicates that a dose limiting factor of neothramycin is nausea and vomiting, and a maximum tolerated dose of a single injection is 60 mg/m2. A dose schedule of 30-40 mg/m2 appears to be an optimal dose for Phase II study.