Development of irAEs was associated with survival outcome of nivolumab treatment in patients with advanced or recurrent NSCLC. Further studies are needed to confirm our findings.

No abstract

The epidermal growth factor receptor directed antibody, cetuximab, is an effective clinical therapy for patients with colorectal, head and neck and non-small cell lung cancer patients particularly for those with KRAS and BRAF wild type cancers. Treatment in all patients is limited eventually by the development of acquired resistance but little is known about the underlying mechanism. Here we show, that activation of ERBB2 signaling, either through ERBB2 amplification or through heregulin upregulation, leads to persistent ERK 1/2 signaling and consequently cetuximab resistance. Inhibition of ERBB2 or disruption of ERBB2/ERBB3 heterodimerization restores cetuximab sensitivity in vitro and in vivo. A subset of colorectal cancer patients that exhibit either de novo or acquired resistance to cetuximab based therapy possess ERBB2 amplification or high levels of circulating heregulin. Collectively, these findings identify two distinct resistance mechanisms, both of which promote aberrant ERBB2 signaling, that mediate cetuximab resistance. Moreover, these results suggest that ERBB2 inhibitors, in combination with cetuximanb, represent a rational therapeutic strategy that should be assessed in cetuximab-resistant cancers.

Transient receptor potential channels have recently been implicated in physiological functions in a urogenital system. In this study, we investigated the role of transient receptor potential vanilloid 4 (TRPV4) channels in a stretch sensing mechanism in mouse primary urothelial cell cultures. The selective TRPV4 agonist, 4␣-phorbol 12,13-didecanoate (4␣-PDD) evoked Ca 2؉ influx in wild-type (WT) urothelial cells, but not in TRPV4-deficient (TRPV4KO) cells. We established a cellstretch system to investigate stretch-evoked changes in intracellular Ca 2؉ concentration and ATP release. Stretch stimulation evoked intracellular Ca 2؉ increases in a stretch speed-and distance-dependent manner in WT and TRPV4KO cells. In TRPV4KO urothelial cells, however, the intracellular Ca 2؉ increase in response to stretch stimulation was significantly attenuated compared with that in WT cells. Stretch-evoked Ca 2؉ increases in WT urothelium were partially reduced in the presence of ruthenium red, a broad TRP channel blocker, whereas that in TRPV4KO cells did not show such reduction. Potent ATP release occurred following stretch stimulation or 4␣-PDD administration in WT urothelial cells, which was dramatically suppressed in TRPV4KO cells. Stretch-dependent ATP release was almost completely eliminated in the presence of ruthenium red or in the absence of extracellular Ca 2؉ . These results suggest that TRPV4 senses distension of the bladder urothelium, which is converted to an ATP signal in the micturition reflex pathway during urine storage. Transient receptor potential vanilloid 4 (TRPV4),3 a member of the TRP superfamily of cation channels, is a Ca 2ϩ -permeable channel activated by a wide variety of physical and chemical stimuli (1, 2). TRPV4 was originally viewed as an osmo-or mechano-sensor, because the channel opens in response to hypotonicity-induced cell swelling (3-5) and shear stress (6). Alternatively, TRPV4 can be activated by diverse chemical stimuli such as synthetic phorbol ester 4␣-phorbol 12,13-didecanoate (4␣-PDD) (7), a botanical agent (bisandrographolide A), anandamide metabolites such as arachidonic acid and epoxyeicosatrienoic acids, as well as moderate warmth (Ͼ27°C) (8 -10). TRPV4 is widely expressed throughout the body, including renal epithelium, auditory hair cells, skin keratinocytes, hippocampus neurons, endothelial cells, and urinary bladder epithelium, thereby contributing to numerous physiological processes such as osmoregulation (11, 12), hearing (13), thermal and mechanical hyperalgesia (14, 15), neural activity in the brain (16), skin barrier recovery (17), and cell volume regulation (18). Therefore, the TRPV4 channel is now considered a multimodal transducer in various tissues and cells.Non-neuronal cells within the urinary bladder wall (notably the transitional epithelial cells (urothelial cells)) function as a barrier against ions, solutes, and infection and also participate in the detection of physical and chemical stimuli (19 -21). The urothelium expresses various sensory receptors and channe...

Background: The Piezo1 channel was recently identified as a genuine mechanosensor in mammalian cells. Results: Urothelial cells exhibited a Piezo1-dependent increase in cytosolic Ca 2ϩ concentrations in response to mechanical stretch stimuli, leading to ATP release. Conclusion: Piezo1 senses extension of the bladder urothelium, which is converted into an ATP signal. Significance: Inhibition of Piezo1 might provide a new treatment for bladder dysfunction.

* At the time of this consultation, these definitions are not included in the current ICS terminology. RECOMMENDATIONS OF THE INTERNATIONAL SCIENTIFIC COMMITTEE 2. EVALUATION The following phrases are used to classify diagnostic tests and studies: • A highly recommended test is a test that should be done on every patient. This section should also be read in conjunction with the relevant committee reports. RECOMMENDATIONS OF THE INTERNATIONAL SCIENTIFIC COMMITTEE 6. ANORECTAL PHYSIOLOGY TESTING Endocoil MRI has high accuracy for detecting anal sphincter injury but is second line after endoanal ultrasound. Patients with faecal incontinence may benefit from assessment with MRI, particularly those with anorectal malformations and/or previous anal sphincter surgery. Defaecography may be useful and is recommended in patients with faecal incontinence, who have failed conservative therapies, and are possible candidates for laparoscopic ventral rectopexy. * Consider CONTINENCE PRODUCTS for temporary support during treatment Recent VVF Primary simple Consider Catheter, evaluate weekly Established VVF Primary complex Healed Persistant leakage Recurrence Post-irradiation Vaginal repair Consider timing Surgical repair Consider timing Consider interposition material If small, consider catheter, evaluate weekly Surgical repair 6-12 months Consider interposition material Surgical repair Consider timing Consider interposition material Assess fistula closure & assess continence status MANAGEMENT OF IATROGENIC URETERIC FISTULAE HISTORY CLINICAL ASSESSMENT MANAGEMENT* PRESUMED DIAGNOSIS Extra-urethral vaginal urinary leakage and/or signs of ureteric obstruction Clinical examination Urethro-cystoscopy Imaging (Xray/CT/ MRI, US) Evaluate upper urinary tract obstruction * Consider CONTINENCE PRODUCTS for temporary support during treatment Ureterovaginal fistula Endoluminal technique (stenting, nephrostomy) for at least 6 weeks Unable to stent (initially)... Re-evaluate for fistula closure, ureteric obstruction Persisting fistula or ureteric obstruction Ureteric reimplantation (open, laparoscopic or robotic) Healed Long-term follow-up for stricture and hydropephrosis * Consider CONTINENCE PRODUCTS for temporary support during treatment Patient education, adequate fibre diet and fluid intake; regular bowel care, preferably ± 3 times a week

T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.

Registered at clinicaltrials.gov (NCT00966004). Objective• To evaluate the efficacy and safety of the β3-adrenoceptor agonist mirabegron, in a Japanese population with overactive bladder (OAB). Patients and Methods• This randomised, double-blind, placebo-controlled phase III study enrolled adult patients experiencing OAB symptoms for ≥24 weeks. Patients with ≥ 8 micturitions/24 h and ≥1 urgency episode/24 h or ≥1 urgency incontinence episode/24 h were randomised to once-daily placebo, mirabegron 50 mg or tolterodine 4 mg (as an active comparator, without testing for non-inferiority of efficacy and safety) for 12 weeks.• The primary endpoint was the change in the mean number of micturitions/24 h from baseline to final assessment. Secondary endpoints included micturition variables related to urgency and/or incontinence and quality-of-life domain scores on the King's Health Questionnaire.• Safety assessments included adverse events (AEs), post-void residual urine volume, laboratory variables, vital signs and 12-lead electrocardiogram. Results• A total of 1139 patients were randomised to receive placebo (n = 381), mirabegron 50 mg (n = 380) or tolterodine 4 mg (n = 378). Demographic and baseline characteristics were similar among the treatment groups.• At final assessment, mirabegron was significantly superior to placebo in terms of mean [SD] Conclusions• Mirabegron 50 mg once daily is an effective treatment for OAB symptoms, with a low occurrence of side effects in a Japanese population.