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Objective:It has been reported that akathisia is a neurological side effect induced by antiemetic drugs and/or antipsychotics. Akathisia can occur in any area of the body, but respiratory akathisia is an unusual type of akathisia. Cases of respiratory akathisia in cancer patients taking antiemetic drugs have not previously been reported.Methods:We report on a case of a cancer patient taking prochlorperazine as an antiemetic drug who experienced dyspnea accompanied by severe restlessness associated with respiration. By administration of biperiden, his restlessness in respiration and dyspnea promptly disappeared.Results:This finding led us to conclude that this cancer patient was experiencing respiratory akathisia.Significance of results:Respiratory akathisia is uncommon. It is important for cancer patients that dyspnea induced by disease progression be ruled out as a cause of the respiratory restlessness. It is necessary to consider the possibility of akathisia in patients that complain of vague anxiety, chest discomfort, or dyspnea following antipsychotic medication.

In the companion Part 1 paper, the jet breakup model incorporated into the VESUVIUS code was described. Herein, initial verification of the VESUVIUS jet breakup modeling by comparison of calculation results against the PREMIX PM10 and FARO L-14 experimental data is discussed. Predictions of the main experimental parameters, which include steam outlet flow rate and “interaction region” development for the PREMIX test and test vessel pressure and level swell for the FARO test, are shown to be in good agreement with the test data. In addition, the change with time of the jet axial profile and two-dimensional spacial distributions of the jet and coolant, which are not available as experimental data, are discussed in an attempt to further clarify molten jet behavior.

To investigate the hypothesis that 5-alpha-reductase inhibitors exert early ameliorative effects on voiding and storage symptoms in men with lower urinary tract symptom-associated benign prostatic hyperplasia.This was a prospective study involving the participation of eight outpatient clinics in Chiba Prefecture, Japan. The patients received dutasteride (0.5 mg) once daily orally for 24 weeks as an add-on to their ongoing therapy with an alpha-1 blocker. The study patients recorded their urinary symptoms every day for 14 days after starting dutasteride. The International Prostate Symptom Score, prostate volume, uroflowmetry results, and residual urine volume were checked at 3 and 6 months after starting dutasteride.A total of eighty-eight patients participated in the present study; 74 were eligible for analysis of the early effects of dutasteride. The median age was 69.6 years (range 54-89), the median prostate volume was 50.3 mL (range 24.7-103.3) and the median International Prostate Symptom Score was 17.6 (range 8-35). The proportion of patients with International Prostate Symptom Score improvements (≥3 points, or ≥25%) or 3 points or more decreased International Prostate Symptom Score were defined effective, 37 (50.0%) and 47 (63.5%) experienced improvement at 1 month after administration, respectively.This is the first prospective clinical study to show the early beneficial effects of 5-alpha-reductase inhibitors for lower urinary tract symptom-associated benign prostatic hyperplasia. Patients with severe symptoms were found to be responsive to dutasteride. The influence of the placebo effect was not denied. Further study is necessary.

A 62-year-old man with pancreatic body cancer underwent distal pancreatectomy without adjuvant gemcitabine(GEM). Because the pancreatic cancer recurred 4 months after surgery, however, he was treated with combination chemotherapy(S- 1+GEM at 750mg/m2). Unfortunately, this combination regimen was ineffective; therefore S-1 was withdrawn and full-dose GEM was administered as second-line treatment. One year of full-dose GEM showed a significant clinical benefit, completely eliminating multiple pulmonary metastases even after a 3-month suspension of chemotherapy. Our findings suggest that GEM monotherapy is a useful mainstream treatment for advanced pancreatic cancer.

A generalized inference engine which takes charge of application of dam operational regulations is designed for a synthesized reservoir control support system. First, the common expression and logical mechanics of operational regulations established for dam reservoirs in Japan are extracted. Second, an inference engine which can treat these logics such as the mutual reference among the provisions of regulations is explored. The system designed here enables us to accommodate each provision of dam operational regulations into a rule as it is, which will be a useful tool not only for inference itself but for providing support information.

Background Pathological complete response (pCR) with neoadjuvant chemotherapy (NAC) has been regarded as a surrogate endpoint for disease-free survival (DFS) and overall survival (OS) of patients with breast cancer. No consensus regarding the definition of pCR has been established; there are several definitions according to a variety of classifications. Eradication of cancer cells in both breast and lymph nodes has been better associated with improved prognosis than in the breast alone. Even in patients diagnosed as having clinically node-negative cancer before NAC, postoperative pathological examination often shows axillary lymph node metastases. Patients and Methods Of the 771 patients with breast cancer who underwent NAC in the Cancer Institute Hospital between January 2000 and May 2009, 146 patients preoperatively diagnosed as having node-negative breast cancer were retrospectively evaluated. We have made the definition of clinically lymph node-negative (N0) as follows: first, ultrasonography before NAC did not show any lymphadenopathy. Second, a cytological procedure confirmed negative study for each patient when ultrasonography suggested lymphadenopathy. Results The median observation period was 79.7 months, and the median age of the subjects was 51 years. Pathological examination at the time of the surgery showed lymph node metastases (ypN+) in 46 patients (31.5%). Histological therapeutic effects revealed ypT0/is in 9 patients (6.2%) and ypTinv in 137 (93.8%). Multivariate analysis demonstrated that younger age (49>), large tumor size, NG3, and ypN+ were significant poor prognostic factors for DFS (p = 0.020, p = 0.008, P = 0.022 and p = 0.010, respectively). Moreover, ypN+ was the only significant poor prognostic factor for OS (p = 0.022). The predictive factors of ypN+ in clinically lymph node–negative breast cancer were ypTinv (p = 0.036) and the luminal type (HR+ and HER2-) (p = 0.029). Conclusion The prognosis of clinically lymph node negative breast cancer depended on ypN+, which was associated with ypTinv and luminal subtype.

BACKGROUND: In neoadjuvant chemotherapy (NAC) for early breast cancer, the pathological response rate in estrogen receptor (ER)-positive tumors has been low in comparison with those of ER-negative tumors. Therefore, surrogate makers other than the pCR rate are needed during NAC for luminal breast cancer. Using MRI, we analyzed the patterns of tumor shrinkage after NAC as a surrogate prognostic factor in low grade luminal breast cancer. METHODS: Of 854 patients who had received NAC in a single institute from Jan. 2000 to Dec. 2009, 183 patients with low grade luminal breast cancer were retrospectively evaluated for this study. They were defined as ER and/or PgR positive in more than 10% of cancer cells and HER2 negative (IHC 0, 1+ or FISH Citation Format: Fukada I, Araki K, Kobayashi K, Gomi N, Horii R, Akiyama F, Takahashi S, Iiwase T, Ohno S, Ito Y. The pattern of tumor shrinkage is associated with prognosis in low grade luminal early breast cancer during neoadjuvant chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-02-13.

546 Background: Diabetes mellitus is one of the major risk factor for renal cell carcinoma (RCC) development. Although, in various cancers, the relationship between diabetes mellitus and worse prognosis is pointed out, the association between RCC prognosis and diabetes mellitus is under discussion. We sought to determine the association between diabetes mellitus with outcome of sunitinib treatment in metastatic RCC (mRCC) patients. Methods: A retrospective study of sunitinib-treated mRCC patients was performed. 69 patients who had been treated with sunitinib in Japanese two institutions (Teikyo University Chiba Medical Center and Chiba University) were entered. Kaplan-Meier and the log-rank test were performed to investigate the association between the pretreatment status of diabetes mellitus and the outcome of the patients who received the treatment with sunitinib. Results: Between 2008 and 2015, 69 mRCC patients were treated with sunitinib. 53 (76.8%) patients received sunitinib treatment as the first line molecular target drug. 15 (21.7%) patients were diagnosed as diabetes mellitus at the time of sunitinib treatment. Median time to treatment failure (TTF) was 7.1 months, cancer specific survival (CSS) was 33.9 months for all patients. With regard to TTF, there was no difference between diabetic and non-diabetic patients, 9 months for diabetic patients and 7.1 months for non-diabetic patients respectively (P = 0.3271). CCS was significantly shorter for diabetic patients, 11 months for diabetic patients and 39.4 months for non-diabetic patients respectively (P = 0.0469). When focusing on HbA1c, CSS was significant longer for the patients with HbA1c under 6.5% than the patients with HbA1c was 6.5 or more, median CSS was 44.5 months and 11.3 months, respectively (P = 0.0055). Conclusions: Diabetes mellitus did not influence the TTF of sunitinib treatment for mRCC patients. Diabetes mellitus may negatively affect the CSS of sunitinib-treated mRCC. Clinicians should consider controlling patient’s HbA1c status at the initiation of sunitinib treatment for mRCC.

We report here a case of reversible posterior leukoencephalopathy syndrome(RPLS)induced by modified FOLFOX6(mFOLFOX6). The patient was a 43-year-old woman who had sigmoid colon cancer with multiple liver metastases. Treatment with mFOLFOX6 was started. Early in the morning of day 11, the patient was transported by ambulance to the hospital due to nausea with headache, disturbed consciousness, and visual disturbance. The patient experienced sudden, severe nausea and subsequently presented generalized tonic-chronic seizures. The seizures subsided after treatment. On the evening of day 11, another episode of generalized tonic-chronic seizures occurred. Status epilepticus developed and tracheal intubation was performed for airway protection. Cranial MRI showed increased signal intensity in both occipital lobes, centered on the boundary between the gray and white matter on FLAIR images. Her condition stabilized with no seizure recurrence following intubation. Although hypertension was present on admission to the emergency room, blood pressure gradually fell to within the normal range without antihypertensive treatment. She was extubated on day 18. There were no neurologic sequelae. Cranial MRI on day 40 showed that the increased intensity in both occipital lobes had almost disappeared. Because the patient's condition was characterized by a reversible central nervous system disorder, RPLS was diagnosed.

To evaluate the safety and efficacy of combination chemotherapy with 5-fluorouracil (5-FU), leucovorin, irinotecan and oxaliplatin (FOLFOXIRI) in Japanese patients with advanced colorectal cancer.This phase I dose-finding study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD) or both of FOLFOXIRI. Patients with UDP-glucuronosyltransferase (UGT) 1A1*6/*6, *28/*28 and *6/*28 genotypes were excluded, because these UGT1A1 genotypes are linked to severe neutropenia in Japanese.A total of 10 Japanese patients with advanced colorectal cancer were studied. The MTD of FOLFOXIRI in these Japanese patients was 165 mg/m(2) irinotecan, 85 mg/m(2) oxaliplatin and 2,400 mg/m(2) 5-FU. Accordingly, the RD of FOLFOXIRI was determined to be 150 mg/m(2) irinotecan, 85 mg/m(2) oxaliplatin and 2,400 mg/m(2) 5-FU. Toxic effects, evaluated until the completion of 4 cycles, were manageable. Grade 3-4 neutropenia occurred in 27% of cycles, but there was no febrile neutropenia. Among the 9 assessable patients, the objective response rate was 89%.We thus determined the RD of FOLFOXIRI in Japanese patients with advanced colorectal cancer who do not have UGT1A1*28/*28, *6/*6 or *6/*28 genotypes. Our results indicate that FOLFOXIRI is a well-tolerated regimen for these Japanese patients.

[1] We model the source mechanism of volcanic tremor at shallow depths of a volcano by hydrothermal dynamics. Steam-water two-phase flow in the pipe is formulated, and its instability, known as density wave oscillation, can produce monotonic characteristics similar to those of a volcanic tremor. The oscillation is closely related to the heat supplied to the system and we quantitatively obtain the upper and lower limits of the heating quantity to realize this monotonic oscillation. This source mechanism can be realized only when the effect of gravity is small (i.e., horizontal flow), since the effect of depressurization due to upwelling is significant for bubble growth with vertical flow including gravity, and heating and vaporization are less important.

To investigate the benefit of alpha1-adrenoceptor antagonist naftopidil on the quality of life (QOL) of patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH/LUTS).A total of 99 men with BPH/LUTS were prospectively recruited. The Short Form-8 (SF-8) was used for generic QOL assessment and each parameter was compared with the norm in these patients. Longitudinal changes were evaluated using the SF-8 and the International Prostatic Symptoms Score (I-PSS) at baseline, 4 and 8 weeks after naftopidil administration. The relationship between SF-8 and I-PSS was analyzed.Five of eight components in the SF-8 were significantly lower than the Japanese national norm at baseline. SF-8 score was improved by naftopidil at 4 and 8 weeks in general health (GH) and physical component summary (PCS) in the patients in their 70s. Mental health (MH) and mental component summary (MCS) were improved at 8 weeks in patients in their 60s. When analyzing the whole cohort, SF-8 GH, role emotional (RE) and MH had improved at 8 weeks, which was similar to the norm, and bodily pain (BP) results were better. Compared with the baseline, total I-PSS, storage/voiding symptoms and QOL index scores improved significantly under naftopidil. Each component of I-PSS (except for hesitancy) correlated with SF-8 sub-scales (except for BP) to some extent.BPH/LUTS impairs generic QOL, which is improved by naftopidil treatment. SF-8 can be a useful instrument to assess the efficacy of BPH/LUTS treatment because its simplicity to complete and analyze, and its meaningful relationship to I-PSS.

Objectives: To examine the pre-emptive analgesic effect of the non-steroidal anti-inflammatory drug zaltoprofen against rigid cystoscopy-associated pain, and compare it with the effect of an anesthetic gel. Methods: Forty men periodically undergoing follow-up office cystoscopy were enrolled in this prospective study. The effects of lidocaine gel alone or in combination with zaltoprofen, were examined. The following parameters were assessed using an 11-point numerical rating scale: pain during injection of gel into the urethra, insertion of rigid cystoscope, and the endoscopic examination of the urinary bladder, pain at the first urination after cystoscopy, and at the first urination in the following morning at home. Results: Pain scores with pre-emptive zaltoprofen plus lidocaine gel were significantly lower than the ones with lidocaine gel alone at the time points of inserting rigid cystoscope into the urethra, viewing inside the urinary bladder and the first urination after cystoscopy. The efficacy of zaltoprofen was more significant in the patients with higher baseline pain score. There was no correlation between pain scores and bladder cancer grading, number of tumors, and time from surgery. Conclusions: Pre-emptive zaltoprofen is able to control cystoscopy-associated pain, which translates into better quality of life for patients. Thus, its use is recommended in the management of these patients.

S-1 is an oral anticancer agent that combines tegafur, a prodrug of 5-fluorouracil (5-FU), and 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase. We examined the effects of aging on the pharmacokinetics of the components of S-1. The median area under the concentration-time curve (AUC) of active 5-FU did not significantly differ between 10 patients 75 years or older and 53 patients younger than 75 years (P = 0.598, Mann-Whitney U test). It is interesting to note that the median oral clearance of tegafur in patients 75 years or older was significantly lower than that in patients younger than 75 years (P = 0.011). Furthermore, the median AUC of CDHP was significantly higher in patients 75 years or older than in those younger than 75 years (P = 0.004). This effect was caused by reduced renal function in the elderly, because CDHP is excreted in the urine by glomerular filtration. The opposing effects of aging on the oral clearance of tegafur and the AUC of CDHP may offset each other, leading to unchanged systemic exposure of 5-FU.

BACKGROUND S-1 is an oral anticancer agent that combines tegafur (FT) with 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate. The recommended initial dose of S-1 is 120 mg/day for patients with a body surface area (BSA) of > or =1.5 m(2) in Japan. METHODS We examined the effects of using this fixed dose on the pharmacokinetics of FT, CDHP, and active 5-fluorouracil (5-FU) on the basis of actual BSA. The pharmacokinetics was compared between patients with a BSA of 1.5-1.75 m(2) and those with a BSA of > or =1.75 m(2). RESULTS The median areas under the time-concentration curves (AUCs) of 5-FU and CDHP were significantly lower in patients with a BSA of > or =1.75 m(2) than in those with a BSA of 1.5-1.75 m(2) (P = 0.005 and 0.006, respectively; Mann-Whitney U-test). There was no difference between the groups in the median AUC of FT. CONCLUSION Systemic exposure to 5-FU is significantly lower in Japanese cancer patients with a large BSA of >1.75 m(2) who received the recommended fixed dose of S-1.

Renal cell carcinoma (RCC) is capable of metastasizing to several organs. Synchronous isolated contralateral adrenal metastasis of the primary RCC is, however, very rare. Herein we report a case of RCC with a huge solitary metastasis to the contralateral adrenal gland that was surgically treated. We scheduled nephrectomy for the left primary RCC and adrenalectomy for the right adrenal tumor. However, at surgery we found a huge right adrenal tumor that had invaded the right kidney, right renal vein, and inferior vena cava. Therefore right nephrectomy was performed simultaneously with resection and reconstruction of the inferior vena cava. Pathological findings demonstrated that the left renal tumor and right adrenal tumor had the same histology. Although the patient required hemodialysis, he remains well at six months postoperatively. So far, there have been only two cases of a solitary contralateral metastatic adrenal tumor that was larger than the primary RCC, thus the present case is the third one.

Laparoscopic surgery is widely accepted for managing renal disease. Thus, the system used to educate and train novice surgeons in laparoscopic surgery becomes important to reduce the risks of surgery during their training. A prospective study was carried out to determine the usefulness of using panoramic views during laparoscopic surgery.Between April 2004 and March 2007, four novice surgeons started learning laparoscopic radical nephrectomy: two carried out surgery without panoramic views and two used panoramic views. Operating time and blood loss for the initial 10 cases of each surgeon were compared. Panoramic views were obtained by interlacing each video frame of the video images electronically; the images were then processed and displayed during each step of laparoscopic surgery.Panoramic, real-time views could be obtained, and they served as navigation maps. The learning curve of surgeons using the panoramic views was shorter than that of surgeons who did not use panoramic views. Time to ligation of renal artery from port placement and the operating time was shorter (69.0 +/- 21.5 min vs 106.8 +/- 44.9 min, P = 0.0016, 212 +/- 42 min vs 254 +/- 46 min, P = 0.0489, respectively) and the estimated blood loss was less for the surgeons who used panoramic views (87 +/- 109 mL vs 334 +/- 268 mL, P = 0.0005).Panoramic views during laparoscopic surgery shortened operating time and reduced blood loss, indicating their usefulness in assisting novice surgeons to carry out procedures safely and accurately.

Polymorphisms of the UDP-glucuronosyltransferase (UGT) 1A1 gene, such as UGT1A1*28 and UGT1A1*6, can cause severe neutropenia and diarrhea in patients who receive irinotecan [1, 2]. Homozygosity for UGT1A1*28 is associated with less efficient glucuronidation of SN-38, the active metabolite of irinotecan, resulting in increased plasma SN-38 concentrations. Four pharmacogenetic trials have demonstrated an association between UGT1A1*28 genotype and irinotecan-induced hematologic toxicity, diarrhea, or both [3]. In response to these findings, the United States Food and Drug Administration has approved genetic testing for UGT1A1*28 and recommends that the initial dose of irinotecan is reduced by at least one level in patients who are homozygous for UGT1A1*28, albeit the effectiveness of such testing remains to be confirmed prospectively. UGT1A1*6 is also associated with severe irinotecan-related toxicity [4]. Given that the area under the time versus concentration curve ratio (SN-38 glucuronide/SN-38) seen in patients homozygous for UGT1A1*28 and *6 are almost equal [4], the impact of these variants on glucuronidation capacity of UGT1A1 for SN-38 is almost the same. The distribution of genotypes associated with these polymorphisms varies considerably among ethnic groups. UGT1A1*28 is found in Japanese and whites, but the allele frequency in Japanese is lower than that in whites [2, 4]. UGT1A1*6 is found in Japanese, but not in whites [4]. Homozygosity for UGT1A1*28 or UGT1A1*6 and heterozygosity for both UGT1A1*6 and UGT1A1*28 are associated with severe irinotecan-related neutropenia in Japanese patients [1, 4]. The Ministry of Health, Labour and Welfare in Japan has therefore recently approved genetic testing for UGT1A1*28 and *6. The value of genetic testing for UGT1A1 depends on genotype frequency and the association of genetic variants with irinotecan-induced toxicity. The higher the frequency of toxicity-related polymorphisms, the greater is the number of patients who would benefit from genetic testing. Large prospective studies are needed to accurately estimate the distribution of UGT1A1 polymorphisms in a given population. We have carried out the largest prospective study to date, examining the distributions of UGT1A1*28 and UGT1A1*6 genotypes in 300 Japanese patients (male/female, 172 of 128) with various solid tumors (200 colorectal, 43 gastric, 15 ovarian, 14 breast, 10 lung, and 18 others). All patients gave written informed consent, and the study protocol was approved by the Institutional Review Board of Saitama Medical University. Genotyping was carried out as described elsewhere [5]. UGT1A1*28 and UGT1A1*6 were in Hardy–Weinberg equilibrium (P > 0.05). Only 2 of 300 patients were UGT1A1*28 homozygotes (0.7%) (Table 1). The frequency of homozygosity for UGT1A1*28 was much lower than that in other prospective studies in Japan (2.3%, 4 of 176) [4]. The frequency of UGT1A1*6 homozygosity was 5.7% (Table 1), higher than that reported previously (2.8%) [4]. Eleven patients were both heterozygous for UGT1A1*6 and UGT1A1*28 (3.7%). The combined frequency of patients with two ‘risk alleles’ (i.e. *28/*28, *6/*6, and *6/*28) was 10.1% (95% confidence interval, 6.8% to 14.0%). Such patients might be at increased risk for irinotecan-related neutropenia. Given the genotype frequencies of UGT1A1*28 and UGT1A1*6, genetic testing for UGT1A1 might not be essential for identifying homozygotes for UGT1A1*28, but useful for identifying homozygotes for UGT1A1*6 as well as heterozygotes for UGT1A1*6 and UGT1A1*28, thereby avoiding severe irinotecan-induced toxicity in Japanese patients. The present results and considerations are likely to have application across East Asia. Prospective evaluations of genetic testing for UGT1A1 polymorphisms, encompassing both medical aspects and cost effectiveness, appear to be warranted, especially in East Asian countries including Japan. Table 1. Genotype frequencies of UGT1A1*28 and UGT1A1*6 in Japanese

S-1 is an oral anticancer agent composed of tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate. CDHP is added to prevent degradation of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase. CYP2A6 is involved in the biotransformation of FT to 5-FU. Thus, we prospectively analyzed the effects of the CYP2A6 genotype, plasma level of CDHP, and patient characteristics on the pharmacokinetic (PK) variability of FT and 5-FU. Fifty-four Japanese patients with metastatic or recurrent cancers who received S-1 were enrolled. The CYP2A6 polymorphisms (*4A, *7, and *9) with deficient or reduced activity were analyzed. All subjects were classified into three groups according to their CYP2A6 genotype: wild type (*1/*1), one-variant allele (*1/any), or two-variant alleles (combination other than *1). The PK of FT, 5-FU, and CDHP were measured on day 1 of treatment. Multivariate regression analysis revealed that oral clearance of FT was associated with the CYP2A6 genotype (analysis of variance [ANOVA], P = 0.000838). The oral clearance of FT seen in patients with the two-variant alleles was significantly lower than those in wild type and the one-variant allele (95% confidence intervals 0.75-2.41 and 0.41-1.82, respectively; Tukey-Kramer test). The area under the time-concentration curve (AUC) of 5-FU was significantly correlated with the AUC of CDHP (ANOVA, P = 0.00126). The AUC of 5-FU and CDHP were inversely correlated with creatinine clearance (ANOVA, P = 0.0164 and P = 0.000762, respectively). Although the CYP2A6 variants are the cause of the PK variability of FT, the AUC of CDHP affected by renal function is the key determinant of the variability in the PK of 5-FU.

Laparoscopic surgery for kidney treatment is a common procedure. However, the efficacy of this procedure in patients with several comorbidities has not been well investigated. We conducted a retrospective comparison of results of laparoscopic surgery between patients with several comorbidities and patients with no comorbidity to access the efficacy and safety of this procedure.The subjects were 20 patients with three or more comorbidities (group A) and 46 patients with less than three comorbidities (group B). These 66 patients were 48 men and 18 women with a mean age of 62.3 years (age range, 24-83 years). The data from these two groups were compared for American Society of Anesthesiology (ASA) physical status score, previous surgical history, duration of surgery, estimated blood loss, tumor size, complications during and after surgery, conversion rates, time to oral intake, and length of hospital stay.The initial ASA score and age were significantly higher for the patients with comorbidities (P0.0001, P = 0.0008, respectively). All other variables before, during, and after surgery were similar for both laparoscopic groups. However, the incidence of atelectasis of laparoscopy was higher than that of open surgery.Laparoscopic nephrectomy for patients with comorbidities is safe and minimally invasive. Further investigation to prevent atelectasis is necessary.

The phenotypic effects of UGT1A7 and UGT1A9 genetic polymorphisms on the in vivo pharmacokinetics of irinotecan were examined.Eighty-four Japanese patients with cancer who received irinotecan-based chemotherapy were enrolled. Polymorphisms present in UGT1A7 (T to G transversion at -57 and UGT1A7*2 to *9), UGT1A9 (9 or 10 repeat of T at -118 [-118(T)9 or 10] and UGT1A9*2 to *5), and UGT1A1 (UGT1A1*6, UGT1A1*27, and UGT1A1*28) were analyzed for all patients. Pharmacokinetics of irinotecan were examined in 52 patients.The most frequent haplotype (haplotype I, 56.7%, 95% CI 53.1-60.4) consisted of polymorphisms related to normal catalytic or transcriptional activity [T at -57 and *1 of UGT1A7, -118(T)10 of UGT1A9, and UGT1A1*1]. The second most frequent haplotype (haplotype II, 15.0%, 95% CI 12.4-18.3) consisted of polymorphisms related to reduced catalytic or transcriptional activity [-57TG and *3 of UGT1A7 and -118(T)9 of UGT1A9 linked to UGT1A1*6]. The AUC(SN-38)/AUC(SN-38G) ratios in three patients homozygous for haplotype II were significantly higher than those in 20 patients with I/I diplotype (P = 0.011). Neither of these patients had UGT1A1*28.Genetic linkage of UGT1A7 and UGT1A9 polymorphisms to UGT1A1*6, related to reduced catalytic and transcriptional activities of UGTs, is associated with the decreased glucuronosyltransferase activity for SN-38 in Japanese patients with cancer.

We sequenced from 5'-franking region to intron 1 (to 337 bp downstream from exon 1) of the UDP-glucuronosyltransferase (UGT) 1A9 gene prepared from 55 Japanese cancer patients. Seven single nucleotide polymorphisms (SNPs) were found. Two of them were UGT1A9 -118(T)n (n=10) and UGT1A9*5, and four were reported SNPs in intron 1 of UGT1A9 gene (89540C>T, 89549G>A, 89616T>A and 89710A>C). A novel SNP (89587T>C) was found. The sequence is as follows: SNP, 050824FujitaK001; Gene Name, UGT1A9; Accession Number, AF297093; Length, 25 bases; 5'-CCTTCTTGAAGAT/CATGTATTTATAA-3'. Two patients were heterozygous for the mutant allele, resulting in the allele frequency of 1.82%.

Background and Objective: Understanding neoadjuvant chemotherapy (NAC) for early breast cancer, the pathological response rate in estrogen receptor (ER)-positive has been low in comparison with those of ER-negative. Therefore, the luminal breast cancer (LBC) must have heterogeneity in response to NAC. We analyzed the patterns of tumor shrinkage after NAC as a surrogate prognostic factor in LBC using MRI. Methods and Results: Of 854 patients who had received NAC in the single institute from Jan. 2000 to Dec. 2009, 265 LBC were retrospectively evaluated for this study. The LBC was defined as ER and/or PgR positive in more than 10% of cancer cells and HER2 negative (IHC 0, 1+ or FISH Discussion: The tumor shrinkage pattern of MRI could be an important surrogate prognostic factor for NAC in early LBC. Our results suggest that the LBC with non-CS pattern may have the higher heterogeneity which associated with chemotherapy-resistant residual cancer cells.

Gefitinib (Iressa) is an anticancer drug that selectively inhibits tyrosine kinases of epidermal growth factor receptor. Gefitinib might affect CYP3A4-mediated metabolism, since the drug is a substrate of human CYP3A. In this study, we evaluated the effects of gefitinib on drug metabolism catalyzed by human CYP3A4. The effects of gefitinib on the CYP3A4-mediated formation of NPC (7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecin) and that of APC (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin) from irinotecan were examined with the use of human liver and small intestinal microsomes. Gefitinib inhibited the formation of NPC in liver and small intestinal microsomes. The apparent intrinsic metabolic clearance (CL(int)) in the presence of 40 microM gefitinib was equivalent to about 26% of control in liver microsomes and 45% of control in small intestinal microsomes. Gefitinib stimulated the formation of APC by CYP3A4. CL(int) in the presence of 20 microM gefitinib with human liver microsomes was about 1.9 times higher than control. In human small intestinal microsomes, APC formation was enhanced by the addition of gefitinib at concentrations 20 microM or higher. CL(int) in the presence of 40 microM gefitinib was 2.8 times higher than control. Thus, we discovered that gefitinib inhibited the formation of NPC but stimulated the formation of APC from irinotecan.

Gefitinib (Iressa) is an anticancer drug that selectively inhibits tyrosine kinases of epidermal growth factor receptor. Gefitinib might affect CYP3A4-mediated metabolism, since the drug is a substrate of human CYP3A. In this study, we evaluated the effects of gefitinib on drug metabolism catalyzed by human CYP3A4. The effects of gefitinib on the CYP3A4-mediated formation of NPC (7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecin) and that of APC (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin) from irinotecan were examined with the use of human liver and small intestinal microsomes. Gefitinib inhibited the formation of NPC in liver and small intestinal microsomes. The apparent intrinsic metabolic clearance (CL(int)) in the presence of 40 microM gefitinib was equivalent to about 26% of control in liver microsomes and 45% of control in small intestinal microsomes. Gefitinib stimulated the formation of APC by CYP3A4. CL(int) in the presence of 20 microM gefitinib with human liver microsomes was about 1.9 times higher than control. In human small intestinal microsomes, APC formation was enhanced by the addition of gefitinib at concentrations 20 microM or higher. CL(int) in the presence of 40 microM gefitinib was 2.8 times higher than control. Thus, we discovered that gefitinib inhibited the formation of NPC but stimulated the formation of APC from irinotecan.

In a recent issue of European Journal of Cancer, Lipton et al. report results from three phase 3 trials in patients with bone metastases from various malignant tumors, comparing the efficacy and safety of denosumab (120 mg subcutaneously monthly) versus zoledronic acid (4 mg intravenously monthly). The authors conclude that denosumab is superior to zoledronic acid for the prevention of first and multiple skeletal-related events. For breast cancer patients with bone metastases, bone-modifying agent therapies can include denosumab 120 mg subcutaneously every 4 weeks, intravenous pamidronate 90 mg over no less than 2 h, or zoledronic acid 4 mg over no less than 15 min every 3–4 weeks, which is recommended if the patient has a calculated serum creatinine clearance of more than 60 mg/min. However, doses of these two bisphosphonates should be modified when the serum creatinine clearance is between 30 and 60 mL/min. Furthermore, when renal insufficiency is indicated by serum creatinine clearance being less than 30 mL/min, the use of bisphosphonate should be avoided. It is also recommended to monitor

A 56-year-old woman was referred for an abnormally dense area in the right upper lung field detected at medical checkup. This shadow had been pointed out frequently since she was 38 years old, but no pathological diagnosis of lung cancer had been given. The size of the abnormal area had gradually increased over the 18 years. Since lung cancer was suspected on the basis of the radiographic findings, she underwent open lung biopsy. Pathologically, the tumor tissue showed a lepidic growth pattern on the wall of preexisting alveoli; and formation of fibrotic foci caused by the collapse of alveoli and the microscopic destruction of the elastic fiber framework were seen in the tumor. There was no vascular invasion or lymphatic infiltration in the tumor. It was diagnosed as well-differentiated nonmucinous adenocarcinoma, p-T2 N0 M0. Although this tumor was untreated for 18 years from the first detection using chest radiography, the critical invasive features were not in evidence pathologically.

Squamous cell carcinoma of the lung can be divided into two types according to the location of the primary site: the central type and the peripheral type. The clinicopathologic factors in the peripheral type of lung squamous cell carcinoma have not yet been fully evaluated. A total of 204 surgically resected lung squamous cell carcinomas were reviewed with special reference to their location, histologic characteristics based on tumor growth patterns, and clinicopathologic factors. The central type and the peripheral type accounted for 95 and 109 cases, respectively. Although the patient population of the peripheral type was older, with a lower pathologic stage, lower lymphatic vessel involvement, and lymph node metastasis, the Kaplan-Meier survival proportions did not differ significantly between these two groups. Based on the histologic growth pattern, the peripheral type was classified under three subgroups as follows: 1). the alveolar space-filling type, 2). the expanding type, and 3). the combined type. Among these three types, the alveolar space-filling type showed neither lymphatic vessel invasion nor lymph node metastasis and had the most favorable prognosis. The central and peripheral types of lung squamous cell carcinoma have different clinicopathologic characteristics and should be classified under respectively different categories.

Background: There are no definitive predictive markers, except HER2 overexpression, for anti-HER2 therapeutic sensitivity of patients (Pts) with HER2-positive breast cancer. The aim of this study was to evaluate clinical predictive factors for lapatinib plus capecitabine (LAPCAP) in Pts with HER2 positive metastatic breast cancer (HER2MBC). Methods: This retrospective observational study was used data from our single institutional medical record system from June 2009 to March 2013. Evaluation of female Pts with HER2MBC who were treated with LAPCAP (LAP at 1250 mg/day continuously plus CAP at 2000 mg/m2 on days 1 through 14 of a 21-day cycle) included baseline clinical characteristics, dose modifications of LAPCAP, clinical efficacy, and incidence of adverse events (AEs). Dose-intensity was compared with reference standard regimens. The Kaplan Meier method was used to estimate time to progression free survival (PFS). Results: A total 76 Pts were included in this analysis. At a median follow-up of 20 months, median age was 56 years (range, 36 to 75) and 41 of 76 Pts had received prior (neo- or) adjuvant chemotherapy including 18 trastuzumab (Tmab) containing regimen. Visceral metastases (Mets) were identified in 49, bone Mets in 37, lymph nodes Mets in 36, brain Mets in 17, and chest wall Mets in 16. The median number of prior chemotherapy or hormonal therapy for MBC before LAPCAP was 2 (range, 0 to 13), and 66 of 76 Pts had previously received Tmab containing regimen with taxanes for 40 Pts, vinorelbine for 36, CAP for 29, and hormonal therapies for 15. In LAPCAP, the overall response rate was 21% including 2 CRs and 14 PRs, and the clinical-benefit rates which had more than 6-month SD was 60%. During initial 12 months observation, 93% of Pts had any AEs. The most common AEs were hand-foot syndrome (HFS) in 55 Pts. Those Pts who had HFS had better PFS than those who did not have (p = 0. 23×10−4). Since HFS was one of the well-known AEs associated with CAP, we sought whether CAP dose influenced PFS or not. However, we did not find any relationship between cumulative or relative dose intensity of CAP and PFS in Pts who treated with LAPCAP. Because several studies with EGFR-targeted agents showed a positive correlation between cutaneous toxicities and outcomes, we sought whether the incidence of any AEs other than HFS influenced PFS in 76 Pts. HFS, and diarrhea, as well as skin rash were statistically significant favorable factors (p = 0. 23×10−4, 0. 60×10−2, and 0. 28×10−1) in Log rank analysis. Furthermore, median PFS of Pts who had all 3 AEs (n = 21) were 377 days, while 84 days (n = 7) who had not (p = 0.58×10−8). We did not find any other clinical predictive factors except these 3 AEs. Furthermore, we compared 20 Pts with longer PFS who had more than 12-month to 26 Pts with shorter PFS that had less than 6-month. Longer PFS had more statistically significant incidence of diarrhea (p = 0. 49×10−2), HFS (p = 0. 49×10−2), and skin rash (p = 0.36×10−1) than shorter one. Conclusions: In LAPCAP, dose of CAP did not influence PFS, but EGFR inhibitor related toxicities might be alternative predicative markers for LAPCAP in HER2MBC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-45.

We report a case of MALT lymphoma (malignant lymphoma of mucosa-associated lymphoid tissues) involved in the salivary glands, the renal sinus and the prostate. The masses have been progressing very slowly and the patient has remained alive without any treatment for 5 years from the first symptom of this disease.

e15521 Background: Almost renal cancers are renal cell carcinoma (RCC). Short term treatment results are excellent with 90% or more disease specific and overall survival at 5year. Follow up schedule of NCCN guideline for low risk group was up to 5 years after surgery. Although, we have experienced late recurrence in such a low risk cases. Therefore, we examined the recurrence of T1 and T2 renal carcinoma in our institute, retrospectively. Methods: Between March 1997 and September 2009, 580 patients with renal carcinoma were undergone surgical excision of renal tumor at Chiba University Hospital. In these cases,349 patients were T1 without metastasis. We analyzed the clinopathological deta of these 349 patents. Univariate and multivariate analysis were conducted to identify the prognostic factor of T1a or T1b patients with surgical excision. Results: During follow up, 5, 10, 15 and 20 years overall survival rate(OS) of T1a were 98.1%, 98.1%, 90.6% and 90.6%, respectively. Those of T1b were 95.8%, 92.7%, 90.2% and 90.2%, respectively. 5, 10, 15 and 20 years disease free survival rate (DFS) of T1a was 93.1%, 86.6%, 76.8%, 38.4%, respectively. 5, 10, 15 and 20 years DFS of T1b was 82.9 %, 66.5%, 58%, 50.8% ,respectively. 33% of metastasis was lung 10% of metastasis was contralateral kidney. Conclusions: 20 years OS of T1a was an excellent, however, 20 years DFS was 38.4%. Life expectancy of Japanese men and women in 2009 were 79.59 years old and 86.44 years old. Almost patients with T1a renal carcinoma might have a late recurrence. We think it is necessary to long follow p schedule for T1 cancer and partial nephrectomy is recommended.

e11587 Background: The important characteristics of breast cancer is its tumor heterogeneity and response to neoadjuvant chemotherapy (NAC). We analyzed the patterns of tumor shrinkage as a prognostic indicator after NAC for luminal breast cancer. Methods and Results. Methods: Of 854 patients who had received NAC in the single institute between January 2000 and December 2009, 265 luminal breast cancerwere retrospevively examined. Luminal breast cancer was defined as ER and/or PgR positive in more than 10% of cancer cells and HER2 negative (IHC 0, 1+ or FISH ), strong ER/PgR positivity and concentric shrinkage as significantly favorable, and lymph node metastases as significantly unfavorable prognostic factors. Multivariate analysis for OS identified tumor size as significantly unfavorable prognostic factors(p=0.012). Conclusions: the tumor shrinkage pattern could be an important prognostic factor for luminal breast cancer and this suggests that a concentric shrinkage pattern of response may be infrequently associated with chemotherapy-resistant residual cancer cells.

Testicular and paratesticular neoplasms resembling common ovarian epithelial tumors are rare. They most commonly occur in the paratesticular area as serous subtype, probably from appendix testis or metaplasia of the mesothelium.1 The mucinous subtype is particularly rare.2, 3 We report a case of mucinous cystadenoma occurring in the testis. To our knowledge this is only the second such case reported in the literature.

Eribulin mesylate (eribulin), a novel microtubule-targeted inhibitor, was approved ‘inoperable or recurrent breast cancer’ on April 2011 in Japan. In therapeutic system, trastuzumab is used for patients with HER2-positive breast cancer but the safety of combination of eribulin with trastuzumab is not established. And so, we conducted the clinical phase I study of eribulin in combination with trastuzumab in patients with HER2-positive breast cancer to evaluate dose limiting toxicity (DLT), and investigate tolerability and safety. Six patients with prior chemotherapy including trastuzumab and taxanes for advanced or metastatic breast cancer were evaluated in DLT evaluation periods (for 21 or 28 days after drug administration). Eribulin (1.4 mg/m2) was administered as an IV bolus on days 1 and 8 every 3-week cycle, which is approved dosage and schedule, and trastuzumab was administered as an IV infusion weekly (method A). As a result, no adverse events corresponding to DLT were observed, and the common adverse events were neutropenia and leukopenia. On day 15 after drug administration, one of six patients showed the slight decrease in left ventricular ejection fraction, but it was recovered on day 22. And thus, the combination of eribulin with trastuzumab was tolerable in DLT evaluation periods, and the safety profile in this study was similar to that in the past clinical studies of eribulin monotherapy. On the other hand, since the acute cardiac failure was observed, it was thought that the assessment of cardiac function in the combination of eribulin with trastuzumab should be carried out carefully.

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Background: Epothilones are a new class of cytotoxic agents that induce tubulin polymerization. Sagopilone (ZK-EPO), the fully synthetic, third-generation epothilone, is a highly potent tubulin stabilizer that has shown substantial antitumor activity against a broad range of tumor models. The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics of sagopilone in Japanese patients (pts) with refractory solid tumors. Methods: Pts with histologically or cytologically confirmed advanced solid tumors that were refractory to conventional antineoplastic treatment, or for whom no standard therapy was available were enrolled on the trial. sagopilone was given as a 30-minute intravenous infusion once every 3 weeks up to a maximum of 6 courses; the starting dose was 12.4 mg/m2. Treatment was continued until disease progression or unacceptable toxicity occurred. Results: Seventeen Japanese pts (8 male and 9 female, median age 52 years; range 27–66) have received the study drug. Six patients were treated at dose of 12.4 mg/m2, 6 at 16.5 mg/m2, and 5 at 22.0 mg/m2. The most common adverse events (AEs) were peripheral neuropathy in 14 pts (82.4%), nausea and lymphocytopenia in 13 each (76.5%), leukopenia and arthralgia in 12 each (70.6%), and neutropenia in 11 (64.7%). Nine pts (52.9%) experienced at least 1 Grade (Gr) 3 treatment-related AEs including peripheral neuropathy in 5 pts (29.4%); in the 3rd and 6th course at 12.4 mg/m2, and in the 1st (2 pts) and 2nd course at 22.0 mg/m2. All of them improved after discontinuation of the study treatment. No pts experienced Gr 4 or 5 AEs. Seven pts (41.2%) had at least 1 DLT during the study. At 12.4 mg/m2 dose, 4 pts experienced DLTs: Gr 3 peripheral neuropathy in 2 pts as well as Gr 2 liver enzyme increase and Gr 2 weight decrease that persisted for 5 weeks in 1 pt each. No DLT was observed at 16.5 mg/m2, but 3 of 5 pts treated at 22.0 mg/m2 had Gr 3 dose-limiting peripheral neuropathy. The PK data demonstrated that Cmax and AUC of sagopilone increased in a dose-dependent manner. Mean systemic clearance was between 616 and 765 mL/min (CV, 20.7% to 32.4%), and mean distribution volume at the steady state ranged from 3075 to 3688 L (CV, 19.6% to 50.1%). Mean terminal half-life was between 74.4 and 93.1 h (CV, 16.4% to 32.5%). Although incidence of neuropathy seemed to depend on the dose, no clear relationships between the toxicity and PK parameters were observed. No pts had a CR or PR. Nine pts had SD. Prolonged SD over 12 weeks was observed in 2 pts with breast cancer. Conclusions: Sagopilone demonstrated clinically favorable safety and tolerability with indications of antitumor activity in heavily pretreated Japanese pts with solid tumors. MTD was 16.5 mg/m2, and the main and dose-limiting toxicity was peripheral neuropathy. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C104.