Author Correction: Normothermic Microwave Irradiation Induces Death of HL-60 Cells through Heat-Independent Apoptosis.

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Normothermic Microwave Irradiation Induces Death of HL-60 Cells through Heat-Independent Apoptosis.

Microwaves have been used in various cancer therapies to generate heat and increase tumor cell temperature; however, their use is limited by their side-effects in normal cells and the acquisition of heat resistance. We previously developed a microwave irradiation method that kills cultured cancer cells, including a human promyelomonocytic leukemia (HL-60) cell line, by maintaining a cellular temperature of 37 °C during treatment. In the present study, we investigated the mechanisms underlying HL-60 cell death during this treatment. The microwave-irradiated HL-60 cells appear to undergo caspase-independent apoptosis, whereby DNA fragmentation was induced by mitochondrial dysfunction-related expression of apoptosis-inducing factor (AIF). Caspase-dependent apoptosis was also interrupted by the loss of apoptotic protease-activating factor 1 (Apaf-1) and caspase 9. Moreover, these cells did not exhibit a heat-stress response, as shown by the lack of heat shock protein 70 (HSP70) upregulation. Alternatively, in HL-60 cells heated at 42.5 °C, HSP70 expression was upregulated and a pathway resembling death receptor-induced apoptosis was activated while mitochondrial function was maintained. Collectively, these results suggest that the cell death pathway activated by our 37 °C microwave irradiation method differs from that induced during other heating methods and support the use of normothermic microwave irradiation in clinical cancer treatments.

Effects of Normothermic Conditioned Microwave Irradiation on Cultured Cells Using an Irradiation System with Semiconductor Oscillator and Thermo-regulatory Applicator.

We investigated the effects of microwave irradiation under normothermic conditions on cultured cells. For this study, we developed an irradiation system constituted with semiconductor microwave oscillator (2.45 GHz) and thermos-regulatory applicator, which could irradiate microwaves at varied output powers to maintain the temperature of cultured cells at 37 °C. Seven out of eight types of cultured cells were killed by microwave irradiation, where four were not affected by thermal treatment at 42.5 °C. Since the dielectric properties such as ε', ε" and tanδ showed similar values at 2.45 GHz among cell types and media, the degree of microwave energy absorbed by cells might be almost the same among cell types. Thus, the vulnerability of cells to microwave irradiation might be different among cell types. In HL-60 cells, which were the most sensitive to microwave irradiation, the viability decreased as irradiation time and irradiation output increased; accordingly, the decrease in viability was correlated to an increase in total joule. However, when a high or low amount of joules per minute was supplied, the correlation between cellular viability and total joules became relatively weak. It is hypothesized that kinds of cancer cells are efficiently killed by respective specific output of microwave under normothermic cellular conditions.

Management of obstructive colorectal cancer: evaluation of preoperative bowel decompression using ileus tube drainage.

PURPOSE: This study evaluated a better treatment for patients with obstructive colorectal cancer (CRC) that have a poor prognosis. METHOD: This study compared the outcomes of 138 patients with obstructive CRC, including 70 primary resections, 50 resections after bowel decompression using an ileus tube, and 18 delayed resections after colostomy. RESULTS: The ileus tube and delayed resection groups included more left-sided primary lesions. The physiologic POSSUM, types 3-4, tumor size, CEA, and hospital stay of the delayed resection group were different, in comparison to both the primary resection and ileus tube groups. The histopathological type and depth of invasion of the delayed resection group included less well types and more T4 than those of the ileus tube group. The operative blood loss of the delayed resection group was more than that of the ileus tube group. There were no differences in the overall and disease-free survival among the three groups. CONCLUSION: Separately analyzing the data of the right-sided cancer group and the left-sided cancer group demonstrated that primary resection might be acceptable for right-sided obstructive CRC and delayed resection might be done for patients with poorer general conditions (high PPS) and poorer oncological prognostic factors such as more type 3/type 4 cases, a larger tumor size, a less well-differentiated histopathological type, more T4 cases, and a higher CEA level.

Clinical impact of a macroscopically complete resection of colorectal cancer with peritoneal carcinomatosis.

BACKGROUND: So far, few reports have focused on the clinicopathological features and patterns of recurrence after a complete resection of peritoneal carcinomatosis (PC) of colorectal origin. The purpose of the present study was to show the clinicopathological features of a macroscopically complete resected tumor and the pattern of recurrence after the curative resection of colorectal PC. METHODS: In 153 patients with colorectal PC, 31 patients who underwent a complete resection of a synchronous primary lesion of a colorectal PC between 1998 and 2007 were assessed retrospectively. RESULTS: Clinicopathological differences were observed in the tumor location, presence of extraperitoneal metastases, extent of PC, and presence of lymph node metastases between a macroscopically complete resection and noncomplete resection patients (P = .045, P < .0001, P < .001, and P = .039, respectively). Tumor recurrence after the complete resection of colorectal PC was observed in 24 patients (77.4%). The 5-year survival rate after complete resection was 36.0%. The survival rate in the macroscopically complete resection group was higher than in the incomplete resection group (P < .001). The 5-year intra- and extraperitoneal recurrence survival rates were 63.9% and 33.8%, respectively. No significant clinicopathological factors affected intraperitoneal recurrence-free survival. Conversely, a univariate analysis using the log-rank test revealed that extended PC and presence of lymph node metastases were poor factors affecting extraperitoneal recurrence (P = .009 and P = .023, respectively). Eleven of 31 patients survived for 5 years after resection. Two of the 4 patients with liver metastases had received a hepatectomy. CONCLUSION: Although the 5-year survival rate after a macroscopically complete resection for colorectal PC approached 36.0%, 77.4% of patients developed intra- and extraperitoneal recurrence. Extended PC and presence of lymph node metastases were poor factors affecting extraperitoneal recurrence.

[Efforts toward qualitative and quantitative improvements of cancer clinical trials at regional designated cancer care hospitals-through full support for cancer clinical trials by oncology pharmacy specialist and data manager].

BACKGROUND: S-1, an oral fluoropyrimidine, is one of the standard chemotherapeutic agents for the treatment of metastatic gastric cancer(MGC). However, the most effective second-line regimen after failure of treatment with first-line agents such as S-1 is yet to be determined. The aim of this study was to investigate the various second-line chemotherapy regimens in MGC patients. METHODS: We retrospectively studied patients with MGC who received second-line treatment after failure of the first-line S-1 or S-1/cisplatin treatment. The overall survival times with each second-line regimen were determined using the Kaplan-Meier method, and the effect on overall survival was analyzed using Cox regression analysis. RESULTS: The median survival time for all patients was 14. 2 months(95% confidence interval(CI): 12. 88-15. 43 months)with a 1-year survival rate of 60. 4%. Kaplan-Meier analysis revealed that the second-line regimens containing irinotecan significantly improved the median survival time as compared to regimens without irinotecan(median survival time: 16. 5 and 13. 8 months, respectively). Cox regression analysis showed that irinotecan-containing regimens were associated with improved overall survival(hazard ratio: 0. 165; 95% CI: 0. 041-0. 665). CONCLUSION: The use of irinotecan-containing regimens as second-line chemotherapy after failure of first-line S-1 therapy may be beneficial for MGC patients.

A wound protector shields incision sites from bacterial invasion.

BACKGROUND: Superficial surgical site infection (SSI) can be caused by bacterial invasion during surgery. We investigated whether bacteria are found at the wound margin during surgery and whether a wound protector (WP; Alexis® Wound Retractor; Applied Medical, Rancho Santa Margarita, CA) contributes to preventing invasion of the incision margin. METHODS: We studied 272 patients who underwent gastrointestinal surgery (115 gastric, 157 colorectal, including emergency operations) between October 2005 and July 2007. The WP was used in all operations. After the intra-abdominal procedures were complete, bacterial swabs were taken from the abdominal cavity side of the WP and from the incision margin and used to prepare smears and cultures. After the swabbing, peritoneal lavage was performed using 3,000-5,000 mL of physiologic saline, and, after suture of the fascia, 500-1,000 mL of physiologic saline was used to irrigate the subcutaneous tissue. RESULTS: Nine gastric surgery patients and 15 colorectal surgery patients had positive cultures from the abdominal cavity. No patients had positive cultures from the incision margin. Of the 24 patients with positive cultures, three suffered SSIs, all of whom had undergone colorectal surgery. Of the patients who had negative cultures, SSI occurred in only one patient, who had undergone colorectal surgery. CONCLUSIONS: These results suggest that the WP protects an incision site from bacterial invasion.

A case of pathological complete response of advanced rectal cancer to preoperative chemoradiotherapy using S-1.

In patients with advanced rectal cancer, preoperative chemoradiotherapy is superior to postoperative chemoradiotherapy because of causing less toxicity and achieving higher rates of sphincter preservation and curative resection. We treated a patient who had advanced rectal cancer with preoperative chemotherapy using S-1 and concurrent radiotherapy. S-1 was orally administered at a dose of 100 mg/day during the first cycle (two-week on and one week off). During the third cycle, radiotherapy was initiated concurrently and a total dose of 45 Gy was given. The most severe adverse event was grade 3 leukopenia during the third cycle. On day 42 after completing radiotherapy, low anterior resection with diverting colostomy was performed. Histological examination found no viable cancer cells in the resected specimens, including the primary tumor site and lymph nodes. Thus, a pathological complete response was achieved. Postoperatively, anastomotic leakage occurred, but it was resolved with transanal drainage. Preoperative chemoradiotherapy using S-1 contributed to sphincter preservation and curative resection in this patient. This regimen was both effective and well-tolerated, suggesting that it could be useful for advanced rectal cancer.

[Construction of a system for proper TS-1 application].

TS-1 is an oral anti-tumor drug, which contains 5-chloro-2, 4-dihydroxypyridine (CDHP), a compound mainly excreted in urine. Since the CDHP concentration is increased among patients with impaired renal function, the frequency of side effects of TS-1 increases in such patients. Therefore, we constructed a computer-aided system that enables prompt monitoring of creatinine clearance (Ccr) calculated from the serum creatinine levels of patients prescribed TS-1 at the time pharmacists prepare the medicine. With this system, we found two cases who were prescribed TS-1, despite their decreased Ccr. One was a patient whose estimated Ccr was less than 30 mL/min/m2. With such renal malfunction, pharmacokinetics of the drug was considerably changed compared with normal control, and the dosage should be reduced. The other case presented with severe jaundice and had only a mild decrease of renal function (Ccr: 50 mL/min/m2). So we measured the concentration of uracil in the urine and performed a drug lymphocyte stimulation test for further investigation of concomitant affecting factors. Our system is useful because it can show pharmacists both the dosage TS-1 patients take and their renal function at a glance in real time. This system can be adapted for every medicine which might accumulate in patients with renal dysfunction.

The ratio between metastatic and examined lymph nodes is an independent prognostic factor for patients with resectable middle and distal bile duct carcinoma.

BACKGROUND: The lymph node ratio, defined as the ratio between the number of lymph node metastasis and the total number of lymph nodes examined, has been reported to be an important prognostic factor in other gastrointestinal carcinomas except middle and distal bile duct carcinomas. METHODS: Between 1991 and 2004, 62 consecutive patients who underwent surgery for middle and distal bile duct carcinoma were retrospectively analyzed concerning prognostic factors. RESULTS: The median number of lymph nodes examined was 12 (range 5 to 38). The overall 5-year survival rates of patients with lymph node ratio of 0, lymph node ratio of 0 to .2, and lymph node ratio >.2 were 62%, 41%, and 0%, respectively. A multivariate analysis revealed that a lymph node ratio >.2 and perineural invasion were independent predictive factors for survival. CONCLUSIONS: Lymph node ratio >.2 is an important factor to predict survival after resected middle and distal bile duct carcinoma.

Significance of urinary glucaric acid measurement and its application to paclitaxel therapy.

Individual variations in P-450 activity affect the in vivo pharmacokinetics as well as the efficacy and side effect of drugs. It is proposed that urinary glucaric acid (GA) level may indirectly represent P-450 activity and may therefore be an indicator of P- 450 activity in the clinical setting. However, no standard method has been developed so far. Metabolism of paclitaxel (PTX), an anticancer drug, is mediated by P-450. If P-450 activity could be predicted by measuring urinary GA level during PTX administration and individual blood PTX concentration could be inferred, urinary GA level would be a potent tool to predict the efficacy and side effects of the drug. We therefore measured the urinary GA levels of patients on antiepileptics that are suggested to induce P-450 and those of control subjects, to determine whether urinary GA level could be an indicator of P-450 activity. Then, we examined the relationship between urinary GA level and blood PTX concentration and looked into the possibility of predicting pharmacokinetics based on the relationship between urinary GA level and area under the blood concentration-time curve (AUC). The means+/-S. D. of urinary [(GA level)/(Cr level) x 10] levels of 16 patients on antiepileptic medication and 24 control subjects were 0. 98 mg/mL+/-0. 91 and 0. 19 mg/mL+/-0. 07, respectively. The urinary GA levels of patients on antiepileptic medication were significantly higher than those of control subjects. On the other hand, the relationship between AUC and urinary GA levels in eight patients on PTX showed that AUC tended to become large when urinary GA levels were low. The above results reveal that measuring urinary GA level by the easy and noninvasive way of urine collection would enable us to predict P-450 activity and infer blood PTX concentration.

Individual differences in rate-limiting reactions during metabolism of irinotecan hydrochloride.

UNLABELLED: Irinotecan hydrochloride (CPT-11) is converted to SN-38 by carboxylesterase, SN-38 is conjugated by UDP-glucuronosyl- transferase (UGT) to SN-38G. Individual differences in enzyme activity influence the efficacy of this anticancer agent and the adverse reactions it induces. In this study, individual differences in the metabolism of this drug were determined by calculating its c 1 on version (CPT-11 to SN-38) and conjugation ratios (SN-38 to SN-38G) from blood concentrations of CPT-11, SN-38, and SN-38G at immediately and 60 min after a 90-min intravenous infusion of CPT-11. Changes in conversion and conjugation during long-term infusion of CPT-11 were also investigated. The median conversion and conjugation ratios were 0.0155 and 2.812, respectively (n=48). Based on these values, the patients were classified into four types: low-low type (10.4%), low-high type (31.2%), high-low type (31.2%), and high high type (27.1%). Prolongation of infusion time resulted in an increase in the conversion ratio in the low-high type and an increase in the conjugation ratio in the high-low type. These changes, however, were very slight in the high-high type. Thus, a longer infusion time made it possible to increase the number of doses in the low-high type and minimize adverse reactions in the high-low type. CONCLUSION: In patients found to have a low SN-38 conversion ratio or SN-38G conjugation ratio based on simple assessment of data obtained by 2-point blood sampling, modification of infusion time may allow pharmacokinetic changes that confer a clinical benefit.

[Palliative care team in National Hospital Organization Osaka Minami Medical Center].

Preparation of a system of palliative care support is called for by The Basic Act on Anti-Cancer Measures and The Basic Plans for National Cancer Strategy. The Organization of Hospitals for Cancer Treatment should play a very important role in the regional palliative care network. The palliative care team in the Organization of Hospitals for Cancer Treatment should promote palliative care support throughout regional hospitals. In 2007, we established a palliative care team at the National Hospital Organization Osaka Minami Medical Center. We have drawn up a detailed report on the activities of palliative care team in our medical center.

Microwave cell death: molecular analysis using DNA electrophoresis, PCR amplification and TUNEL.

Microwave cell death (MCD) is unique in that microscopic morphology and antigenicity are well preserved, while enzymatic activity is lost. The aim of the present study was to carry out DNA electrophoresis, polymerase chain reaction (PCR) amplification and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) examination of MCD. DNA electrophoresis indicated only a thick band of large DNA immediately after microwave treatment, which became a smear 6 h later and indicated a delayed type of DNA degradation over 2 weeks. Neither a DNA smear characteristic of oncosis nor DNA ladder patterns characteristic of apoptosis were found in MCD. PCR of p53 in MCD showed a single band at the same level of control of non-microwave treated cells. MCD was negatively stained on TUNEL. These results provide further evidence that MCD is distinct from oncosis and apoptosis, in addition to showing unique morphological and antigenic preservation and enzymatic inactivation.

[Significance of urinary uracil measurement following administration of DPD inhibitory fluoropyrimidine(DIF)products].

Individual differences in 5-FU metabolism are mainly attributed to individual differences in the activity of DPD, an enzyme that can metabolize more than 85% of 5-FU. Because urinary uracil is a reflection of DPD activity, it is measured to predict and prevent the occurrence of side effects caused by pyrimidine-type chemotherapeutic agents. From urinary uracil values measured in 84 gastrointestinal cancer patients, 0-60 mmol/g.creatinine was set as a standard. In patients whose urinary uracil values exceeded the standard, 5-FU tended to be accumulated when S-1, a DIF product, was administered and side effects, such as anorexia, vomiting and diarrhea occurred immediately after the start of S-1 administration. If an appropriate DIF product is selected and its dosage set based on the patient's urinary uracil value, the occurrence of side effects would be reduced. Subsequently, a continuation of medication would be possible.

Assessment of liver function for successful hepatectomy in patients with hepatocellular carcinoma with impaired hepatic function.

BACKGROUND/PURPOSE: This study aimed to construct a formula for assessing liver function in order to prevent post-hepatectomy liver failure. METHODS: A formula was constructed by analyzing data from 28 patients with hepatocellular carcinoma (HCC) with liver cirrhosis operated on between 1981 and 1984. Next, we evaluated the validity of this formula in 207 hepatectomy patients operated on from 1985 to 1999. For 145 hepatectomy patients operated on from 2000 to 2006, this formula was calculated before surgery in order to assess their risk of hepatectomy. RESULTS: The formula for liver functional evaluation, constructed from preoperative hepatic function parameters, was: liver failure score = 164.8 - 0.58 x Alb - 1.07 x HPT + 0.062 x GOT - 685 x K. ICG - 3.57 x OGTT. LI + 0.074 x RW, where Alb is albumin (g/dl); HPT, hepaplastin test (%); GOT, glutamate oxaloacetate transaminase (U/l); K. ICG, K value of indocyanine green clearance test; OGTT. LI, 60-min/120-min glucose level in 75-g oral glucose tolerance test. linearity index of OGTT; and RW, weight of resected liver (g). We decided that a score below 25 would be safe for hepatectomy. CONCLUSIONS: The mortality rate decreased from 3.9% in 1985--1999 to 1.3% in 2000--2006. This finding allows us to conclude that the formula is valid for assessing the risk of post-hepatectomy liver failure.

[Study of a relationship between a change in the urinary uracil value after a S-1 long-term administration and the recurrence of stomach cancer].

S-1 has been reported good results in the treatment of stomach cancer. However, a DPD activity change has also been reported as one of the causes for a recurrence though some recurrence cases observing a state of tumor being unchanged continuously for more than 1 year. Therefore the urinary uracil value, which could simply be predicted in the DPD activity at the time of a recurrence after having administered S-1 for a long-term, was measured. And the urinary uracil value was examined whether it could become an index of recurrence compared with a healthy 5-person example as reference. In the result, a monthly difference in change of the urinary uracil values of the reference was small. However, the urinary uracil values in patients who were administered S-1 more than 6 months but recurred, were significantly lower comparing with the healthy 5-person example. We concluded from this study that the change in DPD activity due to an induction of DPD by 5-FU and metastasis of cancer caused the recurrence and lower a urinary value. The urinary uracil value reflecting DPD activity of the whole body could be used as an index of recurrence at the time of long-term dosage of S-1. Furthermore, a measurement of the urinary uracil value seems to be promising for estimation and evaluation of the cure.

Nonhepatocytic malignant mixed tumor of the liver in adults: report of a long surviving case.

A primary nonhepatocytic malignant mixed tumor in the liver contains both epithelial and mesenchymal components, and the incidence in adults is extremely rare. A 45-year-old female was admitted because of abdominal fullness. Abdominal imaging studies revealed a huge cystic tumor with a mural nodule in the right lobe. A right trisegmentectomy and an invaded partial diaphragm resection were performed. Diagnosis was established after surgery. The patient is still alive 11 years after surgery, and to our knowledge is the longest surviving patient with a primary nonhepatocytic malignant mixed primary tumor of the liver.

Laparoscopic resection for gastrointestinal stromal tumors of the stomach.

BACKGROUND: We reviewed our experience with primary gastrointestinal tumors (GISTs) after surgical treatment. METHODS: Between 1998 and 2003, 56 patients who underwent surgical treatment for primary GIST of the stomach were enrolled in this study. Statistical analyses of the risk factors for recurrence were assessed. RESULTS: The proportion of cases undergoing laparoscopic surgery was 25 of 56 (44%) in these retrospective data. The site of recurrence was only the liver in all cases. These recurrent cases were defined as high-risk category. Tumors measuring over 2 cm in size tended to recur earlier, namely within 32 months. A statistical analysis showed a statistically significant correlation between the disease progression and the pathological phenotype. CONCLUSIONS: This retrospective study has shown that an initial laparoscopic resection of gastric GISTs is feasible even when the tumor size is relatively small (2-5 cm). The pathological phenotype (especially tumor mitosis) directly correlates to the patient's survival even if the resected tumor size was relatively small.

[Determining S-1 dosage at hospitals prioritizing cancer chemotherapy].

Although it is recommended that the standard S-1 dosage should be based on how large the body surface area is, an on-site setting of the appropriate dosage is often lower than the standard one, depending on the individual's condition and considering possible side effects and so, on. Here, we investigated usage conditions for S-1 as a part of field training for expert pharmacists at our hospital that performs total clinical treatments. Decreases in dosage per day for elderly patients were although the standard dosage is generally determined according to the amount of a patient's body surface. We conducted a retrospective survey with a total 90 patients by creating a tree-diagram to identify a reduction standard. It was found that the S-1 dosage was decreased when there were side effects, aggravation in performance status, decrease in kidney function, old age, combined injection chemotherapy, and a decrease in radiation therapy performance. The dosage decreases without such medical reasons were seen in only 4 of the 90 patients. The individual target dosage on the basis of daily medical examination.