Vision-based estimation of manipulation forces by deep learning of laparoscopic surgical images obtained in a porcine excised kidney experiment.

In robot-assisted surgery, in which haptics should be absent, surgeons experience haptics-like sensations as "pseudo-haptic feedback". As surgeons who routinely perform robot-assisted laparoscopic surgery, we wondered if we could make these "pseudo-haptics" explicit to surgeons. Therefore, we created a simulation model that estimates manipulation forces using only visual images in surgery. This study aimed to achieve vision-based estimations of the magnitude of forces during forceps manipulation of organs. We also attempted to detect over-force, exceeding the threshold of safe manipulation. We created a sensor forceps that can detect precise pressure at the tips with three vectors. Using an endoscopic system that is used in actual surgery, images of the manipulation of excised pig kidneys were recorded with synchronized force data. A force estimation model was then created using deep learning. Effective detection of over-force was achieved if the region of the visual images was restricted by the region of interest around the tips of the forceps. In this paper, we emphasize the importance of limiting the region of interest in vision-based force estimation tasks.

Efficacy and Tolerability of Second-line Pembrolizumab With Radiation Therapy in Advanced Urothelial Carcinoma.

BACKGROUND/AIM: Considering the limited data available on immune checkpoint inhibitors and radiation combination therapy in advanced urothelial carcinoma, this study evaluated the survival benefit and associated toxicity of adding radiation therapy to second-line pembrolizumab. PATIENTS AND METHODS: We retrospectively examined 24 consecutive patients with advanced bladder or upper urinary tract urothelial carcinoma and for whom second-line pembrolizumab was initiated between August 2018 and October 2021 in combination with radiation therapy (with curative intent in 12 patients, and palliative intent in 12 patients). Their survival outcomes and toxicities were compared with those of propensity-score-matched cohorts from a Japanese multicenter study with similar characteristics who received pembrolizumab monotherapy. RESULTS: The median follow-up periods after pembrolizumab initiation were 15 months for the curative cohort and 4 months for the palliative cohort. The median overall survival was 27.7 months for the curative cohort and 4.8 months for the palliative cohort. Compared with the matched pembrolizumab monotherapy cohort, overall survival was better among the curative cohort although not statistically significant (p=0.13), but similar between the palliative and matched pembrolizumab monotherapy cohorts (p=0.44). There was no difference in the incidence of grade ≥2 adverse events between the combination and monotherapy cohorts, irrespective of the intent of radiation therapy. CONCLUSION: The combination of radiation therapy and pembrolizumab can be performed with a clinically acceptable safety profile, and the addition of radiation therapy to immune checkpoint inhibitors may improve survival outcome after pembrolizumab treatment in cases where the intent of radiation therapy is curative.

Limited predictive impact of tumor size dynamics on further tumor shrinkage after 4 cycles of first-line chemotherapy in patients with advanced urothelial carcinoma.

PURPOSE: To investigate the correlation between tumor size changes during the initial 4 cycles of first-line chemotherapy and tumor shrinkage following 2 additional cycles of chemotherapy in patients with advanced urothelial carcinoma (aUC) who experienced disease control after initial chemotherapy. METHODS: We retrospectively reviewed 128 patients with aUC who received first-line chemotherapy. We analyzed 51 patients with disease control (stable disease or better) at the end of the fourth cycle. Of these, 47 patients received 1 to 2 additional cycles of chemotherapy, whereas the remaining patients underwent observation. For patients who received additional chemotherapy, the change in tumor size after additional chemotherapy (cycles 5-6) was defined as "no shrinkage" (tumor growth), "minor shrinkage" (no tumor growth or ≤10% reduction in tumor size), or "shrinkage" (>10% reduction in tumor size). Then, we investigated the relationship between the rate of tumor size change during the initial 4 cycles and that after additional chemotherapy. RESULTS: Of the patients who received additional chemotherapy, the change in tumor size was categorized as no shrinkage in 21 patients (44.7%), minor shrinkage in 18 patients (38.3%), and shrinkage in 8 patients (17%). Regarding predictors of tumor shrinkage after additional chemotherapy, the rate of tumor size change between the cycles 3 and 4 (area under the receiver operating characteristics curve = 0.642) was correlated with the trend of the tumor shrinkage (P = 0.009) and the likelihood of beneficial tumor shrinkage after additional chemotherapy (minor shrinkage + shrinkage; P = 0.02). However, the change in tumor size between cycles 1 and 2, cycles 1 and 4, or cycles 3 and 4 was not satisfactorily predictive of further tumor shrinkage because of substantial overlaps of the tumor size changes. CONCLUSIONS: Only a small subset of patients would have substantial tumor shrinkage by additional cycles after successful induction of 4 cycle chemotherapy. Tumor size dynamics during the initial 4 cycles of chemotherapy displayed limited ability to predict the subset of patients with further tumor shrinkage after additional chemotherapy. Therefore, it might be better to consider switch maintenance immunotherapy for patients who experience disease control after the fourth cycle of first-line chemotherapy.

IFN-Gamma Expression in the Tumor Microenvironment and CD8-Positive Tumor-Infiltrating Lymphocytes as Prognostic Markers in Urothelial Cancer Patients Receiving Pembrolizumab.

Although immune checkpoint inhibitors have shown benefit for advanced urothelial carcinoma (aUC) patients, prognostication of treatment efficacy and response duration remains a clinical challenge. We evaluated the expression of immune markers in the tumor microenvironment and assessed their associations with response to and survival after pembrolizumab treatment in 26 aUC patients. High levels of CD8+ tumor-infiltrating lymphocytes (TILs) were associated with favorable objective responses (23.0% vs. 15.3%, p = 0.0425), progression-free survival (median, 8.8 vs 2.1 months; hazard ratio (HR), 0.24; 95% confidence interval (CI), 0.07-0.66, p = 0.0060), and overall survival (median, >24.0 vs. 5.3 months; HR, 0.17; 95% CI, 0.04-0.56, p = 0.0034) compared with low levels. High interferon-gamma (IFNγ) expression levels were associated with longer post-progression survival (median, 4.9 vs. 1.0 months; HR, 0.18; 95% CI, 0.04-0.59, p = 0.0027) compared with low expression. Multivariate analysis incorporating clinical prognosticators demonstrated that the coincidence of low CD8+ T cells/IFNγ was an independent factor for unfavorable overall survival after pembrolizumab treatment (HR, 4.07; 95% CI, 1.36-12.73; p = 0.0125). The combination of low CD8+ TILs and IFNγ expression was an independent prognostic factor with predictive ability equivalent to previously reported clinical prognosticators.

Modification of Platinum-based Systemic Chemotherapy for Advanced Urothelial Carcinoma in Patients With Suboptimal Renal Function.

BACKGROUND/AIM: Standard chemotherapy for advanced urothelial carcinoma (UC) patients with moderate renal dysfunction has not yet been established. PATIENTS AND METHODS: We retrospectively assessed outcomes of patients with advanced UC who underwent first-line chemotherapy with full-/reduced-dose gemcitabine plus cisplatin (GC-f/GC-r) or full-/reduced-dose gemcitabine plus carboplatin (G-Car-f/G-Car-r) according to renal function. RESULTS: Seventy-eight patients were included in this study. The objective response rate was 42%, 30%, 42%, and 27% for the GC-f, GC-r, G-Car-f, and G-Car-r groups, respectively. For the GC-r and G-Car-f groups, the median progression-free survival and the median overall survival was 4.5 vs. 7.0 months (p=0.07) and 7.5 months vs. 12.0 months (p=0.124), respectively. Grade 3/4 thrombocytopenia occurred more frequently in the GC-r group than the G-Car-f group (80% vs. 38%, p=0.021). CONCLUSION: G-Car-f could be more beneficial than GC-r for patients with advanced UC who have moderate renal dysfunction.

Antitumor effect of WEE1 blockade as monotherapy or in combination with cisplatin in urothelial cancer.

Overcoming cisplatin (CDDP) resistance is a major issue in urothelial cancer (UC), in which CDDP-based chemotherapy is the first-line treatment. WEE1, a G2 /M checkpoint kinase, confers chemoresistance in response to genotoxic agents. However, the efficacy of WEE1 blockade in UC has not been reported. MK-1775, a WEE1 inhibitor also known as AZD-1775, blocked proliferation of UC cell lines in a dose-dependent manner irrespective of TP53 status. MK-1775 synergized with CDDP to block proliferation, inducing apoptosis and mitotic catastrophe in TP53-mutant UC cells but not in TP53-WT cells. Knocking down TP53 in TP53-WT cells induced synergism of MK-1775 and CDDP. In UMUC3 cell xenografts and two patient-derived xenograft lines with MDM2 overexpression, in which the p53/cell cycle pathway was inactivated, AZD-1775 combined with CDDP suppressed tumor growth inducing both M-phase entry and apoptosis, whereas AZD-1775 alone was as effective as the combination in RT4 cell xenografts. Drug susceptibility assay using an ex vivo cancer tissue-originated spheroid system showed correlations with the in vivo efficacy of AZD-1775 alone or combined with CDDP. We determined the feasibility of the drug susceptibility assay using spheroids established from UC surgical specimens obtained by transurethral resection. In conclusion, WEE1 is a promising therapeutic target in the treatment of UC, and a highly specific small molecule inhibitor is currently in early phase clinical trials for cancer. Differential antitumor efficacy of WEE1 blockade alone or combined with CDDP could exist according to p53/cell cycle pathway activity, which might be predictable using an ex vivo 3D primary culture system.

Expression of serotonin receptor HTR4 in glucagon-like peptide-1-positive enteroendocrine cells of the murine intestine.

Serotonin (5-hydroxytryptamine [5-HT]) synthesized and released in enterochromaffin (EC) cells participates in various functions in the gastrointestinal tract by acting on a diverse range of 5-HT receptors (HTRs) expressed on smooth muscle, enteric neurons, and epithelial cells. We previously observed that genes encoding HTR2A, HTR2B, and HTR4 are expressed in murine intestinal organoids, suggesting the expression of these HTRs in intestinal epithelial cells. The present study investigated the localization of these HTRs in the murine intestine by immunofluorescence staining. HTR2A, HTR2B, and HTR4 localized in individual solitary cells in the epithelium, while HTR2C was observed in the lamina propria. In the epithelium, HTR2A, HTR2B, and HTR4 colocalized with 5-HT, and HTR4 colocalized with glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). Murine intestinal organoids show a colocalization pattern that is similar to in vivo HTR2A and HTR4 with 5-HT, GLP-1, and PYY. Intraperitoneal and intragastric administration of tegaserod, an HTR4 agonist, failed to alter plasma GLP-1 levels in fasted mice. However, intragastric but not intraperitoneal administration of tegaserod reduced dietary lipid-induced increases of plasma GLP-1 levels. This action of tegaserod was inhibited by co-administration of RS39604, an HTR4 antagonist. These results suggest that murine ileal GLP-1/PYY-producing enteroendocrine (EE) cells express HTR4, while 5-HT-producing EC cells express HTR2A, HTR2B, and HTR4. In addition, the observations regarding in vivo GLP-1 secretion suggest that HTR4 signaling in ileal EE cells suppresses dietary lipid-induced GLP-1 secretion. We thus propose that EC and EE cells may interact with each other through paracrine signaling mechanisms.

Trp53 Mutation in Keratin 5 (Krt5)-Expressing Basal Cells Facilitates the Development of Basal Squamous-Like Invasive Bladder Cancer in the Chemical Carcinogenesis of Mouse Bladder.

The biological processes of urothelial carcinogenesis are not fully understood, particularly regarding the relationship between specific genetic events, cell of origin, and molecular subtypes of subsequent tumors. N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced mouse bladder cancer is widely accepted as a useful model that recapitulates the pathway of human bladder tumorigenesis from dysplasia to invasive cancer via carcinoma in situ. However, the long and variable time of tumorigenesis often hinders efficient preclinical or translational research. We hypothesized that Trp53 mutation in specific types of urothelial cells facilitates efficient development of clinically relevant bladder cancer. Using lineage tracing, we showed that Trp53 mutation in Krt5-expressing cells resulted in more efficient tumorigenesis of mouse muscle-invasive bladder cancer (MIBC) with squamous differentiation compared with Trp53 mutation in Upk2-expressing cells, or wild-type or hemizygous Trp53 in the entire urothelium. Mouse MIBC that developed at 24 weeks of BBN treatment showed morphologic and genetic similarities to the basal squamous subtypes of human MIBC, irrespective of pre-induction of Trp53 mutation or whether the cell of origin was Krt5- or Upk2-expressing cells. Our findings suggest that intermediate cells as well as basal cells also can give rise to basal-like MIBC, with pre-induction of Trp53 mutation accelerating MIBC. Thus, in BBN chemical carcinogenesis, pre-induction of Trp53 mutation in basal cells facilitates efficient modeling of the basal squamous subtype of human MIBC.

Enhancement of transduction efficiency using Adeno-associated viral vectors by chemical pretreatment to mice bladder urothelium.

Adeno-associated virus (AAV) vectors have been recognized as promising tools for gene delivery. The bladder is a seemingly ideal organ for virus transfer, with easy access through the urethra enabling organ-specific delivery. However, achieving adequate transduction efficiency in the urothelium has been a major challenge because of the barrier function of the glycosaminoglycan (GAG) layer. We investigated optimal pretreatments of the bladder urothelium to maximize transduction efficiency by AAV vectors in vivo. Murine bladders were pretreated with five different chemical agents followed by transurethral instillation with an AAV2 vector encoding a tdTOMATO reporter. After 7 days, transduction efficiency of the urothelium was evaluated. Bladder urothelia pretreated with HCl showed clear evidence of AAV infection and gene delivery. Mice treated with 0.1 N HCl for 4 min showed significantly higher survival rates (nearly 80 %) compared with mice receiving other pretreatment regimens. AAV vector transduction in the urothelium was observed in seven of 20 mice (35 %), and the mean transduction efficiency in these mice was 14.5 %. Thus, HCl pretreatment enhanced transduction efficiency of the mice bladder urothelium by an AAV vector in vivo. Pretreatment with 0.1 N HCl for 4 min was the optimal condition to maximize survival and transduction efficiency of the urothelium.

Systematic chemical screening identifies disulfiram as a repurposed drug that enhances sensitivity to cisplatin in bladder cancer: a summary of preclinical studies.

BACKGROUND: Since the standard gemcitabine and cisplatin (GC) chemotherapy for advanced bladder cancer yields limited therapeutic effect due to chemoresistance, it is a clinical challenge to enhance sensitivity to GC. METHODS: We performed high-throughput screening by using a library of known chemicals and repositionable drugs. A total of 2098 compounds were administered alone or with GC to human bladder cancer cells, and chemicals that enhanced GC effects were screened. RESULTS: Disulfiram (DSF), an anti-alcoholism drug, was identified as a candidate showing synergistic effects with cisplatin but not with gemcitabine in multiple cell lines. Co-administration of DSF with GC affected cellular localisation of a cisplatin efflux transporter ATP7A, increased DNA-platinum adducts and promoted apoptosis. Micellar DSF nanoparticles (DSF-NP) that stabilised DSF in vivo, enhanced the inhibitory effect of cisplatin in patient-derived and cell-based xenograft models without severe adverse effects. A drug susceptibility evaluation system by using cancer tissue-originated spheroid culture showed promise in identifying cases who would benefit from DSF with cisplatin. CONCLUSIONS: The present study highlighted the advantage of drug repurposing to enhance the efficacy of anticancer chemotherapy. Repurposing of DSF to a chemotherapy sensitiser may provide additional efficacy with less expense by using an available drug with a well-characterised safety profile.

Efficacy of Immediate Postoperative Instillation of Chemotherapy for Primary Non-Muscle-Invasive Bladder Cancer in Real-World Clinical Practice.

BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) can be treated using transurethral resection (TUR), but high incidence of intravesical recurrence remains a clinical challenge. Single immediate postoperative instillation of chemotherapy (IPIOC) is controversial for NMIBC patients with intermediate recurrence risk. The aim of the present study was to report the efficacy and toxicity of IPIOC, particularly in intermediate-risk NMIBC patients, in the real-world setting. PATIENTS AND METHODS: We retrospectively analyzed 363 consecutive patients with primary NMIBC who underwent radical TUR at Kyoto University Hospital between 2007 and 2016. RESULTS: In low-risk patients, recurrence-free survival (RFS) was significantly better for IPIOC than non-IPIOC (2-year RFS: 89.3% vs. 59.4%; P = .001). In intermediate-risk patients, IPIOC was associated with significantly longer RFS compared with non-IPIOC (2-year RFS: 85.5% vs. 58.2%; P = .011). IPIOC and bacillus Calmette-Guérin (BCG) were independent predictors for post-TUR recurrence (non-IPIOC vs. IPIOC: hazard ratio [HR], 2.33; 95% confidence interval [CI], 1.14-4.88; P = .02; non-BCG vs. BCG: HR, 2.22; P = .045, 95% CI, 1.02-5.30). In the high-risk group, only BCG was an independent prognostic factor of recurrence in a multivariate Cox proportional hazards model (HR, 2.55; P = .006, 95% CI, 1.32-4.87). There were no significant differences between the BCG-only group and the IPIOC with BCG group in Grade 3 or more local (16 patients [21%] vs. 21 patients [24%]; P = .61) or systemic (3 patients [4%] vs. 6 patients [7%]; P = .40) toxicity rates. CONCLUSION: Our study showed the efficacy of IPIOC for the prevention of intravesical recurrence in primary intermediate-risk NMIBC patients regardless of BCG therapy.

[The Safety of Laparoscopic Radical Cystectomy during Initial Phases in a Japanese Multicenter Cohort].

We evaluated the safety of laparoscopic radical cystectomy (LRC) during initial phases and its learning curve in a Japanese multicenter cohort by studying 436 patients who underwent LRC with no robot assistance at 10 institutions in Japan. We divided the patients into three groups according to cumulative surgical volume at each institution (first 10 cases, 11-30 cases, after 31 cases in each institution), and compared perioperative and pathologic variables among the three groups. The first, second, and third groups included 100, 166, 170 patients, respectively. The preoperative variables were similar in the three groups except for the rate of neoadjuvant chemotherapy. The methods of LRC procedure, such as urinary diversion, the extent of lymph node dissection, and concomitant urethrectomy or nephroureterectomy, were similar in the three groups. Mean operative time was 629, 562 and 531 minutes, respectively, and mean blood loss was 755, 650 and 435 ml, respectively. Both values decreased over time with the institution's experience. There was no significant difference among the three groups in the rate of positive surgical margin, the number of retrieved lymph nodes, and the rate of intra- and postoperative complications. LRC was safely performed during initial phases with an acceptable complication rate and without compromising oncological results, although operative time was longer and blood loss increased.

[A Case of Pulmonary Tumor Thrombotic Microangiopathy in Castration-Resistant Prostate Cancer].

A man aged 83 years under treatment with enzalutamide for castration-resistant prostate cancer presented with general malaise and exertional dyspnea. The underlying cause could not be identified by further investigations. On the 5th hospital day, he died due to a sudden exacerbation of dyspnea. The results of an autopsy indicated tumor emboli and stenosis of small pulmonary arteries with the fibrocellular intimal thickening, and therefore our final diagnosis was pulmonary tumor thrombotic microangiopathy.

[The Study of Surgical Outcome for Robotic-Assisted Laparoscopic Radical Prostatectomy : Experience of a Single Surgeon with 70 Initial Cases].

We investigated the surgical outcome for robotic-assisted laparoscopic radical prostatectomy (RALP) withinitial 70 prostate cancer cases performed by a single surgeon between June 2014 and May 2016. The surgeon had a previous experience of more than 400 cases of laparoscopic radical prostatectomy (LRP). Comparative study of the surgical outcome was made between the first 35 patients (group 1) and the second 35 patients (group 2). The console time without lymph node dissection significantly decreased from group 1 to 2 (193 min vs 158 min, p=0.002). Among specific 3 parts of the console operation (part 1 : until the bladder neck transection, part 2 : until the prostate removal and part 3 : urethrovesical anastomosis), duration of parts 1 and 2 similarly decreased witha significant difference of 0. 001 and 0. 002, respectively. Continence recovery rates 1 month after RALP were significantly higher in group 2 than in group 1 (group1 : 48.5% vs group 2 : 74.2%, p=0.02). Between groups 1 and 2, the positive surgical margin rates of both pT2 and pT3 were similar (group 1 : 20. 8 and 50. 0%, group 2 : 17. 2 and 50. 0%, respectively). The perioperative 8 complications (11.4%) were classified into Clavien-Dindo grades 1 and 2. Our surgical outcome of initial 70 RALP cases was considered as comparable to that reported from the high volume centers.

[Urethral Hemangioma with Repeated Urinary Retention by Posterection Hematuria].

A 73-year-old man presented to our hospital due to postejaculation gross hematuria and dysuria. Three months after onset, urinary retention occurred repeatedly. Under general anesthesia, cystourethroscopy following drug-induced erection was performed. A solitary sessile lesion with varicosis was found between the verumontanum and external sphincter. The tumor was resected endoscopically and recurrence was not observed during the follow-up period. Histological examination revealed a cavernous hemangioma of the urethra. Urologists should keep in mind that urethral hemangioma can be a cause of hematuria after erection or ejaculation.

[Urinary Diversion Using an Appendicovesicostomy for Idiopathic Urethral Stricture : A Case Report].

A 55-year-old woman was referred to our hospital with dysuria. We were unable to catheterize her using a nelaton catheter because of a urethral stricture, resulting in a large residual urine volume on ultrasonography. The circumference of the periurethral tissue was also thickened and the entire length of the urethra was stenotic, without apparent cause, on magnetic resonance imaging. Biopsy did not reveal malignancy. The pathological diagnosis of the periurethral tissue was simply fibrosis, and there was no definitive diagnosis. We decided to place a guidewire to attempt transurethral dilation, but it was unsuccessful because of the urethral stricture. The patient then underwent Mitrofanoff appendicovesicostomy. Three years later, there was no difficulty with catheterization through the appendix, despite her suffering from a bladder stone during the interim. We consider the Mitrofanoff appendicovesicostomy a good substitute technique for catheterization in patients with very severe urethral stricture.

Organoids as an ex vivo model for studying the serotonin system in the murine small intestine and colon epithelium.

Intestinal organoids were recently established as an ex vivo model of the intestinal epithelium. The present study investigated the serotonin (5-hydroxytryptamine, 5-HT) system using organoids. Organoids from murine small intestinal and colonic crypts were successfully cultured. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that small intestinal and colonic organoids express mRNAs encoding tryptophan hydroxylase-1 (TPH1) (the rate-limiting enzyme of 5-HT synthesis), serotonin reuptake transporter (SERT), 5-HT receptor (HTR)2A, HTR2B, and HTR4. SERT mRNA levels were significantly higher in the small intestine than in the colon in both the mucosal tissues and organoids, as estimated by quantitative real-time RT-PCR. Although the 5-HT concentration and levels of chromogranin A (CgA) (an enteroendocrine cell marker), TPH1, and HTR4 mRNAs were significantly higher in the colonic mucosa than the small intestinal mucosa, they were the same in small intestinal and colonic organoids. There were no significant differences in HTR2A and HTR2B mRNA levels between the small intestine and colon in either the mucosal tissues or organoids. Immunofluorescence staining showed that the number of CgA-positive cells in the colonic organoids appeared to increase upon culturing with acetate. Acetate supplementation significantly increased CgA, TPH1, and HTR4 mRNA levels in the colonic organoids. We propose that organoids are useful for investigating the 5-HT system in the intestinal epithelium, even though colonic organoids may require gut microbiota-derived factors such as short-chain fatty acids.

Evaluation of Intravesical Prostatic Protrusion as a Predictor of Dutasteride-Resistant Lower Urinary Tract Symptoms/Benign Prostatic Enlargement With a High Likelihood of Surgical Intervention.

OBJECTIVE: To investigate factors predicting that combination therapy would be insufficient in terms of efficacy, necessitating conversion to surgical intervention, in patients with lower urinary tract symptoms and/or benign prostatic enlargement. MATERIALS AND METHODS: In total, 218 patients given combination therapy for 6 months or more were enrolled in our study. Candidate factors for surgical intervention before dutasteride administration were statistically analyzed. We also examined the proportion of stromal components in resected specimens of the intravesical prostatic protrusion (IPP) portion using the point-counting technique according to IPP grades. RESULTS: Combination therapy was effective and was thus continued in 172 patients, whereas 46 required surgical intervention. The comparison between these two groups, by multivariate analysis, revealed significant differences in IPP and total International Prostate Symptom Score (IPSS). IPP (odds ratio 1.133, P <.001) was the strongest independent factor predicting conversion to surgical intervention. Receiver operating characteristic analysis identified the optimal cutoff value of IPP to be 8 mm (area under the curve: 0.9). This value yielded a sensitivity of 91% and a specificity of 72%. In addition, the mean proportion of stromal components in resected specimens of IPP according to IPP grades was grade I: 96.7%, grade II: 57.8%, and grade III: 21.4% (P <.001 for all), respectively. CONCLUSION: Our results suggest that in lower urinary tract symptoms and/or benign prostatic enlargement associated with severe IPP, combination therapy might have insufficient efficacy due to a low proportion of stromal components, necessitating conversion to surgical intervention.

Intestinal epithelial cells promote secretion of leptin and adiponectin in adipocytes.

Although leptin and adiponectin are the predominant adipokines, how their circulating levels are regulated is incompletely understood. The present study tested whether intestinal epithelial cells influence the expression and secretion of these adipokines by adipocytes. Leptin gene expression and secretion by cultured human primary adipocytes and Simpson-Golabi-Behmel Syndrome adipocytes increased upon coculture with human enterocytic Caco-2 cells or incubation in conditioned medium of Caco-2 cells. Although adiponectin secretion increased, its mRNA levels decreased. Tissue homogenate of the ileum (but not the jejunum, colon, or liver) of nonobese C57BL/6J mice also stimulated leptin and adiponectin secretion by cultured murine 3T3-L1 adipocytes. However, ileal homogenate of obese KK-Ay mice had no effect on leptin and adiponectin secretion. We propose that as yet unidentified humoral factors released from intestinal epithelial cells are involved in regulating circulating leptin and adiponectin levels. Decreased production of such factors may contribute to hyperphagia in KK-Ay mice.

[A case of adrenal metastasectomy in renal cell carcinoma after neoadjuvant therapy with sunitinib].

A 58-year-old man had undergone laparoscopic radical nephrectomy for right renal cell carcinoma. The histopathological diagnosis was clear cell carcinoma, grade 2＞3, pT1b. Two years and 10 months postoperatively, computed tomography scans demonstrated an enhanced mass on the right adrenal gland. As we could not detect other metastatic lesions, it was diagnosed as solitary adrenal metastasis of renal cell carcinoma. Albeit metastasectomy was planned with curative intent, right hemihepatectomy was also required for surgical removal because the tumor was adherent to the right lobe of the liver broadly and had indistinct margins. So we started neoadjuvant therapy with sunitinib. Eight courses of treatment shrunk the metastatic tumor enough to allow it to be removed completely without partial hepatectomy. Neoadjuvant therapy with the molecular targeted drugs may provide an effective option for metastasectomy in renal cell carcinoma regarding increased curability and decreased the risk of an operation.