The Impact of Aging on Symptom Prevalence and Management in Terminally ill Patients With Cancer.

CONTEXT: With global population aging, the number of older patients with cancer is increasing. However, few data are available on palliative care for these patients. OBJECTIVES: To evaluate differences in symptom prevalence and the need for medical interventions among patients of different ages in a palliative care unit. METHODS: In this retrospective analysis, a consecutive sample of 1032 terminally ill patients with cancer were categorized into the following age ranges: <70, 70-79, 80-89, and ≥90 years. We evaluated symptom prevalence, the need for palliative medicines, opioid dose on the day before death, and the need for palliative sedation. Trend tests were used to examine whether the prevalence of findings increased or decreased with age. RESULTS: As age increased, significant decreasing trends were observed in the prevalence of pain, dyspnea, fatigue, constipation, nausea, drowsiness, difficulty sleeping, anxiety, and dysuria but not in appetite loss, edema, sputum production, or delirium. As age increased, significant decreasing trends were also observed in the need for opioids, benzodiazepines, antiemetics, and anticholinergics. The median opioid doses in the <70, 70-79, 80-89, and ≥90 years age groups were 118, 72, 48, and 48 mg oral morphine equivalents/day, respectively (P < 0.0001). The need for palliative sedation showed a significant decreasing trend as age increased (P < 0.0001). CONCLUSION: We found age to be inversely related to symptom prevalence and medical interventions among terminally ill patients with cancer, contributing to the understanding of the experience of older patients with cancer.

[Emergency Medication Kits in Home Palliative Care].

The majority of patients with in-home palliative care desire to remain at home through their end of life. However, symptomatic crises, unless promptly controlled, can cause unwanted hospital admissions. In the past 2 decades, it has become common to place a package of several medications in the patient's home for family caregivers to use to treat symptoms when the oral route is lost. These emergency medication kits(EMK)are capable of addressing the common symptoms that arise at end of life, such as pain, dyspnea, delirium, and retained respiratory secretions. The EMK are for the patient or family caregivers to use at the direction of their home hospice nurse or physician. Medications in the EMK are selected for their versatility in potentially addressing multiple symptoms, and their ability to be administered buccally, sublingually, or transdermally, simplifying administration by family caregivers. The EMK facilitate timely symptom control, allowing families to avoid emergency department visits, unscheduled nursing visits, and usually result in cost savings. Additionally, family caregivers feel empowered by its presence in their home and its contribution to patient, family caregiver and nurse satisfaction. To date in Japan, the literature related to the use and impact of EMKs is sparse. Further investigation is needed into the use, clinical efficacy, and impact of the EMK.

Multitask Imaging Monitor for Surgical Navigation: Combination of Touchless Interface and Head-Mounted Display.

As a result of the dramatic improvements in the resolution, wearability, and weight of head-mounted displays (HMDs), they have become increasingly applied in the medical field as personal imaging monitors. The combined use of a multiplexer with an HMD allows the wearer to simultaneously and seamlessly monitor multiple streams of imaging information through the HMD. We developed a multitask imaging monitor for surgical navigation by combining a touchless surgical imaging control system with an HMD. This system is composed of a standard color digital video camera mounted on the HMD and computer software that enables the identification of the number of pictured fingertips from the video camera image. The HMD wearer uses this information as a touchless interface for the operating multiplexer, which can control the arrays and types of imaging information displayed on the HMD. We used this system in an experimental demonstration during a single-port gasless partial nephrectomy. The use of this multitask imaging monitor using a touchless interface would refine the surgical workflow, especially during surgical navigation.

Heat shock protein 90 targeting therapy: state of the art and future perspective.

Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone that plays a role in stabilizing and activating more than 200 client proteins. It is required for the stability and function of numerous oncogenic signaling proteins that determine the hallmarks of cancer. Since the initial discovery of the first Hsp90 inhibitor in the 1970s, multiple phase II and III clinical trials of several Hsp90 inhibitors have been undertaken. This review provides an overview of the current status on clinical trials of Hsp90 inhibitors and future perspectives on novel anticancer strategies using Hsp90 inhibitors.

Client Proteins and Small Molecule Inhibitors Display Distinct Binding Preferences for Constitutive and Stress-Induced HSP90 Isoforms and Their Conformationally Restricted Mutants.

The two cytosolic/nuclear isoforms of the molecular chaperone HSP90, stress-inducible HSP90α and constitutively expressed HSP90ß, fold, assemble and maintain the three-dimensional structure of numerous client proteins. Because many HSP90 clients are important in cancer, several HSP90 inhibitors have been evaluated in the clinic. However, little is known concerning possible unique isoform or conformational preferences of either individual HSP90 clients or inhibitors. In this report, we compare the relative interaction strength of both HSP90α and HSP90ß with the transcription factors HSF1 and HIF1α, the kinases ERBB2 and MET, the E3-ubiquitin ligases KEAP1 and RHOBTB2, and the HSP90 inhibitors geldanamycin and ganetespib. We observed unexpected differences in relative client and drug preferences for the two HSP90 isoforms, with HSP90α binding each client protein with greater apparent affinity compared to HSP90ß, while HSP90ß bound each inhibitor with greater relative interaction strength compared to HSP90α. Stable HSP90 interaction was associated with reduced client activity. Using a defined set of HSP90 conformational mutants, we found that some clients interact strongly with a single, ATP-stabilized HSP90 conformation, only transiently populated during the dynamic HSP90 chaperone cycle, while other clients interact equally with multiple HSP90 conformations. These data suggest different functional requirements among HSP90 clientele that, for some clients, are likely to be ATP-independent. Lastly, the two inhibitors examined, although sharing the same binding site, were differentially able to access distinct HSP90 conformational states.

Gasless laparoendoscopic single-port clampless sutureless partial nephrectomy for peripheral renal tumors: perioperative outcomes.

OBJECTIVES: To describe the technical aspects of gasless laparoendoscopic single-port clampless sutureless partial nephrectomy for peripheral renal tumors, and to evaluate its outcomes, including surgical, pathological, and short-term oncological and functional outcomes. METHODS: Between January 2010 and June 2013, 103 patients with peripheral renal tumors suggestive of renal cell carcinoma underwent gasless laparoendoscopic single-port partial nephrectomy. In all cases, an attempt was made to accomplish partial nephrectomy without vascular clamping using ultrasonic coagulating and bipolar sealing devices. Hemostasis was achieved by coagulation and hemostatic agents without reconstructing the renal parenchyma. RESULTS: Of the 103 patients, gasless laparoendoscopic single-port partial nephrectomy was accomplished without vascular clamping and parenchymal suture in all but two patients (98%). Median operative time and blood loss were 191 min and 244 mL, respectively. One patient (1%) received allogeneic blood transfusion. The median postoperative time to full recovery was 3 days. Three major complications (3%, all grade 3 urinary leakage) were observed. Of 92 renal cell carcinoma patients, four (4%) had positive surgical margins, most of which underwent thermal degeneration histologically. In 91 non-metastatic renal cell carcinoma patients, 3-year local recurrence-free, progression-free, cancer-specific and overall survival rates were 100%, 99%, 100%, and 100%, respectively (mean follow-up period, 21 months). In the 103 patients, the median percent decrease in estimated glomerular filtration rate 3 months after partial nephrectomy was 2.4%. CONCLUSIONS: Gasless laparoendoscopic single-port clampless sutureless partial nephrectomy can be accomplished in almost all cases of peripheral renal tumors. This surgery is technically feasible and safe, yielding acceptable short-term oncological outcomes and maximal preservation of renal function.

Patient's Self-monitoring of Transurethral Surgical Images Using a Head-mounted Display.

We present an application of head-mounted display (HMD) to patient's self-monitoring of transurethral resection of bladder tumor (TURB). Six patients wore the HMD as an imaging monitor to view the operation in real-time during their TURB. Following the operation, the patients completed a questionnaire that evaluates understanding of the state of their disease and satisfaction with the HMD. As a result, monitoring the operation in real time through the HMD helped to increase patients' understanding of the state of their disease and satisfaction. For selected patients, the use of HMD could help to increase the patient's understanding of their disease.

Diagnostic performance and safety of a three-dimensional 14-core systematic biopsy method.

OBJECTIVE: To investigate the diagnostic performance and safety of a three-dimensional 14-core biopsy (3D14PBx) method, which is a combination of the transrectal six-core and transperineal eight-core biopsy methods. PATIENTS AND METHODS: Between December 2005 and August 2010, 1103 men underwent 3D14PBx at our institutions and were analysed prospectively. Biopsy criteria included a PSA level of 2.5-20 ng/mL or abnormal digital rectal examination (DRE) findings, or both. The primary endpoint of the study was diagnostic performance and the secondary endpoint was safety. We applied recursive partitioning to the entire study cohort to delineate the unique contribution of each sampling site to overall and clinically significant cancer detection. RESULTS: Prostate cancer was detected in 503 of the 1103 patients (45.6%). Age, family history of prostate cancer, DRE, PSA, percentage of free PSA and prostate volume were associated with the positive biopsy results significantly and independently. Of the 503 cancers detected, 39 (7.8%) were clinically locally advanced (≥cT3a), 348 (69%) had a biopsy Gleason score (GS) of ≥7, and 463 (92%) met the definition of biopsy-based significant cancer. Recursive partitioning analysis showed that each sampling site contributed uniquely to both the overall and the biopsy-based significant cancer detection rate of the 3D14PBx method. The overall cancer-positive rate of each sampling site ranged from 14.5% in the transrectal far lateral base to 22.8% in the transrectal far lateral apex. As of August 2010, 210 patients (42%) had undergone radical prostatectomy, of whom 55 (26%) were found to have pathologically non-organ-confined disease, 174 (83%) had prostatectomy GS ≥7 and 185 (88%) met the definition of prostatectomy-based significant cancer. CONCLUSIONS: This is the first prospective analysis of the diagnostic performance of an extended biopsy method, which is a simplified version of the somewhat redundant super-extended three-dimensional 26-core biopsy. As expected, each sampling site uniquely contributed not only to overall cancer detection, but also to significant cancer detection. 3D14PBx is a feasible systematic biopsy method in men with PSA <20 ng/mL.

Bimodal pattern of the impact of body mass index on cancer-specific survival of upper urinary tract urothelial carcinoma patients.

AIM: To clarify how body mass index (BMI) affects the risk of death from upper urinary tract urothelial carcinoma (UUTUC) we investigated the impact of BMI on UUTUC using a Japanese multicenter database. PATIENTS AND METHODS: Between January 1995 and December 2010, 1,329 patients with upper urinary tract tumors were treated in 13 institutions in Japan. From this group, a cohort of 1,014 patients treated with radical nephroureterectomy was retrospectively reviewed. BMI was categorized into the following three groups: BMI <22.5, BMI 22.5 to <25 and BMI ≥ 25. The association between each group and cancer-specific survival (CSS) was analyzed using Cox proportional hazards regression models. RESULTS: The median BMI was 22.4 kg/m(2) (interquartile range, 20.5-24.8). Out of all patients, 213 (21%) died of UUTUC. Hazard ratios of the BMI ≥ 25 and the BMI <22.5 group were 1.76 and 1.66, respectively. CONCLUSION: Both higher and lower BMI affect the prognosis of UUTUC treated with radical nephroureterectomy.

The HSP90 inhibitor ganetespib synergizes with the MET kinase inhibitor crizotinib in both crizotinib-sensitive and -resistant MET-driven tumor models.

The proto-oncogene MET is aberrantly activated via overexpression or mutation in numerous cancers, making it a prime anticancer molecular target. However, the clinical success of MET-directed tyrosine kinase inhibitors (TKI) has been limited due, in part, to mutations in the MET kinase domain that confer therapeutic resistance. Circumventing this problem remains a key challenge to improving durable responses in patients receiving MET-targeted therapy. MET is an HSP90-dependent kinase, and in this report we show that HSP90 preferentially interacts with and stabilizes activated MET, regardless of whether the activation is ligand-dependent or is a consequence of kinase domain mutation. In contrast, many MET-TKI show a preference for the inactive form of the kinase, and activating mutations in MET can confer resistance. Combining the HSP90 inhibitor ganetespib with the MET-TKI crizotinib achieves synergistic inhibition of MET, its downstream signaling pathways, and tumor growth in both TKI-sensitive and -resistant MET-driven tumor models. These data suggest that inclusion of an HSP90 inhibitor can partially restore TKI sensitivity to previously resistant MET mutants, and they provide the foundation for clinical evaluation of this therapeutic combination in patients with MET-driven cancers.

Successful reduction of hospital-acquired methicillin-resistant Staphylococcus aureus in a urology ward: a 10-year study.

BACKGROUND: To eradicate hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) using a stepwise infection control strategy that includes an avoidance of antimicrobial prophylaxis (AMP) based on surgical wound classification and an improvement in operative procedures in gasless single-port urologic surgery. METHODS: The study was conducted at an 801-bed university hospital. Since 2001, in the urology ward, we have introduced the stepwise infection control strategy. In 2007, surveillance cultures for MRSA in all urological patients were commenced. The annual incidence of MRSA was calculated as a total number of newly identified MRSA cases per 1,000 patient days. Trend analysis was performed using a Poisson regression. RESULTS: Over the study period, 139,866 patients, including 10,201 urology patients, were admitted to our hospital. Of these patients, 3,719 patients, including 134 ones in the urology ward, were diagnosed with MRSA throughout the entire hospital. Although the incidence of MRSA increased throughout the entire hospital (p = 0.002), it decreased significantly in the urology ward (p < 0.0001). Of the 134 cases, 45 (33.6%) were classified as "imported," and 89 (66.4%) as "acquired." In the urology ward, the incidence of acquired MRSA decreased significantly over time (p < 0.0001), whereas the incidence of imported MRSA did not change over time (p = 0.66). A significant decrease (p < 0.0001) in the incidence of clinically significant MRSA infection over time was found. CONCLUSIONS: Stepwise infection control strategy that includes a reduction or avoidance of antimicrobial prophylaxis in minimally invasive surgery can contribute to a reduction in hospital-acquired MRSA. TRIAL REGISTRATION: Current study has approved by the institutional ethical review board (No.1141).

Diabetes mellitus with obesity is a predictor of recurrence in patients with non-metastatic renal cell carcinoma.

OBJECTIVE: To investigate the associations of diabetes mellitus with recurrence and prognosis after surgery for non-metastatic renal cell carcinoma and the effect modification of obesity on the above relationships. METHODS: We retrospectively evaluated 543 patients with non-metastatic renal cell carcinoma (pT1-4N0M0) who underwent radical or partial nephrectomy. The association of diabetes mellitus with recurrence was analyzed using the Kaplan-Meier method and the Cox regression model. We also examined whether the above relationships were modified by obesity using subgroup analysis and tests of interaction. For subgroup analysis, the body mass index was categorized as non-obese (<25 kg/m(2)) and obese (≥25 kg/m(2)). RESULTS: Eighty-two patients (15.1%) had a history of diabetes mellitus. During the mean follow-up of 66.7 months, 68 patients (12.5%) developed recurrence. Although the body mass index was not associated with recurrence, diabetes mellitus was an independent predictor of recurrence in multivariate analysis (hazard ratio 2.43, P = 0.003), along with tumor diameter, grade and pathological T stage. In further subgroup analysis, the same relationship between diabetes mellitus and recurrence was clearly shown in the obese group (hazard ratio 4.07, P = 0.010), but not in the non-obese group (hazard ratio 1.95, P = 0.125). At the same time, obesity modified the effect of diabetes mellitus on recurrence with a trend (P-interaction = 0.086). In the obese group, 5-year recurrence-free survival rates were 75.3 and 91.9% for diabetes mellitus and non-diabetes mellitus patients, respectively (P < 0.001). Restricting analyses to patients with clear cell type histology did not materially change these results. CONCLUSIONS: Diabetes mellitus is a predictor of recurrence following surgery for non-metastatic renal cell carcinoma, especially in obese patients.

Zoledronic acid sensitizes renal cell carcinoma cells to radiation by downregulating STAT1.

Zoledronic acid (ZOL), a third-generation bisphosphonate that strongly inhibits osteoclast activity, is widely used for the treatment of bone metastasis from a variety of malignancies, including renal cell carcinoma (RCC). We previously reported that zoledronic acid (ZOL) clinically potentiates antitumor effects of radiotherapy (RT) on bone metastases from RCC. To date, however, it remains unknown whether ZOL radiosensitizes RCC and if it does, how. Here, we demonstrated that ZOL directly radiosensitizes RCC cells independent of osteoclast activity by potentiating the caspase-3-mediated apoptosis pathway. The radiosensitization by ZOL was observed in 786-O, A-498, and ACHN cells but not in Caki-1 cells. As its underlying molecular mechanism, we found that the signal transducer and activator of transcription 1 (STAT1) plays a key role. The three RCC cell lines, in which ZOL exerted a radiosensitizing effect, expressed STAT1 abundantly but Caki-1 cells did not. ZOL downregulated endogenous STAT1 expression in 786-O, A-498, and ACHN cells by a post-transcriptional modification. We confirmed that knockdown of endogenous STAT1 by siRNA sensitized 786-O cells to RT equivalently to ZOL, and that introduction of exogenous STAT1 rendered Caki-1 cells more RT-resistant. This is the first study to clarify the molecular mechanism by which ZOL directly radiosensitizes tumor cells. Because tumor cells commonly overexpress STAT1 and ZOL reportedly radiosensitizes various types of tumor cells, ZOL warrants further clinical and translational studies as a potent radiosensitizer against RT-resistant tumors overexpressing STAT1.

Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis.

TRAP1 (TNF receptor-associated protein), a member of the HSP90 chaperone family, is found predominantly in mitochondria. TRAP1 is broadly considered to be an anticancer molecular target. However, current inhibitors cannot distinguish between HSP90 and TRAP1, making their utility as probes of TRAP1-specific function questionable. Some cancers express less TRAP1 than do their normal tissue counterparts, suggesting that TRAP1 function in mitochondria of normal and transformed cells is more complex than previously appreciated. We have used TRAP1-null cells and transient TRAP1 silencing/overexpression to show that TRAP1 regulates a metabolic switch between oxidative phosphorylation and aerobic glycolysis in immortalized mouse fibroblasts and in human tumor cells. TRAP1-deficiency promotes an increase in mitochondrial respiration and fatty acid oxidation, and in cellular accumulation of tricarboxylic acid cycle intermediates, ATP and reactive oxygen species. At the same time, glucose metabolism is suppressed. TRAP1-deficient cells also display strikingly enhanced invasiveness. TRAP1 interaction with and regulation of mitochondrial c-Src provide a mechanistic basis for these phenotypes. Taken together with the observation that TRAP1 expression is inversely correlated with tumor grade in several cancers, these data suggest that, in some settings, this mitochondrial molecular chaperone may act as a tumor suppressor.

Antimicrobial prophylaxis is not necessary in clean category minimally invasive surgery for renal and adrenal tumors: a prospective study of 373 consecutive patients.

OBJECTIVE: To assess the feasibility of the nonuse of antimicrobial prophylaxis (AMP) on the incidence of infectious complications after clean category minimally invasive surgery for renal and adrenal tumors. METHODS: We evaluated 415 consecutive patients who underwent gasless laparoendoscopic single-port surgery (GasLESS) for renal or adrenal tumors between 2006 and 2010. Forty-two patients with poorly controlled diabetes mellitus, coexisting infection, or opening of the urinary tract during partial nephrectomy were excluded from this study. The remaining 373 patients underwent radical nephrectomy (n = 187), partial nephrectomy (n = 103), or adrenalectomy (n = 83) without AMP. Perioperative infections were categorized into superficial surgical site infection (SSI), deep SSI, and remote infection (RI) and graded using an established 5-grade modification of the original Clavien-Dindo classification system. We investigated the association between the incidence of infectious complications and clinical or perioperative factors. RESULTS: Infectious complications occurred in 16 cases (4.3%), including 4 superficial SSIs (1.1%), 2 deep SSIs (0.5%), and 10 RIs (2.7%). Neither superficial SSI nor deep SSI was significantly associated with any clinical or perioperative factors. The incidence of RI, however, was associated with longer operative time and higher National Nosocomial Infection Surveillance (NNIS) risk index. All perioperative infections were successfully treated with antibiotics without surgical interventions. No infectious complications equal to or greater than grade IIIa occurred. CONCLUSION: The nonuse of AMP and the on-demand use of antibiotics seem to be sufficient for perioperative infectious management in clean category minimally invasive surgery for renal and adrenal tumors.

Potential role of Hsp90 inhibitors in overcoming cisplatin resistance of bladder cancer-initiating cells.

For metastatic bladder cancer patients, systemic cisplatin (CDDP)-based combination chemotherapy is the first-line choice of treatment. Although up to 70% of advanced bladder cancer patients initially show good tumor response to this form of combination chemotherapy, over 90% of good responders relapse and eventually die of the disease. According to the cancer stem cell theory, this phenomenon is attributable to the re-growth of bladder cancer-initiating cells (BCICs) that have survived chemotherapy. In this study, the authors have isolated BCICs from cultured human bladder cancer cells to analyze their sensitivity to CDDP and to investigate whether heat-shock protein 90 (Hsp90) inhibitors potentiate the cytotoxicity of CDDP on BCICs. First, the authors have confirmed that a CD44+ subpopulation of 5637 cells met the requirements to be considered tumor-initiating cells. These BCICs were more resistant to CDDP and exhibited more activity in the Akt and ERK oncogenic signaling pathways when compared with their CD44- counterparts. The Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), which simultaneously inactivated both Akt and ERK signaling at noncytocidal concentrations, synergistically potentiated the cytotoxicity of CDDP against BCICs by enhancing CDDP-induced apoptosis in vitro. The potentiating effect of 17-DMAG was more effective than a combination of the two inhibitors specific for the Akt and ERK pathways. Finally, the authors have confirmed that, though human BCIC xenografts exhibited resistance to a single administration of CDDP and the Hsp90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), 17-AAG sensitized them to CDDP in a mouse model. These data encourage clinical trials of Hsp90 inhibitors as they may improve therapeutic outcomes of CDDP-based combination chemotherapy against advanced bladder cancer.

Low-dose Hsp90 inhibitors tumor-selectively sensitize bladder cancer cells to chemoradiotherapy.

Although radical cystectomy with urinary diversion is the standard treatment for muscle-invasive bladder cancer (MIBC), loss of native bladder frequently impairs patient's quality of life (QOL). Bladder-sparing approach incorporating chemoradiotherapy (CRT) improves QOL while not compromising survival outcomes in MIBC patients. In this approach, complete response to induction CRT is a prerequisite for bladder preservation and favorable oncological outcomes. We investigated a strategy to potentiate CRT response of bladder cancer cells by using Hsp90 inhibitors in preclinical models. Hsp90 inhibitors at low concentrations, which did not exert cytocidal effects but inactivated key anti-apoptotic proteins including erbB2, Akt, and NF-κB, efficiently sensitized bladder cancer cells (T24, 5637 and UM-UC-3 cells) to in vitro CRT by enhancing apoptosis. Importantly, the sensitizing effects were not observed in primarily cultured normal human urothelial cells. We also showed that CRT induces accumulation of nuclear phospho-Akt, which antagonizes apoptosis, and that Hsp90 inhibitors block the cellular process. Hsp90 inhibition sensitized bladder cancer cells to in vitro CRT more effectively than sole or combined inhibition of erbB2 and Akt. In mice UM-UC-3 tumor xenografts model, Hsp90 inhibitors successfully potentiated anti-tumor activity of CRT. These results encourage clinical trials of Hsp90 inhibitors to overcome CRT resistance in patients with MIBC.

ErbB2 and NFκB overexpression as predictors of chemoradiation resistance and putative targets to overcome resistance in muscle-invasive bladder cancer.

Radical cystectomy for muscle-invasive bladder cancer (MIBC) patients frequently impairs their quality of life (QOL) due to urinary diversion. To improve their QOL, a bladder-sparing alternative strategy using chemoradiation has been developed. In bladder-sparing protocols, complete response (CR) to induction chemoradiation is a prerequisite for bladder preservation and favorable survival. Thus predicting chemoradiation resistance and overcoming it would increase individual MIBC patients' chances of bladder preservation. The aim of this study is to investigate putative molecular targets for treatment aimed at improving chemoradiation response. Expression levels of erbB2, NFκB, p53, and survivin were evaluated immunohistochemically in pretreatment biopsy samples from 35 MIBC patients in whom chemoradiation sensitivity had been pathologically evaluated in cystectomy specimens, and associations of these expression levels with chemoradiation sensitivity and cancer-specific survival (CSS) were investigated. Of the 35 patients, 11 (31%) achieved pathological CR, while tumors in the remaining 24 patients (69%) were chemoradiation-resistant. Multivariate analysis identified erbB2 and NFκB overexpression and hydronephrosis as significant and independent risk factors for chemoradiation resistance with respective relative risks of 11.8 (P = 0.014), 15.4 (P = 0.024) and 14.3 (P = 0.038). The chemoradiation resistance rate was 88.5% for tumors overexpressing erbB2 and/or NFκB, but only 11.1% for those negative for both (P <0.0001). The 5-year CSS rate was 74% overall. Through multivariate analysis, overexpression of erbB2 and/or NFκB was identified as an independent risk factor for bladder cancer death with marginal significance (hazard ratio 21.5, P = 0.056) along with chemoradiation resistance (P = 0.003) and hydronephrosis (P = 0.018). The 5-year CSS rate for the 11 patients achieving pathological CR was 100%, while that for the 24 with chemoradiation-resistant disease was 61% (P = 0.018). Thus, erbB2 and NFκB overexpression are relevant to chemoradiation resistance and are putative targets aimed at overcoming chemoradiation resistance in MIBC.

[Successful treatment with multidisciplinary therapy including low-dose chemoradiotherapy against metastatic recurrences of small cell carcinoma of the renal pelvis: a case report].

Primary small cell carcinoma of the renal pelvis is a rare and aggressive disease; reportedly, a mean survival is only 8 months. A 78 year-old woman with chronic kidney disease was referred to our hospital complaining of asymptomatic gross hematoturia. On imaging studies and voided urine cytology, diagnosis of right renal pelvic cancer (cT2N0M0) was made. She underwent total nephroureterectomy. Pathological diagnosis was small cell carcinoma, infiltrating into the renal parenchyma, with lymphovascular invasion. Post-operatively, hemodialysis was introduced. Five months after the operation, new lesions developed in the right adrenal gland, aortocaval lymph nodes and subcutaneous layer of the right back. The subcutaneous mass was surgically removed and low-dose chemoradiotherapy (sigma 45 Gy/25 Fr/32 d + cisplatin 10 mg/d for 2 d x 2) was given to the other lesions. Although the lesions regressed to CR, new small masses emerged in the muscle layers of the right flank 14 months after total nephroureterectomy. Low-dose chemoradiotherapy (sigma 40 Gy/20 Fr/29 d + cisplatin 10 mg/d for 2 d x 2) to these lesions successfully brought CR. She is alive without any evidence of disease at 3 years after total nephroureterectomy.