tRNA-Derived Fragments as Biomarkers in Bladder Cancer.

Bladder cancer (BC) diagnosis is reliant on cystoscopy, an invasive procedure associated with urinary tract infections. This has sparked interest in identifying noninvasive biomarkers in body fluids such as blood and urine. A source of biomarkers in these biofluids are extracellular vesicles (EVs), nanosized vesicles that contain a wide array of molecular cargo, including small noncoding RNA such as transfer RNA-derived fragments (tRF) and microRNA. Here, we performed small-RNA next-generation sequencing from EVs from urine and serum, as well as from serum supernatant. RNA was extracted from 15 non-cancer patients (NCPs) with benign findings in cystoscopy and 41 patients with non-muscle invasive BC. Urine and serum were collected before transurethral resection of bladder tumors (TUR-b) and at routine post-surgery check-ups. We compared levels of tRFs in pre-surgery samples to samples from NCPs and post-surgery check-ups. To further verify our findings, samples from 10 patients with stage T1 disease were resequenced. When comparing tRF expression in urine EVs between T1 stage BC patients and NCPs, 14 differentially expressed tRFs (DEtRFs) were identified. In serum supernatant, six DEtRFs were identified among stage T1 patients when comparing pre-surgery to post-surgery samples and four DEtRFs were found when comparing pre-surgery samples to NCPs. By performing a blast search, we found that sequences of DEtRFs aligned with genomic sequences pertaining to processes relevant to cancer development, such as enhancers, regulatory elements and CpG islands. Our findings display a number of tRFs that may hold potential as biomarkers for the diagnosis and recurrence-free survival of BC.

En bloc radical cystectomy: An overview of the technique and oncological results.

Objectives: To reduce recurrence after radical cystectomy (RC), we developed a technique based on the principles of the circumferential resection margin used during total mesorectal excision for rectal cancer, namely, en bloc radical cystectomy (EbRC). Patients and methods: The study included all patients in Mid-Norway (population of 739 k) with high-grade superficial or muscle invasive bladder cancer considered for radical treatment according to European guidelines, from January 2012 to August 2021, except for three patients receiving trimodal therapy. One hundred forty-five patients were treated with EbRC and 188 patients with standard RC (stdRC). There were no exclusion criteria. Both groups included open and robot-assisted techniques. EbRC entails cystectomy with extended pelvic lymph node dissection. The technique focuses on systematic uninterrupted mobilisation of all lymphatic tissue from the circumferential resection margin towards the bladder pedicles, and resecting the tissue en bloc with the bladder. Results: The 3-year recurrence-free survival (RFS) was 86% for EbRC versus 67% for stdRC. The hazard ratio for overall survival in multivariable cox regression analyses after EbRC versus stdRC was 0.30 (95% CI 0.16-0.57, p ≤ 0.001). The improved outcomes persisted in propensity score-matched analyses. There were no differences in Clavien-Dindo 3 and 4 complications (12.4% vs. 11.7%), nor 90-day mortality (2.1% vs. 1.6%). Conclusion: Improved oncological results with EbRC versus stdRC mirror the historical data after total mesorectal excision was initiated over 35 years ago in rectal cancer surgery. EbRC is safe and the preliminary oncological results are promising.

Can a Dinosaur Think? Implementation of Artificial Intelligence in Extracorporeal Shock Wave Lithotripsy.

BACKGROUND: Extracorporeal shock wave lithotripsy (ESWL) of kidney stones is losing ground to more expensive and invasive endoscopic treatments. OBJECTIVE: This proof-of-concept project was initiated to develop artificial intelligence (AI)-augmented ESWL and to investigate the potential for machine learning to improve the efficacy of ESWL. DESIGN SETTING AND PARTICIPANTS: Two-dimensional ultrasound videos were captured during ESWL treatments from an inline ultrasound device with a video grabber. An observer annotated 23 212 images from 11 patients as either in or out of focus. The median hit rate was calculated on a patient level via bootstrapping. A convolutional neural network with U-Net architecture was trained on 57 ultrasound images with delineated kidney stones from the same patients annotated by a second observer. We tested U-Net on the ultrasound images annotated by the first observer. Cross-validation with a training set of nine patients, a validation set of one patient, and a test set of one patient was performed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Classical metrics describing classifier performance were calculated, together with an estimation of how the algorithm would affect shock wave hit rate. RESULTS AND LIMITATIONS: The median hit rate for standard ESWL was 55.2% (95% confidence interval [CI] 43.2-67.3%). The performance metrics for U-Net were accuracy 63.9%, sensitivity 56.0%, specificity 74.7%, positive predictive value 75.3%, negative predictive value 55.2%, Youden's J statistic 30.7%, no-information rate 58.0%, and Cohen's κ 0.2931. The algorithm reduced total mishits by 67.1%. The main limitation is that this is a proof-of-concept study involving only 11 patients. CONCLUSIONS: Our calculated ESWL hit rate of 55.2% (95% CI 43.2-67.3%) supports findings from earlier research. We have demonstrated that a machine learning algorithm trained on just 11 patients increases the hit rate to 75.3% and reduces mishits by 67.1%. When U-Net is trained on more and higher-quality annotations, even better results can be expected. PATIENT SUMMARY: Kidney stones can be treated by applying shockwaves to the outside of the body. Ultrasound scans of the kidney are used to guide the machine delivering the shockwaves, but the shockwaves can still miss the stone. We used artificial intelligence to improve the accuracy in hitting the stone being treated.

Differentially Expressed Extracellular Vesicle-Contained microRNAs before and after Transurethral Resection of Bladder Tumors.

Bladder cancer (BC) is currently diagnosed and monitored by cystoscopy, a costly and invasive procedure. Potential biomarkers in urine, blood, and, more recently, extracellular vesicles (EVs), have been explored as non-invasive alternatives for diagnosis and surveillance of BC. EVs are nanovesicles secreted by most cell types containing diverse molecular cargo, including different types of small RNAs, such as microRNA (miRNA). In this study, we performed next-generation sequencing of EV-contained miRNA isolated from urine and serum of 41 patients with non-muscle invasive BC (27 stage Ta, 14 stage T1) and 15 non-cancer patients (NCP) with benign cystoscopy findings. MiRNA sequencing was also performed on serum supernatant samples for T1 patients. To identify potential BC-specific biomarkers, expression levels of miRNA in presurgery samples were compared to those at postsurgery check-ups, and to NCPs. Results showed that two miRNAs, urinary EV-contained miR-451a and miR-486-5p, were significantly upregulated in presurgery samples from T1 patients compared to postsurgery check-up samples. This was confirmed in a replica EV/RNA isolation and sequencing run of 10 T1 patients from the primary run; however, analyses revealed no differential expression of miRNAs in serum EVs, serum supernatant, or when comparing BC patients to NCPs. This is the first study to investigate EV-containing miRNA sequencing in pre- and postsurgery BC patient samples and our findings suggest that urinary EV-contained miR-451a and miR-486-5p may be potential biomarkers for recurrence-free survival of BC patients with stage T1 disease.

Clinical markers of morbidity, mortality and survival in bladder cancer patients treated with radical cystectomy. A systematic review.

Context: Radical cystectomy and pelvic lymph node dissection (RC and PLND) are an essential part of the treatment paradigm in high risk bladder cancer. However, these patients have high rates of morbidity and mortality related both to the treatment and to the disease.Objective: To provide overview of current literature about clinical markers that can be used to predict and improve BC-patient outcomes at the time of RC and PLND and to study if they are properly validated.Evidence acquisition: A systematic literature search was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria between January 1990 and October 2018 to identify English written original and review articles relevant to this topic. Prospective and retrospective studies were included.Evidence synthesis: There are several risk factors identified from non-randomised trials that can be improved before surgery to reduce perioperative mortality and morbidity. These include poor nutritional status, anaemia, renal function and smoking. Preoperative nomograms have also been developed to help decision-making and to inform patients about the risks of surgery. They can be used to estimate risk of postoperative mortality after RC and PLND with accuracy varying from 70 to 86%. These nomograms are largely based on retrospective data. Likewise, nomograms developed to calculate estimates about patient's overall and cancer specific survival have the same limitations.Conclusion: Clinical markers to predict morbidity, mortality and survival in patients with bladder cancer treated with RC and PLND may help to improve patient outcomes and treatment decision-making, but available data come from small retrospective trials and have not been properly validated. Prospective, multi-centre studies are needed to implement and disseminate predictive clinical markers and nomograms such that they can be utilised in treatment decision-making in daily practice.

Myeloma-derived extracellular vesicles mediate HGF/c-Met signaling in osteoblast-like cells.

Multiple myeloma is an incurable cancer of antibody-producing plasma cells. Hepatocyte growth factor (HGF), a cytokine aberrantly expressed in half of myeloma patients, is involved in myeloma pathogenesis by enhancing myeloma growth and invasiveness, and may play a role in myeloma bone disease by inhibiting osteoblastogenesis. In this study, we investigated whether extracellular vesicles (EVs) may play a role in HGF signaling between myeloma cells and osteoblast-like target cells. EVs from the HGF-positive cell line JJN-3 and the HGF-negative cell line INA-6, and from bone marrow plasma and primary human myeloma cells, were isolated using sequential centrifugation techniques and the presence of HGF on the EV-surface was investigated with ELISA. EVs from both cell lines were added to an established bioassay where HGF is known to induce interleukin-11 secretion in osteoblast-like cells. Our results show that HGF was bound to the surface of JJN-3-derived EVs, while INA-6-derived EVs were negative for HGF. Only JJN-3-derived EVs induced IL-11 secretion in osteoblast-like recipient cells. When osteoblast-like cells were preincubated with a specific HGF-receptor (c-Met) inhibitor, no induction of interleukin-11 was observed. Downstream c-Met phosphorylation was demonstrated by immunoblotting. EVs isolated from bone marrow plasma and primary myeloma cells were HGF-positive for a subset of myeloma patients. Taken together, this work shows for the first time that HGF bound on the surface of myeloma-derived EVs can effectuate HGF/c-Met signaling in osteoblast-like cells. Myeloma-derived EVs may play a role in myeloma bone disease by induction of the osteoclast-activating cytokine interleukin-11 in osteoblasts.

"Two hits - one stone"; increased efficacy of cisplatin-based therapies by targeting PCNA's role in both DNA repair and cellular signaling.

Low response rate and rapid development of resistance against commonly used chemotherapeutic regimes demand new multi-targeting anti-cancer strategies. In this study, we target the stress-related roles of the scaffold protein PCNA with a cell-penetrating peptide containing the PCNA-interacting motif APIM. The APIM-peptide increased the efficacy of cisplatin-based therapies in a muscle-invasive bladder cancer (MIBC) solid tumor model in rat and in bladder cancer (BC) cell lines. By combining multiple omics-levels, from gene expression to proteome/kinome and metabolome, we revealed a unique downregulation of the EGFR/ERBB2 and PI3K/Akt/mTOR pathways in the APIM-peptide-cisplatin combination treated cells. Additionally, the combination treatment reduced the expression of anti-apoptotic proteins and proteins involved in development of resistance to cisplatin. Concurrently, we observed increased levels of DNA breaks in combination treated cells, suggesting that the APIM-peptide impaired PCNA - DNA repair protein interactions and reduced the efficacy of repair. This was also seen in cisplatin-resistant cells, which notably was re-sensitized to cisplatin by the APIM-peptide. Our data indicate that the increased efficacy of cisplatin treatment is mediated both via downregulation of known oncogenic signaling pathways and inhibition of DNA repair/translesion synthesis (TLS), thus the APIM-peptide hits both nuclear and cytosolic functions of PCNA. The novel multi-targeting strategy of the APIM-peptide could potentially improve the efficacy of chemotherapeutic regiments for treatment of MIBC, and likely other solid tumors.

Clinical Research Office of the Endourological Society Global GreenLight Laser Study: Outcomes from a contemporary series of 713 patients.

OBJECTIVE: To evaluate the outcome in patients undergoing photoselective vaporization of the prostate for benign prostatic obstruction as part of the Clinical Research Office of the Endourological Society Global GreenLight Laser Study. METHODS: Data were collected on 713 patients with lower urinary tract symptoms suggestive of benign prostatic obstruction undergoing photoselective vaporization of the prostate at 25 centers worldwide, between April 2010 and April 2012. Three types of GreenLight laser powers were used: 80 W, 120 W or 180 W. Intraoperative and postoperative complications were recorded. Outcome parameters measured at baseline, 6-12 weeks, 6 months and 12 months were: uroflow measurements, International Prostate Symptom Score; prostate-specific antigen and International Index of Erectile Function. RESULTS: Operating time was shortest with the 180-W laser at 53.8 min. Intraoperatively, bleeding occurred in 3.1% of patients. Statistically significant changes were reported in maximum flow rate, postvoid residual urine, International Prostate Symptom Score, quality of life score and prostate-specific antigen (P < 0.01) at each time-point assessed for the 80- and 120-W lasers as well as for the 180-W laser, with the exception of prostate-specific antigen at 6 months and 12 months. There were 14 Clavien-Dindo grade III-A complications and two grade III-B. The incontinence rate at 12 months was 6.3%, 4.5%, and 2.6% for the 80, 120 and 180 W lasers, respectively. The overall blood transfusion rate was 0.4%. CONCLUSIONS: Objective and subjective improvement after GreenLight laser treatment worldwide was significant at 1-year follow up. Morbidity and complications were low. Although not a randomized control study, the data can provide an indication of the outcome of the different GreenLight laser powers.

Increased Anticancer Efficacy of Intravesical Mitomycin C Therapy when Combined with a PCNA Targeting Peptide.

Non-muscle-invasive bladder cancers (NMIBCs) are tumors confined to the mucosa or the mucosa/submucosa. An important challenge in treatment of NMIBC is both high recurrence and high progression rates. Consequently, more efficacious intravesical treatment regimes are in demand. Inhibition of the cell's DNA repair systems is a new promising strategy to improve cancer therapy, and proliferating cell nuclear antigen (PCNA) is a new promising target. PCNA is an essential scaffold protein in multiple cellular processes including DNA replication and repair. More than 200 proteins, many involved in stress responses, interact with PCNA through the AlkB homologue 2 PCNA-interacting motif (APIM), including several proteins directly or indirectly involved in repair of DNA interstrand crosslinks (ICLs). In this study, we targeted PCNA with a novel peptide drug containing the APIM sequence, ATX-101, to inhibit repair of the DNA damage introduced by the chemotherapeutics. A bladder cancer cell panel and two different orthotopic models of bladder cancer in rats, the AY-27 implantation model and the dietary BBN induction model, were applied. ATX-101 increased the anticancer efficacy of the ICL-inducing drug mitomycin C (MMC), as well as bleomycin and gemcitabine in all bladder cancer cell lines tested. Furthermore, we found that ATX-101 given intravesically in combination with MMC penetrated the bladder wall and further reduced the tumor growth in both the slow growing endogenously induced and the rapidly growing transplanted tumors. These results suggest that ATX-101 has the potential to improve the efficacy of current MMC treatment in NMIBC.

Experimental gastrocystoplasty in rats: risk of developing ECLoma.

OBJECTIVE: There are no clinical reports on the risk of carcinoids in the gastric segment following gastrocystoplasty. The aim of the present study was to examine whether gastric carcinoids could develop in a rat model of gastrocystoplasty. MATERIALS AND METHODS: Rats were subjected to gastrocystoplasty in which 10% of the oxyntic part of the stomach was removed (i.e. 10% fundectomy), gastrocystoplasty with 90% fundectomy (known to induce hypergastrinemia), sham operation, or no operation, and were followed up for 6 months. Tissue specimens of bladder and stomach were analyzed by means of pathology and immunohistochemistry. RESULTS: Atrophy of gastric glands in the augmented bladders was found after gastrocystoplasty with either 10% or 90% fundectomy. Gastrocystoplasty with 90% fundectomy resulted in hyperplasia of the oxyntic mucosa, enterochromaffin-like (ECL) cell hyperplasia and ECLoma in the remnant stomach, and atrophy of the oxyntic mucosa and ECLoma in the gastric segment of the bladder. CONCLUSIONS: ECLoma could develop in the gastric segment of the bladder after gastrocystoplasty, particularly in the setting of hypergastrinemia. The tumorigenesis of ECLoma seems to follow the same pathological pathway regardless of whether the oxyntic mucosa is located in the stomach or the bladder.

Tissue responses to hexyl 5-aminolevulinate-induced photodynamic treatment in syngeneic orthotopic rat bladder cancer model: possible pathways of action.

Orthotopic bladder cancer model in rats mimics human bladder cancer with respect to urothelial tumorigenesis and progression. Utilizing this model at pT1 (superficial stage), we analyze the tissue responses to hexyl 5-aminolevulinate-induced photodynamic therapy (HAL-PDT). In comparison to untreated rats, HAL-PDT causes little change in tumor-free rat bladder but induces inflammatory changes with increased lymphocytes and mononuclear cell infiltration in rat bladders with tumor. Immunohistochemistry reveals that HAL-PDT is without effect on proliferating cell nuclear antigen expression within the tumor and increases caspase-3 expression in both normal urothelium and the tumor. Transmission electron microscopy reveals severe mitochondrial damage, formations of apoptotic bodies, vacuoles, and lipofuscin bodies, but no microvillus-formed niches in HAL-PDT-treated bladder cancer rats. Bioinformatics analysis of the gene expression profile indicates an activation of T-cell receptor signaling pathway in bladder cancer rats without PDT. HAL-PDT increases the expression of CD3 and CD45RA in the tumor (determined by immunohistochemistry). We suggest that pathways of action of HAL-PDT may include, at least, activations of mitochondrial apoptosis and autophagy, breakdown of cancer stem cell niches, and importantly, enhancement of T-cell activation.

Cancer immunoediting from immunosurveillance to tumor escape in microvillus-formed niche: a study of syngeneic orthotopic rat bladder cancer model in comparison with human bladder cancer.

Cancer cells can develop an attenuated immunogenicity and/or create an immunosuppressive microenvironment to prevent tumor eradication by host immune system, the so-called "cancer immunoediting" hypothesis. The aim of the present study was to find evidence for this hypothesis by using a rat orthotopic bladder cancer model. Fisher rats were inoculated with AY-27 cells (a Fisher rat bladder cancer cell line). Cultured cancer cells, rat and human bladder cancer tissues, and publicly available microarray data from human bladder cancer were analyzed by means of bioinformatics and morphology. Results showed that 12 of 24 differentially expressed pathways were concordant in connection to cell cycle and proliferation between rats and humans (both non-muscle-invasive and muscle-invasive tumors) and that 11 of the 24 pathways, including major histocompatibility complex, were related to host immunosurveillance with activations of T cells and natural killer cells in rats. The altered pathways and morphogenesis of this rat model corresponded more closely with those of human muscle-invasive rather than non-muscle-invasive tumors. A unique ultrastructure displaying microvillus-formed niches was found in small areas within the tumor of both rats and humans. These niches were interconnected with desmosomes between cancer cells and without infiltration of lymphocytes. The expression of E-cadherin, selectins, PGP9.5, vascular endothelial growth factor, caspase-3, CD133, Oct-4, nestin, CD3, and CD45RA was lower in the tumor than in the adjacent normal epithelium. We suggest that the microvillus-formed niche that harbors a few implanted cancer cells might be the compartment that prevents the tumor eradication by the host immune system.

A rat model of intravesical delivery of small interfering RNA for studying urinary carcinoma.

PURPOSE: siRNA has been used successfully in loss-of-function studies in vitro, but neither in vivo nor in clinical applications. The aims of the present study were (1) to establish rat models for in vivo delivery of siRNA to bladder cancer, and (2) to identify potential targets for siRNA. METHODS: The rat models of human urinary carcinoma and rat urinary carcinoma cell line (AY-27) were induced by tobacco-related chemical carcinogens, either N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) or N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). A syngeneic orthotopic bladder cancer model was established by inoculation of AY-27 cells. A fluorescence-labelled negative control siRNA with cationic and neutral liposomes was tested both in vitro (AY-27 cells) and in vivo. RESULTS: siRNA was highly accumulated in the cancer cells as early as 12 h and remained at least for 24 h after a single dose in vivo. Numerous CD3+ T cells appeared mainly in the periphery area of the tumour. Bioinformatics analysis revealed a list of concordantly highly expressed genes, possible siRNA targets, in the animal models as well as human urinary carcinoma. Literature search on siRNA and bladder cancer provided a list of genes used as siRNA targets. CONCLUSION: The methodology and data presented in the present study provide a number of opportunities for basic research on urinary carcinogenesis and for translational research on evaluation of siRNA therapeutic strategies for urinary carcinoma in the native organ, where hormonal, neural and immunological processes more closely resemble the clinical situation.

Gene expression profiling and pathway analysis of superficial bladder cancer in rats.

OBJECTIVES: To reveal the gene expression profile and pathways involved in host-tumor interactions in a rat orthotopic syngeneic bladder cancer model. METHODS: Rat bladder cancer cells (AY-27 cell line) were inoculated intravesically into female Fischer rats. The bladders were analyzed at 7, 14, and 28 days by histologic examination and at 14 days with Affymetrix GeneChip with a newly developed bioinformatics program for the Kyoto Encyclopedia of Genes and Genomes (KEGG). RESULTS: The cancer had developed into Stage Ta and carcinoma in situ (Tis) after 7 days, Stage T1 after 14 days, and Stage T3 after 28 days in the bladder. At 14 days, >4000 genes were found to be differentially expressed and 20 KEGG pathways were actively involved in the bladder. The molecular pathway for (human) bladder cancer development was activated, and, at the same time, pathways in connection with the host immune responses were altered, including antigen processing and presentation, the T-cell receptor signaling pathway, natural killer cell-mediated cytotoxicity, the Toll-like receptor signaling pathway, and the B-cell receptor signaling pathway. Moreover, the cell adhesion molecules associated with the immune system were upregulated, but those associated with the neural system were downregulated. CONCLUSIONS: The bladder cancer developed aggressively despite active host immune responses. Conceivably, the cancer immunoediting process is associated with the progression of bladder cancer in this model.

2-year followup pressure flow studies of prostate photoselective vaporization using local anesthesia with sedation.

PURPOSE: We report 2-year pressure flow studies and other clinical outcomes of photoselective prostate vaporization with the patient under general or spinal anesthesia vs local anesthesia with sedation. MATERIALS AND METHODS: The study included 150 unselected patients with an average age of 73 years (range 51 to 92) and a mean American Society of Anesthesiologists score of 2.4 (median 2.0), of whom 33% were medicated with acetylsalicylic acid and 5% were on anticoagulation with warfarin. Photoselective prostate vaporization was performed under general or spinal anesthesia in the first 67 patients and under local anesthesia with light sedation in the remaining 83. RESULTS: No patient who received local anesthesia required conversion to general anesthesia. The median preoperative to postoperative decrease in hemoglobin was 0.55 gm/dl and no patient required blood transfusion. The median postoperative catheterization requirement was 2 hours after local anesthesia and 9 hours after general or spinal anesthesia. Median time from operation to hospital discharge was 12 hours in the local anesthesia group and 24 hours in the general or spinal anesthesia group (p <0.001). At 12 and 24 months postoperatively significant and stable improvements were found in certain measures, including prostate specific antigen, transrectal ultrasound measurement, post-void residual urine volume, International Prostate Symptom Score, quality of life score, maximum and average flow, and the bladder outlet obstruction index. CONCLUSIONS: Photoselective prostate vaporization using local anesthesia with sedation provides excellent intraoperative safety and expedient postoperative recovery. Compared to photoselective prostate vaporization performed with the patient under general or spinal anesthesia it leads to equally significant symptom relief and stable improvement in pressure flow outcomes at 1 and 2 years of followup.

Monitoring of hexyl 5-aminolevulinate-induced photodynamic therapy in rat bladder cancer by optical spectroscopy.

Monitoring of the tissue response to photodynamic therapy (PDT) can provide important information to help optimize treatment variables such as drug and light dose, and possibly predict treatment outcome. A urinary bladder cancer cell line (AY-27) was used to induce orthotopic transitional cell carcinomas (TCC) in female Fischer rats, and hexyl 5-aminolevulinate (HAL, 8 mM, 1 h)-induced PDT was performed on day 14 after instillation of the cancer cells (20 J/cm(2) fluence at 635 nm). In vivo optical reflectance and fluorescence spectra were recorded from bladders before and after laser treatment with a fiberoptic probe. Calculated fluorescence bleaching and oxygen saturation in the bladder wall were examined and correlated to histology results. Reflectance spectra were analyzed using a three-layer optical photon transport model. Animals with TCC treated with PDT showed a clear treatment response; decreased tissue oxygenation and protoporphyrin IX (PpIX) fluorescence photobleaching were observed. Histology demonstrated that 3 of 6 animals with treatment had no sign of the tumor 7 days after PDT treatment. The other 3 animals had significantly reduced the tumor size. The most treatment-responsive animals had the highest PpIX fluorescence prior to light irradiation. Thus, optical spectroscopy can provide useful information for PDT. The model has proved to be very suitable for bladder cancer studies.

Gastric bypass surgery causes body weight loss without reducing food intake in rats.

BACKGROUND: It is a common dogma that gastric bypass (GB) induces early satiety and consequent reductions in food intake and nutrient absorption. The aim of the present study was to analyze feeding behavioral and metabolic changes in rats after GB. METHODS: Male Sprague-Dawley rats at the ages of 23 and 42 weeks were placed in metabolic cages connected with a comprehensive laboratory animal monitoring system. At the age of 48 weeks they were subjected to either GB or sham operation, and then placed in metabolic cages at 51 and 62 weeks (or 3 and 14 weeks postoperatively). RESULTS: GB rats lost 20% of the body weight within 2-3 weeks and remained at this lower level until the end of the study at 14 weeks postoperatively. Satiety ratio was higher during daytime than nighttime in both sham-operated and GB rats, but was not significantly different between the two groups. Neither daily accumulated food intake nor food intake per 100 g of body weight was different between sham-operated and GB rats. Apparently, GB rats ate more frequently during daytime and had smaller meal size during nighttime at 3 weeks postoperatively. These changes were not present at 14 weeks postoperatively. Energy density in the feces was the same in GB and sham-operated rats postoperatively. Energy expenditure declined with age, but increased in GB rats compared with age-matched sham-operated rats. CONCLUSIONS: GB reduced the body weight without causing early satiety, reducing food intake or inducing malabsorption. It did, however, increase energy expenditure.

Is gastrin partially responsible for body weight reduction after gastric bypass?

BACKGROUND: The rationale for bariatric surgery is to reduce food intake by gastric restriction and/or malabsorption by intestinal bypass. Unlike ghrelin, gastrin is released in response to food intake. Here we studied the possible role of gastrin in the reduction of body weight after gastric bypass surgery. METHODS: Rats were divided into four experimental groups and were subjected to different treatments: sham operation, gastric bypass, sham operation + gastrin infusion, and gastric bypass + gastrin infusion. The gastric bypass was done by anastomosing the esophagus to the duodenal bulb without bypassing the intestine. Gastrin-17 was infused continuously for 2 months via subcutaneously implanted osmotic minipumps. Body weights were recorded; serum gastrin and ghrelin levels were measured, and the stomachs were analyzed morphologically. RESULTS: Gastric bypass resulted in reducing the body weight, stomach weight, thickness of the oxyntic mucosa, serum gastrin concentration, and activity of the ECL cells. Gastrin infusion prevented mucosal atrophy and ECL cell inactivation, and attenuated the body weight reduction that occurred following gastric bypass. Circulating ghrelin and ghrelin-producing A-like cells in stomachs that had undergone gastric bypass were unchanged with or without gastrin infusion and are thus unlikely to be responsible for the reduced body weight. CONCLUSION: We suggest that hypogastrinemia and impaired ECL cell function in the oxyntic mucosa of the stomach might be partially responsible for the reduction in body weight that occurs after gastric bypass.