Factors Associated With Discharge Destination in Advanced Cancer Patients With Bone Metastasis in a Japanese Hospital

Objective To analyze patient characteristics of cancer rehabilitation and outcomes at our hospital. Methods This retrospective study analyzed 580 patients, who underwent cancer rehabilitation at our hospital and rehabilitation outcome after therapy were investigated. The relationship between the initial Barthel index and discharge outcomes was investigated, with a special focus on cancer patients with bone metastasis. The Barthel index and performance status (Eastern Cooperative Oncology Group) before and after rehabilitation were analyzed, and threshold value of home discharge was calculated from a receiver operating characteristic curve (ROC). General criteria for home discharge from our hospital included independence in performing basic activities of daily living such as bathing, feeding, and toileting or availability of home support from a family member/caregiver. Results The outcomes after rehabilitation among all the patients were as follows: discharge home 59%, death 13%, and others 27%. Statistical differences were observed between the initial and final values of the Barthel index in patients with bone metastasis, who could be discharged home (p=0.012). ROC analysis of the initial Barthel index for predicting home discharge revealed a threshold value of 60, sensitivity of 0.76, and specificity of 0.72. Conclusion The patients with bone metastasis had a lower rate of home discharge and a higher rate of mortality than all the study patients who underwent cancer rehabilitation at our hospital. It is proposed that at the time of initiation of rehabilitation for patients with bone metastasis, an initial Barthel index lower than 60 might predict a worse outcome than home discharge

Ultrasound-guided intramural inoculation of orthotopic bladder cancer xenografts: a novel high-precision approach

Orthotopic bladder cancer xenografts are essential for testing novel therapies and molecular manipulations of cell lines in vivo. Current xenografts rely on tumor cell inoculation by intravesical instillation or direct injection into the bladder wall. Instillation is limited by the lack of cell lines that are tumorigenic when delivered in this manner. The invasive model inflicts morbidity on the mice by the need for laparotomy and mobilization of the bladder. Furthermore this procedure is complex and time-consuming. Three bladder cancer cell lines (UM-UC1, UM-UC3, UM-UC13) were inoculated into 50 athymic nude mice by percutaneous injection under ultrasound guidance. PBS was first injected between the muscle wall and the mucosa to separate these layers, and tumor cells were subsequently injected into this space. Bioluminescence and ultrasound were used to monitor tumor growth. Contrast-enhanced ultrasound was used to study changes in tumor perfusion after systemic gemcitabine/cisplatin treatment. To demonstrate proof of principle that therapeutic agents can be injected into established xenografts under ultrasound guidance, oncolytic virus (VSV) was injected into UM-UC3 tumors. Xenograft tissue was harvested for immunohistochemistry after 23–37 days. Percutaneous injection of tumor cells into the bladder wall was performed efficiently (mean time: 5.7 min) and without complications in all 50 animals. Ultrasound and bioluminescence confirmed presence of tumor in the anterior bladder wall in all animals 3 days later. The average tumor volumes increased steadily over the study period. UM-UC13 tumors showed a marked decrease in volume and perfusion after chemotherapy. Immunohistochemical staining for VSV-G demonstrated virus uptake in all UM-UC3 tumors after intratumoral injection. We have developed a novel method for creating orthotopic bladder cancer xenograft in a minimally invasive fashion. In our hands this has replaced the traditional model requiring laparotomy, because this model is more time efficient, more precise and associated with less morbidity for the mice

Risk stratification for the prognosis of patients with chemoresistant urothelial cancer treated with pembrolizumab

The use of immune checkpoint inhibitors to treat urothelial carcinoma (UC) is increasing rapidly without clear guidance for validated risk stratification. This multicenter retrospective study collected clinicopathological information on 463 patients, and 11 predefined variables were analyzed to develop a multivariate model predicting overall survival (OS). The model was validated using an independent dataset of 292 patients. Patient characteristics and outcomes were well balanced between the discovery and validation cohorts, which had median OS times of 10.2 and 12.5 mo, respectively. The final validated multivariate model was defined by risk scores based on the hazard ratios (HRs) of independent prognostic factors including performance status, site of metastasis, hemoglobin levels, and the neutrophil-to-lymphocyte ratio. The median OS times (95% confidence intervals [CIs]) for the low-, intermediate-, and high-risk groups (discovery cohort) were not yet reached (NYR) (NYR–19.1), 6.8 mo (5.8-8.9), and 2.3 mo (1.2-2.6), respectively. The HRs (95% CI) for OS in the low- and intermediate-risk groups vs the high-risk group were 0.07 (0.04-0.11) and 0.23 (0.15-0.37), respectively. The objective response rates for in the low-, intermediate-, and high-risk groups were 48.3%, 28.8%, and 10.5%, respectively. These differential outcomes were well reproduced in the validation cohort and in patients who received pembrolizumab after perioperative or first-line chemotherapy (N = 584). In conclusion, the present study developed and validated a simple prognostic model predicting the oncological outcomes of pembrolizumab-treated patients with chemoresistant UC. The model provides useful information for external validation, patient counseling, and clinical trial design

Planarian Hedgehog/Patched establishes anterior–posterior polarity by regulating Wnt signaling

100年来の謎に迫る－体の極性を決める仕組みを解明しました. 京都大学プレスリリース. 2009-12-08.Despite long-standing interest, the molecular mechanisms underlying the establishment of anterior–posterior (AP) polarity remain among the unsolved mysteries in metazoans. In the planarians (a family of flatworms), canonical Wnt/β-catenin signaling is required for posterior specification, as it is in many animals. However, the molecular mechanisms regulating the posterior-specific induction of Wnt genes according to the AP polarity have remained unclear. Here, we demonstrate that Hedgehog (Hh) signaling is responsible for the establishment of AP polarity via its regulation of the transcription of Wnt family genes during planarian regeneration. We found that RNAi gene knockdown of Dugesia japonica patched (Djptc) caused ectopic tail formation in the anterior blastema of body fragments, resulting in bipolar-tails regeneration. In contrast, RNAi of hedgehog (Djhh) and gli (Djgli) caused bipolar-heads regeneration. We show that Patched-mediated Hh signaling was crucial for posterior specification, which is established by regulating the transcription of Wnt genes via downstream Gli activity. Moreover, differentiated cells were responsible for the posterior specification of undifferentiated stem cells through Wnt/β-catenin signaling. Surprisingly, Djhh was expressed in neural cells all along the ventral nerve cords (along the AP axis), but not in the posterior blastema of body fragments, where the expression of Wnt genes was induced for posteriorization. We therefore propose that Hh signals direct head or tail regeneration according to the AP polarity, which is established by Hh signaling activity along the body's preexisting nervous system

Cultivation and characterization of planarian neuronal cells isolated by fluorescence activated cell sorting (FACS)

Studies using molecular markers have revealed that planarians possess a highly organized brain. Here we separated brain neurons from dissociated planarian head cells by fluorescence activated cell sorting (FACS), and characterized them by single cell PCR analysis and cell culture. Dissociated cells were labeled with three different fluorescent dyes, Hoechst 33258, Merocyanine 540, and Propidium Iodide (PI), and fractioned by FACS. Interestingly, we have succeeded in identifying a cell fraction specific to the head, which we have named the head-abundant cell fraction (HAC). Most of the HAC expressed neuron-specific genes and proteins. When they were cultured in vitro, they showed an ability to extend neurites on several types of extracellular matrices (ECMs), and, depending on the ECM type used, presented a high level of plasticity in morphology and gene expression