Prognosis of patients with muscle invasive bladder cancer who are intolerable to receive any anti-cancer treatment.

BACKGROUND: The aim of this retrospective study was to evaluate the prognosis of patients who had been diagnosed with muscle invasive bladder cancer (MIBC) and did not receive anti-cancer treatment because of their physical characteristics. METHODS: Between January 2012 and October 2019, 96 patients were diagnosed with MIBC (cT2-4N0M0) in our institution. Of those, 64 patients had undergone radical cystectomy (RC), 6 had received palliative radiation therapy, and 26 had not received any anti-cancer treatment. We further evaluated the 26 patients who had received no anti-cancer treatment. RESULTS: The no anti-cancer treatment group were significantly older (91 vs. 75 years, p<0.001), comprised fewer men (42% vs. 72%, p=0.015), and had poorer performance status (PS) (mean 2.69 vs. 0.32, p<0.001) than the RC group. The follow periods were 9.5 months and 28.5 months, respectively. Median overall survival (OS) was 12 months in the no anti-cancer treatment group, whereas the median OS was not reached during the study period in the RC group. In univariate analysis, OS was significantly associated with estimated GFR (eGFR) less than 30 mL/min/1.73m2 (median OS, 10 vs 16 months, p = 0.044). Multivariate analysis demonstrated that eGFR was significantly associated with OS (hazards ratio 0.267 [95% CI 0.0858-0.8357]; p = 0.0023). CONCLUSIONS: We evaluated the prognosis of patients with untreated MIBC. Their median OS was 12 months and eGFR was a significant prognostic factor. These findings may help in counseling patients about prognosis if no anti-cancer treatment is given.

Photobiomodulation modulates the resolution of inflammation during acute lung injury induced by sepsis.

Sepsis is a big health problem and one of the most common causes of acute lung injury (ALI) leading to high mortality. Pro-resolving mediators play an important role in abrogating the inflammation and promoting tissue homeostasis restoration. ALI treatment is still a clinical health problem, so new therapies are needed. Here, we evaluated the effect of photobiomodulation treatment on the resolution process of ALI induced by lipopolysaccharide (LPS). Male Balb/c mice were submitted to LPS (ip) or vehicle and irradiated or not with light emitting diode (LED) 2 and 6 h after LPS or vehicle injection, and the parameters were investigated 3 and 7 days after the injections. Our results showed that after 3 days of LED treatment the blood and bronchoalveolar lavage (BAL) cells as well as interleukins (IL) including IL-6 and IL-17 were reduced. No differences were observed in the bone marrow cells, tracheal reactivity, and lipoxin A4 and resolvin E2. Indeed, after 7 days of LED treatment the bone marrow cells, lymphocytes, and lipoxin A4 were increased, while IL-6, IL-17, and IL-10 were decreased. No differences were observed in the blood cells and tracheal reactivity. Thus, our results showed that LED treatment attenuated ALI induced by sepsis by modulating the cell mobilization from their reserve compartments. In addition, we also showed later effects of the LED up to 7 days after the treatment. This study proposes photobiomodulation as therapeutic adjuvant to treat ALI.

Changes in the Contractile Activity and Reactivity to 5-HT of Smooth Muscles of Rats Following Total Body Irradiation with Accelerated Electrons.

BACKGROUND: Besides its "classical" neurotransmitter function in the central and peripheral nervous systems, serotonin, or 5-hydroxytryptamine (5-HT) is also a local hormone in a number of tissues, including those of the GI tract. Radiation is known to be able to disrupt certain functions of the tract, modulated by 5-HT-signaling pathways, or the serotonin receptors themselves. AIM: The present investigation focused on clarifying the nature and extent of influence of an accelerated electron beam with energy of 9 MeV on the serotonergic mediation of healthy smooth muscle gastric tissue of rats following total body irradiation of the animals. MATERIALS AND METHODS: The study involved a control group and two experimental groups of animals exposed to 1 and 5 Gy, respectively, using Siemens Primus S/N 3561. Circular smooth muscle tissues were isolated from rats 1 hour and 18 hours after they were exposed to 1 and 5 Gy and also 5 days after irradiation from the rats that received a dose of 5 Gy in order to investigate the action of exogenous serotonin at increasing concentrations from 10-8 to 10-4 mol/l. The contractile reactivity of each group SM preparations was registered isometrically. RESULTS: Electron beams with energy of 9 MeV did not damage the contractile apparatus of gastric SM of rats and had a stimulating effect on contractility resulting from rapidly developing processes (1 hour) or later occurring once (5 days). CONCLUSIONS: Difference was observed in the importance of the factors of received dose, lapse of time from irradiation to investigation of SM tissues, and exogenous 5-HT concentration for the changes in SM reactivity in serotonin-induced tonic and phasic responses.

Acute radiation impacts contractility of guinea-pig bladder strips affecting mucosal-detrusor interactions.

Radiation-induced bladder toxicity is associated with radiation therapy for pelvic malignancies, arising from unavoidable irradiation of neighbouring normal bladder tissue. This study aimed to investigate the acute impact of ionizing radiation on the contractility of bladder strips and identify the radiation-sensitivity of the mucosa vs the detrusor. Guinea-pig bladder strips (intact or mucosa-free) received ex vivo sham or 20Gy irradiation and were studied with in vitro myography, electrical field stimulation and Ca2+-fluorescence imaging. Frequency-dependent, neurogenic contractions in intact strips were reduced by irradiation across the force-frequency graph. The radiation-difference persisted in atropine (1µM); subsequent addition of PPADs (100µM) blocked the radiation effect at higher stimulation frequencies and decreased the force-frequency plot. Conversely, neurogenic contractions in mucosa-free strips were radiation-insensitive. Radiation did not affect agonist-evoked contractions (1µM carbachol, 5mM ATP) in intact or mucosa-free strips. Interestingly, agonist-evoked contractions were larger in irradiated mucosa-free strips vs irradiated intact strips suggesting that radiation may have unmasked an inhibitory mucosal element. Spontaneous activity was larger in control intact vs mucosa-free preparations; this difference was absent in irradiated strips. Spontaneous Ca2+-transients in smooth muscle cells within tissue preparations were reduced by radiation. Radiation affected neurogenic and agonist-evoked bladder contractions and also reduced Ca2+-signalling events in smooth muscle cells when the mucosal layer was present. Radiation eliminated a positive modulatory effect on spontaneous activity by the mucosa layer. Overall, the findings suggest that radiation impairs contractility via mucosal regulatory mechanisms independent of the development of radiation cystitis.

The Use of External-beam Radiotherapy for Muscle-invasive Bladder Cancer in Elderly or Medically-fragile Patients.

AIM: To evaluate the clinical results of external-beam radiotherapy (EBRT) for muscle-invasive bladder cancer (MIBC) in elderly or medically-fragile patients. PATIENTS AND METHODS: Twenty-five consecutive patients with MIBC (cT2-4N0-1M0) receiving EBRT were retrospectively analyzed. Their median age was 82 years. Radiotherapy median dose was 60 Gy administered in 30 fractions. RESULTS: Median follow-up period was 14.7 months. Median overall survival (OS) and progression-free survival (PFS) were 14.7 months and 7.8 months, respectively. The OS, cause-specific survival (CSS), and PFS rates at 1-year were 56.0%, 68.5%, and 40.0%, respectively. The local progression-free rates (LPFR) at 6 months and 1 year were 89.3% and 59.5%, respectively. Performance status 3 was a significantly unfavorable factor for OS, CSS, and progression-free survival; clinical N stage was a significantly unfavorable factor for progression-free survival; and lower irradiation dose (≤50.4 Gy) was a significantly unfavorable factor for LPFR. CONCLUSION: EBRT for elderly or medically-fragile patients is feasible, and achieves acceptable local progression-free status.

Ultrasound induces contraction of the bladder smooth muscle.

PURPOSE: To investigate whether the treatment of overt postpartum urinary retention (PUR) with low-intensity pulsed ultrasound (LIPUS) was clinically effective and whether LIPUS could accelerate bladder smooth muscle (BSM) contraction by opening the L-type calcium channels and activating the Ca(2+) signaling pathway. METHODS: Records of 136 patients undergoing PUR were retrospectively reviewed in two different groups for LIPUS and neostigmine between from 2014 to July 2015. The rats BSM strips in vitro were irradiated by LIPUS. The contraction frequency and amplitude were recorded with BL-410F biological experimental system. The BSM cells were constructed and identified by α-actin-specific antibody staining, and the intracellular Ca(2+) concentration was analyzed by flow cytometry. RESULTS: The clinical trial indicated that LIPUS had potential therapeutic effect on PUR (80.6 vs. 64.1 %, p < 0.05), and the BSM strip contractility was increased by LIPUS (p < 0.001), and the concentration of Ca(2+) was markedly enhanced by about twofold than that without LIPUS exposure (p < 0.01). Besides, nimodipine could suppress the contraction of BSM and the concentration of intracellular Ca(2+) which was caused by ultrasound. CONCLUSIONS: The results suggested LIPUS had potential therapeutic effect on PUR and the Ca(2+) signaling pathway was involved in the mechanism. The ultrasound irradiation may provide a new method for PUR therapy.

Light-controlled relaxation of the rat penile corpus cavernosum using NOBL-1, a novel nitric oxide releaser.

PURPOSE: To investigate whether relaxation of the rat penile corpus cavernosum could be controlled with NOBL-1, a novel, light-controllable nitric oxide (NO) releaser. MATERIALS AND METHODS: Fifteen-week-old male Wistar-ST rats were used. The penile corpus cavernosum was prepared and used in an isometric tension study. After noradrenaline (10(-5) M) achieved precontraction, the penile corpus cavernosum was irradiated by light (470-500 nm) with and without NOBL-1 (10(-6) M). In addition, we noted rats' responses to light with vardenafil (10(-6) M), a phosphodiesterase-5 (PDE-5) inhibitor. Next, responses to light in the presence of a guanylate cyclase inhibitor, ODQ (1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one) (10(-5) M), were measured. All measurements were performed in pretreated L-NAME (10(-4) M) conditions to inhibit endogenous NO production. RESULTS: Corpus cavernosal smooth muscle, precontracted with noradrenaline, was unchanged by light irradiation in the absence of NOBL-1. However, in the presence of NOBL-1, corpus cavernosal smooth muscle, precontracted with noradrenaline, relaxed in response to light irradiation. After blue light irradiation ceased, tension returned. In addition, the light response was obviously enhanced in the presence of a PDE-5 inhibitor. CONCLUSIONS: This study showed that rat corpus cavernosal smooth muscle relaxation can be light-controlled using NOBL-1, a novel, light sensitive NO releaser. Though further in vivo studies are needed to investigate possible usefulness, NOBL-1 may be prove to be a useful tool for erectile dysfunction therapy, specifically in the field of penile rehabilitation.

Comparison of biological effects of electromagnetic fields with pulse frequencies of 8 and 50 Hz on gastric smooth muscles.

The influence of electromagnetic fields (EMFs) with rectangular pulse frequencies of 8 and 50 Hz and flux density of 25 µT on contraction, nitric oxide/nitrite synthesis, and intracellular calcium concentration in the gastric smooth muscles of rats was investigated. An approximately 8-Hz field reduced the fast component of contraction induced by KCl depolarization and slowed down the time to reach the maximum of the slow component of contraction, whereas the 50-Hz field increased the fast and slow components and accelerated the time to reach the maximum of the slow component of contraction. After turning off the EMF, the force and character of contraction returned to the control values. In addition, the 8-Hz field increased nitric oxide/nitrite synthesis in the excited smooth muscle tissue with KCl depolarization, while the 50-Hz field had no significant effect. 8- and 50-Hz fields had no significant effects on nitric oxide/nitrite production in non-stimulated tissue. However, the 50-Hz field significantly increased the basic intracellular calcium concentration in smooth muscle cells (SMC) in a time-dependent manner, whereas the 8-Hz field only slightly increased calcium levels. Thus, we showed that responses of gastric smooth muscles to EMFs are pulse-frequency dependent.

Low-level laser therapy inhibits bronchoconstriction, Th2 inflammation and airway remodeling in allergic asthma.

Low-level laser therapy (LLLT) controls bronchial hyperresponsiveness (BHR) associated with increased RhoA expression as well as pro-inflammatory mediators associated with NF-kB in acute lung inflammation. Herein, we explore if LLLT can reduce both BHR and Th2 cytokines in allergic asthma. Mice were studied for bronchial reactivity and lung inflammation after antigen challenge. BHR was measured through dose-response curves to acetylcholine. Some animals were pretreated with a RhoA inhibitor before the antigen. LLLT (660 nm, 30 mW and 5.4 J) was applied on the skin over the right upper bronchus and two irradiation protocols were used. Reduction of BHR post LLLT coincided with lower RhoA expression in bronchial muscle as well as reduction in eosinophils and eotaxin. LLLT also diminished ICAM expression and Th2 cytokines as well as signal transducer and activator of transduction 6 (STAT6) levels in lungs from challenged mice. Our results demonstrated that LLLT reduced BHR via RhoA and lessened allergic lung inflammation via STAT6.

Assessment of airway hyperresponsiveness in murine tracheal rings.

Isolated tracheal rings have often been used to directly measure the contractile output of airway smooth muscle (ASM). Here, we describe the method for excising murine tracheas, mounting tracheal rings in organ baths, and measuring the isometric forces generated by the ASM when stimulated by drug additions or electric field stimulation. The apparatus for the setup and the pathways responsible for stimulation are detailed. Examples of the responses and analyses of two types of ASM stimulation are illustrated: (1) the carbachol concentration-response curve and (2) the frequency-response curve elicited by electric field stimulation.

Photooxidation and antioxidant responses in the earthworm Amynthas gracilis exposed to environmental levels of ultraviolet B radiation.

Ultraviolet (UV) radiation leads to photooxidation in various organisms. Our previous study demonstrated that ultraviolet B (UV-B) radiation is lethal for particular species of earthworms, but the mechanisms responsible for the lethality are unclear. In our current study, we investigated that ultraviolet light causes photooxidative damage and reduces antioxidant responses in the earthworm Amynthas gracilis. Intact earthworms and skin/muscle tissue extracts were exposed to UV-B radiation for in vivo and in vitro studies. Both in vitro and in vivo results showed that the products of photooxidative damage, MDA and H(2)O(2), increased after UV-B exposure. Glutathione peroxidase (GPx) and catalase were inhibited immediately after exposure to high doses (3000J/m(2)) of UV-B radiation in vivo. Catalase activity was increased following a low UV-B dose (500J/m(2)) in vivo, but decreased in response to all dosage levels in vitro. These data indicate that a relationship exists between UV-B induced damage and photooxidation and also that catalase and GPx act as important antioxidants to prevent photooxidation. According to these data, A. gracilis exhibits high sensitivity to environmental levels of UV-B. Therefore, A. gracilis represents a sensitive and cost-effective model organism for investigations of UV-radiation damage and environmental UV stress.

Glutamine supplementation prevents collagen expression damage in healthy urinary bladder caused by radiotherapy.

OBJECTIVE: Patients who have had pelvic radiotherapy as part of their cancer therapy may develop subsequent urinary bladder effects such as hyperactive bladder, incontinence, and dysuria. Therefore, the goal of this study was to evaluate whether glutamine supplementation could prevent collagen expression damage in healthy urinary bladder caused by radiotherapy. METHODS: Fifteen adult Wistar rats were separated into a control group that received food and water ad libitum (C group), an irradiated group that received a single pelvic radiation dose of 1164 cGy (I group), and an irradiated group supplemented with l-glutamine every day during the entire experimental period (0.65 g/kg of body weight; I+G group). All animals were sacrificed 15 d after irradiation. The extracellular matrix and muscle were quantified by a morphometric method. Picro Sirius Red was used to visualize the different collagen types. Reverse transcription-polymerase chain reaction and immunohistochemistry were used to determine collagen type I and III expressions. RESULTS: The extracellular matrix (C group 36.84±4.37, I group 31.64±5.00, I+G group 35.53±2.60, P=0.0001), muscle (C group 36.43±6.15, I group 29.39±7.08, I+G group 31.38±3.14, P=0.0001), and gene expressions of collagen type I (C group 1.067±0.31, I group 0.579±0.17, I+G group 1.816±0.66, P=0.0009) and type III (C group 0.99±0.28, I group 0.54±0.13, I+G group 1.07±0.28, P=0.0080) were decreased in the I group. Apart from muscle, glutamine supplementation prevented these alterations. Immunohistochemistry and Picro Sirius Red showed similar results. CONCLUSION: Supplementation with l-glutamine seems to prevent bladder wall damage in relation to extracellular matrix volumetric density and collagen expression. These results suggest that glutamine supplementation could be efficient in protecting healthy tissues from the adverse effects of radiotherapy.

Electric field stimulation of precision-cut lung slices.

The precision-cut lung slice (PCLS) technique is widely used to examine airway responses in different species. We developed a method to study nerve-dependent bronchoconstriction by the application of electric field stimulation (EFS) to PCLS. PCLS prepared from Wistar rats were placed between two platinum electrodes to apply serial rectangular impulses (5-100 Hz), and bronchoconstriction was studied by videomicroscopy. The extent of airway contractions increased with higher frequencies. Stable repeated airway contractions were obtained at a frequency of 50 Hz, a width of 1 ms, and an output of 200 mA for 2.5 s each minute. Larger airways showed stronger responses. The EFS-triggered contractions were increased by the acetylcholine esterase inhibitor neostigmine (10 µM) and reversed by the muscarinic antagonist atropine (10 µM), whereas the thromboxane protanoid receptor antagonist SQ29548 (10 µM) had no effect. Magnesium ions (10 mM) antagonized airway contractions induced by EFS, but not by methacholine, indicating that nerve endings remain intact in PCLS. Our data further show that the electrically evoked airway contractions in PCLS are mediated by cholinergic nerves, independent of thromboxane and more prominent in larger airways. Taken together these findings show that nerve endings remain intact in PCLS, and they suggest that the present method is useful to study neurogenic responses in airways of different size.

Bronchial thermoplasty.

Even with the use of maximum pharmacological treatment, asthma still remains uncontrolled in some cases. For such cases of uncontrolled asthma, a novel therapy--Bronchial Thermoplasty (BT)--has shown some promising results over the past few years. BT is application of controlled radiofrequency heat via catheter inserted through a flexible bronchoscope, to the bronchial walls. It reduces the smooth muscle mass in bronchial wall and thus results in decreased contractility. Three major trials of BT show that it does not cause any improvement in FEV1. However, BT causes improvement the quality of life and decreases the future exacerbations and emergency hospital visits due to asthma. But the benefit observed was too small to be clinically significant. Follow up (two to five years) results of these BT trials did not show any significant long-term adverse event related to BT. However, further independent large randomized controlled trials and results of application of BT in real hospital settings are needed to define its role in asthma management.

[Normal tissue tolerance to external beam radiation therapy: small bowel]. / Dose de tolérance à l'irradiation des tissus sains: intestin grêle.

The small bowel is a hollow organ involved in the transit and absorption of food. In relation to its anatomical location, a significant amount of this organ is exposed in whole or in part to ionizing radiation in external radiotherapy during abdominal or pelvic irradiation either for primary cancers or metastasis. The acute functional changes during external beam radiation are mainly leading to diarrhea, abdominal pain and bloating. The main late side effects of irradiation of the small intestine are chronic diarrhea, malabsorption with steatorrhea, abdominal spasms, intestinal obstruction, bleeding and fistulas. The architecture of the small intestine may be considered as parallel with a significant correlation between the irradiated volume of small bowel and the likelihood of acute toxicity, whatever the dose. The literature analysis recommends to consider the volume of small bowel receiving 15 Gy (threshold of 100 to 200 cm(3)) but also 30 and 50 Gy (thresholds of 35 to 300 cm(3), depending on the level of dose considered). Modern techniques of conformal radiotherapy with modulated intensity will probably have beneficial impact on small bowel toxicity.

Low-level laser therapy (LLLT) attenuates RhoA mRNA expression in the rat bronchi smooth muscle exposed to tumor necrosis factor-alpha.

Low-level laser therapy (LLLT) has been found to produce anti-inflammatory effects in a variety of disorders. Bronchial smooth muscle (BSM) hyperreactivity is associated with increased Ca+2 sensitivity and increased RhoA mRNA expression. In the current study, we investigated if LLLT could reduce BSM contraction force and RhoA mRNA expression in tumor necrosis factor-alpha (TNF-alpha)-induced BSM hyperreactivity. In the study, 112 male Wistar rats were divided randomly into 16 groups, and BSM was harvested and suspended in TNF-alpha baths for 6 and 24 h, respectively. Irradiation with LLLT was performed with a wavelength of 660 nm for 42 s with a dose of 1.3 J/cm2. This LLLT dose was administered once in the 6-h group and twice in the 24-h group. LLLT significantly decreased contraction force in BSM at 6 h (TNF-alpha + LLLT: 11.65+/-1.10 g/100 mg of tissue) (F=3115) and at 24 h (TNF-alpha+ LLLT: 14.15+/-1.1 g/100 mg of tissue) (F=3245, p<0.05) after TNF-alpha, respectively, when compared to vehicle-bathed groups (control). LLLT also significantly decreased the expression of RhoA mRNA in BSM segments at 6 h (1.22+/-0.20) (F=2820, p<0.05) and 24 h (2.13+/-0.20) (F=3324, p<0.05) when compared to BSM segments incubated with TNF-alpha without LLLT irradiation. We conclude that LLLT administered with this protocol, reduces RhoA mRNA expression and BSM contraction force in TNF-alpha-induced BSM hyperreactivity.

Clinical and dosimetric factors associated with a prolonged feeding tube requirement in patients treated with chemoradiotherapy (CRT) for head and neck cancers.

BACKGROUND: Patients treated with chemoradiotherapy (CRT) for head and neck cancers often require feeding tubes (FTs) due to toxicity. We sought to identify factors associated with a prolonged FT requirement. PATIENTS AND METHODS: We retrospectively reviewed 80 patients treated with CRT for head and neck cancers. The pharyngeal constrictors (PCs), supraglottic larynx (SGL), and glottic larynx (GL) were contoured and the mean radiation doses and the volumes of each receiving >40, 50, 60, and 70 Gy (V40, V50, V60, and V70) were determined. RESULTS: A total of 33 of 80 patients required a FT either before or during the course of CRT. Fifteen patients required the FT for > or = 6 months. On univariate analysis, significant factors associated with a prolonged FT requirement were mean PC dose, PC-V60, PC-V70, SGL dose, SGL-V70, and advanced T3-T4 disease. Multivariate analyses found both PC-V70 and T3-T4 disease as significant factors .The proportions of patients requiring a FT > or = 6 months were 8% and 28% for treatment plans with PC-V70 <30% and > or = 30%, respectively. CONCLUSIONS: Increased radiation dose to the PCs is associated with a higher risk of a prolonged FT need. Dose sparing of the PC muscles may reduce this risk.

Changes in the penile arteries of the rat after fractionated irradiation of the prostate: a pilot study.

INTRODUCTION: External beam radiotherapy for prostate cancer leads to erectile dysfunction in 36%-43% of patients. The underlying mechanism is largely unknown, although some clinical studies suggest that the arterial supply to the corpora cavernosa is responsible. Two animal experimental studies reported on the effects of a single fraction of prostate irradiation on the penile structures. However, irradiation in multiple fractions is more representative of the actual clinical treatment. AIM: The present prospective, controlled study was initiated to investigate the effect of fractionated prostate irradiation on the arteries of the corpora cavernosa. MAIN OUTCOME MEASURES: Histological evaluation of the penile tissue in comparison with control rats at 2, 4, and 9 weeks after irradiation. METHODS: The prostate of twelve rats was treated with external beam radiation in 5 daily fractions of 7.4 gray. Three control rats were treated with sham irradiation. Prostatic and penile tissue was evaluated for general histology (hematoxylin-eosin). The penile tissue was further evaluated after combined staining for collagen (resorcin fuchsin) and alpha-smooth muscle actin (SMA) (Biogenex). RESULTS: The prostate showed adequate irradiation with fibrosis occurring at 9 weeks after irradiation. The corpora cavernosa showed arteries that had developed loss of smooth muscle cells expressing SMA, thickening of the intima, and occlusions. All the control rats maintained normal anatomy. CONCLUSION: This is the first animal experimental study that demonstrates changes in the arteries of the corpora cavernosa after fractionated irradiation to the prostatic area. The preliminary data suggests that erectile dysfunction after radiotherapy might be caused by radiation damage to the arterial supply of the corpora cavernosa.