The impact of crystal phase transition on the hardness and structure of kidney stones.

Calcium oxalate kidney stones, the most prevalent type of kidney stones, undergo a multi-step process of crystal nucleation, growth, aggregation, and secondary transition. The secondary transition has been rather overlooked, and thus, the effects on the disease and the underlying mechanism remain unclear. Here, we show, by periodic micro-CT images of human kidney stones in an ex vivo incubation experiment, that the growth of porous aggregates of calcium oxalate dihydrate (COD) crystals triggers the hardening of the kidney stones that causes difficulty in lithotripsy of kidney stone disease in the secondary transition. This hardening was caused by the internal nucleation and growth of precise calcium oxalate monohydrate (COM) crystals from isolated urine in which the calcium oxalate concentrations decreased by the growth of COD in closed grain boundaries of COD aggregate kidney stones. Reducing the calcium oxalate concentrations in urine is regarded as a typical approach for avoiding the recurrence. However, our results revealed that the decrease of the concentrations in closed microenvironments conversely promotes the transition of the COD aggregates into hard COM aggregates. We anticipate that the suppression of the secondary transition has the potential to manage the deterioration of kidney stone disease.

Safety and effectiveness of avelumab in patients with Merkel cell carcinoma in general clinical practice in Japan: Post-marketing surveillance.

Avelumab, a programmed cell death ligand 1 blocking antibody, was approved for its first indication in Japan in September 2017 to treat unresectable Merkel cell carcinoma (MCC). Given that the pivotal JAVELIN Merkel 200 study only included a few Japanese patients, this post-marketing surveillance (PMS) evaluated the safety and effectiveness outcomes of patients with MCC who received avelumab in general clinical practice in Japan. This prospective, non-comparative, multicenter PMS included data from all patients with unresectable MCC who received avelumab between November 22, 2017 (avelumab launch date) and October 31, 2019. The primary objective was to evaluate avelumab safety (i.e., adverse events [AEs], adverse drug reactions [ADRs], and ADRs of safety specifications). The secondary objective was to evaluate avelumab effectiveness (i.e., objective response rate and overall survival [OS] rate). Seventy-five evaluable patients were included, of whom 81.3% experienced AEs of any grade (57.3% experienced AEs of grade ≥ 3; 41.3% experienced AEs of grade 5) and 61.3% experienced ADRs (14.7% experienced ADRs of grade ≥ 3; no grade 5 ADRs were observed). The most common ADRs were pyrexia (18.7%), infusion related reaction (10.7%), and chills (6.7%). The most common ADRs of safety specifications were infusion reactions (any grade: n = 21 [28.0%]; grade 3 or 4: n = 3 [4.0%]), thyroid dysfunction (n = 7 [9.3%]), and hepatic function disorders (n = 4 [5.3%]). The median observation period was 51 weeks. An objective response was achieved by 34/75 patients (45.3%; complete response, 24.0%; partial response, 21.3%) and 6- and 12-month OS rates were 77.7% and 59.6%, respectively. This PMS confirmed the clinical tolerability and effectiveness of avelumab in patients with MCC, with no new safety concerns. The risk-benefit profile of avelumab was comparable with that observed in clinical trials and remains favorable for use in general clinical practice in Japan.

Using machine learning probabilities to identify effects of COVID-19.

Coronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has had extensive economic, social, and public health impacts in the United States and around the world. To date, there have been more than 600 million reported infections worldwide with more than 6 million reported deaths. Retrospective analysis, which identified comorbidities, risk factors, and treatments, has underpinned the response. As the situation transitions to an endemic, retrospective analyses using electronic health records will be important to identify the long-term effects of COVID-19. However, these analyses can be complicated by incomplete records, which makes it difficult to differentiate visits where the patient had COVID-19. To address this issue, we trained a random Forest classifier to assign a probability of a patient having been diagnosed with COVID-19 during each visit. Using these probabilities, we found that higher COVID-19 probabilities were associated with a future diagnosis of myocardial infarction, urinary tract infection, acute renal failure, and type 2 diabetes.

[A case of rectal cancer with immune thrombocytopenic purpura that achieved a complete response to continued chemotherapy with eltrombopag].

A 73-year-old male patient with postoperative recurrent rectal cancer developed thrombocytopenia after XELOX therapy. Thrombocytopenia persisted despite chemotherapy discontinuation;therefore, he was referred to our department for further evaluation. Bone marrow specimen examination revealed increased immature megakaryocytes and blood test results revealed elevated platelet-associated immunoglobulin G (PA-IgG) levels, leading to immune thrombocytopenic purpura diagnosis. His platelet count recovered after prednisolone therapy. Eltrombopag treatment was introduced considering thrombocytopenia secondary to chemotherapy resumption for rectal cancer. FOLFIRI therapy was continued without platelet count reduction, and PA-IgG levels decreased over time. The patient continued chemotherapy with eltrombopag and achieved a complete treatment response.

Quantitative analysis of calcium oxalate monohydrate and dihydrate for elucidating the formation mechanism of calcium oxalate kidney stones.

We sought to identify and quantitatively analyze calcium oxalate (CaOx) kidney stones on the order of micrometers, with a focus on the quantitative identification of calcium oxalate monohydrate (COM) and dihydrate (COD). We performed Fourier transform infrared (FTIR) spectroscopy, powder X-ray diffraction (PXRD), and microfocus X-ray computed tomography measurements (microfocus X-ray CT) and compared their results. An extended analysis of the FTIR spectrum focusing on the 780 cm-1 peak made it possible to achieve a reliable analysis of the COM/COD ratio. We succeeded in the quantitative analysis of COM/COD in 50-µm2 areas by applying microscopic FTIR for thin sections of kidney stones, and by applying microfocus X-ray CT system for bulk samples. The analysis results based on the PXRD measurements with micro-sampling, the microscopic FTIR analysis of thin sections, and the microfocus X-ray CT system observation of a bulk kidney stone sample showed roughly consistent results, indicating that all three methods can be used complementarily. This quantitative analysis method evaluates the detailed CaOx composition on the preserved stone surface and provides information on the stone formation processes. This information clarifies where and which crystal phase nucleates, how the crystals grow, and how the transition from the metastable phase to the stable phase proceeds. The phase transition affects the growth rate and hardness of kidney stones and thus provides crucial clues to the kidney stone formation process.

Anomalous Crystal Shapes of Topological Crystalline Insulators.

Understanding crystal shapes is a fundamental subject in surface science. It is now well studied how chemical bondings determine crystal shapes via dependence of surface energies on surface orientations. Meanwhile, discoveries of topological materials have led us to a new paradigm in surface science, and one can expect that topological surface states may affect surface energies and crystal facets in an unconventional way. Here, we show that the surface energy of glide-symmetric topological crystalline insulators (TCI) depends on the surface orientation in a singular way via the parity of the Miller index. This singular surface energy of the TCI affects equilibrium crystal shapes, resulting in emergence of unique crystal facets of the TCI. This singular dependence of the topological surface states is unique to the TCI protected by the glide symmetry in contrast to a TCI protected by a mirror symmetry. In addition, we show that such singular surface states of the TCI protected by the glide symmetries can be realized in KHgSb with first-principles calculations. Our results provide a basis for designs and manipulations of crystal facets by using symmetry and topology.

Multicolor imaging of calcium-binding proteins in human kidney stones for elucidating the effects of proteins on crystal growth.

The pathogenesis of kidney stone formation includes multi-step processes involving complex interactions between mineral components and protein matrix. Calcium-binding proteins in kidney stones have great influences on the stone formation. The spatial distributions of these proteins in kidney stones are essential for evaluating the in vivo effects of proteins on the stone formation, although the actual distribution of these proteins is still unclear. We reveal micro-scale distributions of three different proteins, namely osteopontin (OPN), renal prothrombin fragment 1 (RPTF-1), and calgranulin A (Cal-A), in human kidney stones retaining original mineral phases and textures: calcium oxalate monohydrate (COM) and calcium oxalate dihydrate (COD). OPN and RPTF-1 were distributed inside of both COM and COD crystals, whereas Cal-A was distributed outside of crystals. OPN and RPTF-1 showed homogeneous distributions in COM crystals with mosaic texture, and periodically distributions parallel to specific crystal faces in COD crystals. The unique distributions of these proteins enable us to interpret the different in vivo effects of each protein on CaOx crystal growth based on their physico-chemical properties and the complex physical environment changes of each protein. This method will further allow us to elucidate in vivo effects of different proteins on kidney stone formation.

Risk Factors for Failure of Endoscopic Management of Stone-related Ureteral Strictures.

PURPOSE: To investigate factors determining the outcomes of endoscopic management for stone-related ureteral stricture. MATERIALS AND METHODS: Data of patients who underwent endoscopic surgery for ureteral stricture due to stones from January 2016 to April 2020 were retrospectively analyzed. We compared cases successfully treated with endoscopic surgery with cases that resulted in failure. We focused on factors associated with treatment success, including cause and length of stricture, methods of stricture treatment, surgical time, and duration of hydronephrosis before the treatment. Treatment success was defined as improvement in hydronephrosis status. RESULTS: Nineteen patients were treated for stone-related ureteral stricture. Hydronephrosis was successfully improved in 12 patients (63.2%). Seven patients with failed endoscopic management had ureteroscopic lithotripsy- related stricture, whereas 3/12 (25.0%) patients with ureteroscopic lithotripsy-related stricture and 7/12 (58.3%) patients with impacted stone-related stricture were successfully treated by endoscopic management (P = .004). The prevalence of stricture length > 15 mm was significantly higher in the patients with failed management than in the patients with successful management (71.4 vs 16.6%, P = .046). Intraoperative endoscopic observation demonstrated that the mucosa of the ureteroscopic lithotripsy-related stricture had ischemic appearance with relatively long stricture length (P = 0.13) compared to the impacted stone-related stricture. No association was observed between treatment outcome and method of endoscopic management, including laser incision, balloon dilation, or both. CONCLUSION: Ureteroscopic lithotripsy as a cause and stricture length > 15 mm could affect the success rate of endoscopic management of ureteral stricture. In such cases, reconstructive management should probably be considered in the early stages.

A novel approach in creating nephrostomy using a double-lumen access sheath during endoscopic combined intrarenal surgery.

BACKGROUND: This study aimed to evaluate the safety and efficacy of an inner ureteral access sheath (i-UAS) with a double-lumen channel used in ureteroscopic lithotripsy (URS) as a dilator for the percutaneous tract in endoscopic combined intrarenal surgery (ECIRS). METHODS: This was a single-center cohort study conducted from January 2016 to April 2020. We used an i-UAS as a dilator and a double-lumen catheter to insert a safety guidewire during the creation of the nephrostomy tract in ECIRS. Univariate and multivariate analyses were performed to assess the association between the perioperative parameters and the use of i-UAS. The primary endpoint was perioperative complications, and secondary endpoints were stone-free rate (SFR), operative time, fluoroscopy time, and duration of hospitalization. RESULTS: In total, 221 patients were enrolled during the study period. Patients were divided into an i-UAS dilation group (n=108) and a one-shot dilation group (n=113). No differences were observed between the two groups in terms of patient history. Univariate analyses indicated that, in the i-UAS dilation group, the operative time was shorter [105.50 (83.75-143.25) vs. 121.00 (90.00-155.00) min; P=0.02] and the modified Valdivia position was more frequently selected. Multivariate analyses showed no significant differences in the frequency of complications, such as urinary injury or postoperative pyelonephritis, but it showed a significantly shorter operative time as well as fewer tract creation troubles in the i-UAS dilation group. CONCLUSIONS: Using an i-UAS as a dilator and a double-lumen catheter to insert a safety guidewire during ECIRS is a convenient and safe technical method for creating a nephrostomy tract that can reduce the operative time.

Low bone mineral density is a potential risk factor for symptom onset and related with hypocitraturia in urolithiasis patients: a single-center retrospective cohort study.

BACKGROUND: Patients with urolithiasis have a lower bone mineral density (BMD) than those without stones, suggesting a potential correlation between calcium stone formation and bone resorption disorders, including osteopenia and osteoporosis. METHODS: To investigate the influence of BMD on clinical outcomes in urolithiasis, we performed a single-center retrospective cohort study to analyze patients with urolithiasis who underwent both BMD examination and 24-h urine collection between 2006 and 2015. Data from the national cross-sectional surveillance of the Japanese Society on Urolithiasis Research in 2015 were utilized, and additional data related to urinary tract stones were obtained from medical records. The primary outcome was the development of stone-related symptoms and recurrences during follow-up. A total of 370 patients were included in this 10-year study period. RESULTS: Half of the patients had recurrent stones, and the two-thirds were symptomatic stone formers. While only 9% of patients had hypercalciuria, 27% and 55% had hyperoxaluria and hypocitraturia, respectively. There was a positive correlation between T-scores and urinary citrate excretion. Both univariate and multivariate analyses demonstrated that female sex was associated with recurrences (odds ratio = 0.44, p = 0.007), whereas a T-score < - 2.5 and hyperoxaluria were associated with symptoms (odds ratio = 2.59, p = 0.037; odds ratio = 0.45, p = 0.01; respectively). CONCLUSION: These results revealed that low T-scores might cause symptoms in patients with urolithiasis, suggesting the importance of BMD examination for high-risk Japanese patients with urolithiasis having hypocitraturia.

Robot-Assisted Fluoroscopy Versus Ultrasound-Guided Renal Access for Nephrolithotomy: A Phantom Model Benchtop Study.

Objectives: To evaluate the feasibility of robot-assisted fluoroscopy-guided (RAG) puncture and to compare RAG puncture, utilizing a novel robot system for percutaneous renal access, with ultrasound-guided (USG) puncture. Materials and Methods: We conducted a benchtop study with a renal phantom model using the automated needle targeting with an X-ray system. Seventeen urologists participated in this study and performed RAG and USG phantom punctures. The number of needle punctures, device setup time, and fluoroscopic exposure duration were recorded for the analyses. Results: The single puncture success rates of the RAG and USG punctures were 100% and 70.6%, respectively (p = 0.021). The median needle puncture time of RAG puncture was 24% shorter than that of USG puncture (35.0 vs 46.0 seconds; p < 0.001), and the median device setup time of RAG puncture was a minute longer than that of USG puncture (93.0 vs 30.5 seconds; p < 0.001). The median duration of fluoroscopic exposure of RAG puncture was longer than that of USG puncture (38.0 vs 6.5 seconds; p < 0.001). The surgeon's self-assessment results demonstrated that the participating urologists found RAG puncture to be safer and have better visibility than USG puncture; they were also more satisfied with RAG puncture. Subanalysis revealed that, in the RAG group, the attending surgeons had shorter total procedural time than the residents (p = 0.045). Conclusion: RAG puncture showed comparable results and accuracy rates with USG puncture for renal access.

Evaluation of the Dwell-Time and Dose Difference in Intravesical Bacillus Calmette-Guèrin Therapy

Objective: Bacillus Calmette-Guèrin (BCG) intravesical therapy is currently established using a low dose because of the high incidence of side-effects. Moreover, shortening the dwell time of BCG is conducted in some facilities owing to the complications associated with a long dwell time after injection. The method of BCG administration varies in each facility and even with each doctor. We evaluated whether the dwell-time and dose differences in patients who underwent intravesical BCG therapy is related to completion rates, adverse effects, and nonrecurrence rates. Methods: From November 2006 to April 2016, a total of 173 patients who received intravesical BCG therapy after transurethral resection of bladder tumor or transurethral biopsy were evaluated retrospectively. We allocated them into 4 groups based on the dose (40 or 80 mg BCG) and the dwell time (1 or 2 hours). Completion rate, side effects, and nonrecurrence rates were evaluated. Results: No significant improvement in the completion rate or reduction in side-effects was observed in any of the regimens. Although nonrecurrence rates for the 1-hour dwell time tended to be lower than the 2-hour dwell time, the difference was not significant. Conclusion: Our study suggests that reducing the BCG dose or shortening the dwell time does not reduce adverse effects or affect the nonrecurrence rate.

Identification of new urinary risk markers for urinary stones using a logistic model and multinomial logit model.

BACKGROUND: Risk assessment for urinary stones has been mainly based on urinary biochemistry. We attempted to identify the risk factors for urinary stones by statistically analyzing urinary biochemical and inflammation-related factors. METHODS: Male participants (age, 20-79 years) who visited Nagoya City University Hospital were divided into three groups: a control group (n = 48) with no history of stones and two stone groups with calcium oxalate stone experience (first-time group, n = 22; recurring group, n = 40). Using 25-µL spot urine samples, we determined the concentrations of 18 candidate urinary proteins, using multiplex analysis on a MagPix® system. RESULTS: In univariate logistic regression models classifying the control and first-time groups, interleukin (IL)-1a and IL-4 were independent factors, with significantly high areas under the receiver operating characteristic curve (1.00 and 0.87, respectively, P < 0.01 for both). The multivariate models with IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) showed higher areas under the receiver operating characteristic curve (0.93) compared to that for the univariate model with IL-4. In the classification of control, first-time, and recurrence groups, accuracy was the highest for the multinomial logit model with IL-4, GM-CSF, IL-1b, IL-10, and urinary magnesium (concordance rate 82.6%). CONCLUSIONS: IL-4, IL-1a, GM-CSF, IL-1b, and IL-10 were identified as urinary inflammation-related factors that could accurately distinguish control individuals from patients with urinary stones. Thus, the combined analysis of urinary biochemical data could provide an index that more clearly evaluates the risk of urinary stone formation.

Hemothorax during miniaturized endoscopic combined intrarenal surgery under ureteroscope-assisted ultrasound-guided access.

INTRODUCTION: Hemothorax is a rare but life-threatening complication following mini-endoscopic combined intrarenal surgery. Herein, we describe a patient with left staghorn kidney stone who presented with hemothorax following mini-endoscopic combined intrarenal surgery under ureteroscope-assisted ultrasound-guided access. CASE PRESENTATION: A 47-year-old woman with left staghorn kidney stone underwent mini-endoscopic combined intrarenal surgery, after which she developed shortness of breath. Chest radiography and computed tomography confirmed left hemothorax. Conservative management and left intercostal chest drainage were performed without improvement. Subsequently, video-assisted thoracoscopic debridement was performed. CONCLUSION: Hemothorax is a severe complication of mini-endoscopic combined intrarenal surgery, which, regardless of accurate access through an ideal renal calyx under ureteroscope-assisted ultrasound-guided access, may lead to pleural injury. Refinement of the surgical technique and management after percutaneous nephrolithotomy is the key to avoiding life-threatening situations.

Outcomes and Complications of Simultaneous Laparoscopic Cystectomy and Laparoscopic Nephroureterectomy with Umbilical Reduced Port Surgery

Objective: In recent years, although reduced port surgeries (RPS) have been reported for many urological diseases, there have been no reports regarding simultaneous laparoscopic cystectomy and unilateral or bilateral nephroureterectomy with umbilical RPS. Therefore, the aim of this study was to evaluate outcomes and complications of simultaneous laparoscopic cystectomy and unilateral or bilateral nephroureterectomy with umbilical RPS. Methods: We performed a preliminary case series of 4 patients with synchronous upper urinary tract (UUT) tumor and invasive bladder cancer who underwent simultaneous laparoscopic cystectomy and unilateral or bilateral nephroureterectomy with umbilical RPS between 2014 and 2017 at our hospital. Demographic data, pathologic features, the surgical technique, and outcomes were retrospectively analyzed. Result: All 4 patients were men whose median age was 79 years (range 65-85 years) and median body mass index was 24.2 kg/m2 (range 21.5-27.3 kg/m2). The laparoscopic approach was technically successful in all 4 patients without the need for open conversion. The median total operative time was 434 minutes (range 372-481 minutes). The median estimated blood loss was 773 ml (range 153-923 ml), median interval to resuming oral intake was 2 days (range 1-7 days), and median hospital stay was 16 days (range 13-20 days). Conclusion: The reduced port approach is technically feasible in terms of many outcome measures, with significant cosmetic advantages. This method can be performed safely and recommended as a viable option for patients with concomitant UUT and bladder cancer.

Gemcitabine and docetaxel as second-line chemotherapy in elderly patients with metastatic urothelial carcinoma: a retrospective analysis.

BACKGROUND: The objective of this study was to evaluate the efficacy of a combination of gemcitabine and docetaxel (GD) as a second-line treatment for elderly patients with metastatic urothelial carcinoma (mUC). PATIENTS AND METHODS: A total of 122 patients with mUC who were previously treated with platinum-based chemotherapy received second-line GD therapy from July 2010 to June 2016. This consisted of 800 mg/m2 gemcitabine and 40 mg/m2 docetaxel on days 1 and 8 in each 21-day cycle. Using pooled cumulative data, we divided patients into the following three groups based on age: <65 years (Group A), from 65 to 74 years (Group B), and ≥75 years (Group C), and then the data were retrospectively analyzed. All patients were evaluated for treatment-related toxicities and assessed at every cycle by imaging studies. Kaplan-Meier curves were used for survival and recurrence analyses. Furthermore, potential prognostic factors for progression-free survival (PFS) and overall survival (OS) were assessed via univariate and multivariate Cox regression analyses. RESULTS: The median follow-up period was 8.2 months (range: 2.1-100). The median number of treatment cycles was three (range: 1-16) in Group A, three (1-15) in Group B, and two (1-11) in Group C. The objective response rate was not significantly different between the three groups. In addition, PFS and OS from the start of second-line GD therapy were also not significantly different. According to univariate and multivariate analyses of the second-line GD-treated cohort, a good performance status was the only prognostic factor for PFS and OS. In Group C, myelosuppression including predominant neutropenia and anemia, fatigue, and nausea were the main common adverse events. However, the incidence of neutropenia and a reduction in platelets were not significantly different between the three groups. Treatment-related deaths did not occur in this study. CONCLUSION: In this study, GD combination therapy as a second-line treatment for mUC resulted in favorable tumor responses and few treatment-related toxicities, even among elderly patients.

Control of polarization and tumoricidal activity of macrophages by multicellular spheroid formation.

Immune cell-based therapy is a promising approach for cancer immunotherapy. Macrophages can be used for this purpose if their tumoricidal activity and viability are properly controlled. In the present study, we aimed to enhance these properties of macrophages by constructing uniformly sized multicellular spheroids. Mouse macrophage-like J774.1 cells were selected as model macrophages, and poly(N-isopropylacrylamide)-coated polydimethylsiloxane-based microwell plates with an approximate diameter of 750µm were used to prepare J774.1 spheroids. J774.1 spheroids were successfully generated, and the viability of cells in the spheroids was over 95%. J774.1 spheroids showed higher mRNA expression of induced nitric oxide synthase, a marker of M1-type activated macrophages, than monolayered J774.1 cells. The production of reactive oxygen species was also high in J774.1 spheroids, suggesting the existence of hypoxic regions in the spheroids. J774.1 spheroids released more tumor necrosis factor-α than monolayered cells upon stimulation with lipopolysaccharide. Moreover, J774.1 spheroids in the upper compartment of the Transwell system more efficiently inhibited the proliferation of mouse adenocarcinoma colon 26 cells in its lower compartment than monolayered J774.1 cells did. These results indicate that spheroid formation can be used to increase the tumoricidal activity of macrophages for use in cell-based cancer immunotherapy.

Primary diffuse large B-cell lymphoma of the ileal conduit created after radical cystectomy.

INTRODUCTION: Creation of an ileal conduit is associated with complications. A few cases have been reported on tumor development in an ileal conduit; diffuse large B-cell lymphoma originating from an ileal conduit is extremely rare. CASE PRESENTATION: A 62-year-old Japanese man who had undergone radical cystectomy and ileal conduit diversion 6 years previously presented with a whitish bulge that had developed on the surface of the ileal conduit during follow-up visit. Mass biopsy was performed and the histological diagnosis was diffuse large B-cell lymphoma. Positron emission tomography showed no metastatic lesions. We attempted chemotherapy because the tumor cells tested positive for CD20; after six courses of a regimen involving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; diffuse large B-cell lymphoma of the ileal conduit resolved gradually. The patient is alive and remains free from the diagnosed diffuse large B-cell lymphoma. CONCLUSION: We reported an extremely rare case of diffuse large B-cell lymphoma originating from the ileal conduit created after radical cystectomy.

A pilot study of gemcitabine and paclitaxel as third-line chemotherapy in metastatic urothelial carcinoma.

Background: We evaluated the effectiveness of gemcitabine and paclitaxel therapy in patients with metastatic urothelial carcinoma for whom two lines of sequential chemotherapy had been unsuccessful. Methods: A total number of 105 patients who had previously received first-line chemotherapy consisting of gemcitabine and cisplatin or carboplatin, were treated with second-line gemcitabine and docetaxel therapy between June 2006 and May 2015. Of these patients, 15 with an Eastern Cooperative Oncology Group Performance Status of 0 or 1 were administered gemcitabine and paclitaxel as third-line treatment from 2013 after failure of the second-line therapy. For each 21-day cycle, gemcitabine (1000 mg/m2) was administered on days 1, 8, and 15, and paclitaxel (200 mg/m2) on day 1. Patients were assessed for each cycle and any adverse events were noted. Furthermore, a Short Form Health Survey questionnaire was used to assess each patient's quality of life. Results: Third-line gemcitabine and paclitaxel treatment cycles were undertaken for a median of four times (range 2-9). The disease control rate was 80.0%. After second-line gemcitabine and docetaxel therapy was completed, median progression-free survival and median overall survival were determined as 9.8 and 13.0 months, respectively. The only prognostic factor for overall survival, as determined by univariate and multivariate analyses, was third-line gemcitabine and paclitaxel therapy. Neutropenia (66.7%) and thrombocytopenia (53.3%) were noted as the grade 3 treatment-related toxicities. After two cycles of third-line gemcitabine and paclitaxel therapy, the pre- and post-treatment quality of life scores did not differ significantly. Conclusions: Results demonstrate that third-line combination therapy using gemcitabine and paclitaxel is a feasible option for metastatic urothelial carcinoma patients.

Efficient Transdermal Delivery of Alendronate, a Nitrogen-Containing Bisphosphonate, Using Tip-Loaded Self-Dissolving Microneedle Arrays for the Treatment of Osteoporosis.

To improve the transdermal bioavailability and safety of alendronate (ALN), a nitrogen-containing bisphosphonate, we developed self-dissolving microneedle arrays (MNs), in which ALN is loaded only at the tip portion of micron-scale needles by a dip-coating method (ALN(TIP)-MN). We observed micron-scale pores in rat skin just after application of ALN(TIP)-MN, indicating that transdermal pathways for ALN were created by MN. ALN was rapidly released from the tip of MNs as observed in an in vitro release study. The tip portions of MNs completely dissolved in the rat skin within 5 min after application in vivo. After application of ALN(TIP)-MN in mice, the plasma concentration of ALN rapidly increased, and the bioavailability of ALN was approximately 96%. In addition, the decrease in growth plate was effectively suppressed by this efficient delivery of ALN in a rat model of osteoporosis. Furthermore, no skin irritation was observed after application of ALN(TIP)-MN and subcutaneous injection of ALN, while mild skin irritation was induced by whole-ALN-loaded MN (ALN-MN)-in which ALN is contained in the whole of the micron-scale needles fabricated from hyaluronic acid-and intradermal injection of ALN. These findings indicate that ALN(TIP)-MN is a promising transdermal formulation for the treatment of osteoporosis without skin irritation.