Small, soluble metabolites not only are essential intermediates in intracellular biochemical processes, but can also influence neighbouring cells when released into the extracellular milieu1–3. Here we identify the metabolite and neurotransmitter GABA as a candidate signalling molecule synthesized and secreted by activated B cells and plasma cells. We show that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages that secrete interleukin-10 and inhibit CD8+ T cell killer function. In mice, B cell deficiency or B cell-specific inactivation of the GABA-generating enzyme GAD67 enhances anti-tumour responses. Our study reveals that, in addition to cytokines and membrane proteins, small metabolites derived from B-lineage cells have immunoregulatory functions, which may be pharmaceutical targets allowing fine-tuning of immune responses.

The use of immune checkpoint inhibitors to treat urothelial carcinoma (UC) is increasing rapidly without clear guidance for validated risk stratification. This multicenter retrospective study collected clinicopathological information on 463 patients, and 11 predefined variables were analyzed to develop a multivariate model predicting overall survival (OS). The model was validated using an independent dataset of 292 patients. Patient characteristics and outcomes were well balanced between the discovery and validation cohorts, which had median OS times of 10.2 and 12.5 mo, respectively. The final validated multivariate model was defined by risk scores based on the hazard ratios (HRs) of independent prognostic factors including performance status, site of metastasis, hemoglobin levels, and the neutrophil‐to‐lymphocyte ratio. The median OS times (95% confidence intervals [CIs]) for the low‐, intermediate‐, and high‐risk groups (discovery cohort) were not yet reached (NYR) (NYR–19.1), 6.8 mo (5.8‐8.9), and 2.3 mo (1.2‐2.6), respectively. The HRs (95% CI) for OS in the low‐ and intermediate‐risk groups vs the high‐risk group were 0.07 (0.04‐0.11) and 0.23 (0.15‐0.37), respectively. The objective response rates for in the low‐, intermediate‐, and high‐risk groups were 48.3%, 28.8%, and 10.5%, respectively. These differential outcomes were well reproduced in the validation cohort and in patients who received pembrolizumab after perioperative or first‐line chemotherapy (N = 584). In conclusion, the present study developed and validated a simple prognostic model predicting the oncological outcomes of pembrolizumab‐treated patients with chemoresistant UC. The model provides useful information for external validation, patient counseling, and clinical trial design.

Background: Several clinical studies have indicated the efficacy of cilostazol, a selective inhibitor of phosphodiesterase 3, in preventing cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). They were not double-blinded trial resulting in disunited results on assessment of end points among the studies. The randomized, double-blind, placebo-controlled study was performed to assess the effectiveness of cilostazol on cerebral vasospasm. Methods: Patients with aneurysmal SAH admitted within 24 h after the ictus who met the following criteria were enrolled in this study: SAH on CT scan was diffuse thick, diffuse thin, or local thick, Hunt and Hess score was less than 4, administration of cilostazol or placebo could be started within 48 h of SAH. Patients were randomly allocated to placebo or cilostazol after repair of a ruptured saccular aneurysm by aneurysmal neck clipping or endovascular coiling, and the administration of cilostazol or placebo was continued up to 14 days after initiation of treatment. The primary end point was the occurrence of symptomatic vasospasm (sVS), and secondary end points were angiographic vasospasm (aVS) evaluated on digital subtraction angiography, vasospasm-related new cerebral infarction evaluated on CT scan or MRI, and clinical outcome at 3 months of SAH as assessed by Glasgow Outcome Scale, in which poor outcome was defined as severe disability, vegetative state, and death. All end points were evaluated with blinded assessment. Results: One hundred forty eight patients were randomly allocated to the cilostazol group (n = 74) or the control group (n = 74). The occurrence of sVS was significantly lower in the cilostazol group than in the control group (10.8 vs. 24.3%, p = 0.031), and multiple logistic analysis showed that cilostazol use was an independent factor reducing sVS (OR 0.293, 95% CI 0.099-0.568, p = 0.027). The incidence of aVS and vasospasm-related cerebral infarction were not significantly different between the groups. Poor outcome was significantly lower in the cilostazol group than in the control group (5.4 vs. 17.6%, p = 0.011), and multiple logistic analyses demonstrated that cilostazol use was an independent factor that reduced the incidence of poor outcome (OR 0.221, 95% CI 0.054-0.903, p = 0.035). Severe adverse events due to cilostazol administration did not occur during the study period. Conclusions: Cilostazol administration is effective in preventing sVS and improving outcomes without severe adverse events. A larger-scale study including more cases was necessary to confirm this efficacy of cilostazol.

Objectives: To clarify the natural history of asymptomatic renal stones £5 mm in comparison with stones ‡5 mm. Calculi £5 mm are considered insignificant stones, but to what extent stone-related events can occur is unclear.Patients and Methods: In this retrospective study, 207 patients with asymptomatic renal stones confirmed by both CT and ultrasonography performed on the same day were enrolled. A follow-up ultrasound was performed every 6 months. The active indications for surgical intervention included stone relocations into the ureter and stone-related symptoms. The primary endpoint was the rate of surgical intervention.Results: A total of 207 patients (71 cases with stones £5 mm and 136 cases with stones >5 mm) were included in this study. At a median follow-up of 3.3 years, 14 patients (20%) from the £5-mm group and 52 (38%) from the >5-mm group underwent surgical treatment ( p = 0.0067). Moreover, 11 patients (16%) from the £5-mm group and 27 (20%) from the >5-mm group received surgical intervention as they manifested active indications, showing no significant difference ( p = 0.44). As regards stone events, there were no significant differences in spontaneous stone passage, pain, hematuria, and stone growth. Multivariate analysis revealed that age £50 years and a history of stone surgery were significant factors, but stone size was not. Conclusion: About 20% of asymptomatic renal stones £5 mm require surgical treatment within 5 years.

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Objectives To describe the complications and their surgical management after laparoscopic radical cystectomy in a Japanese multicenter cohort. Methods The participants were drawn from a retrospective multicenter study at 10 institutions. We identified 436 patients who underwent laparoscopic radical cystectomy with no robot assistance. Early and late complications were graded according to their Clavien–Dindo classification. The records of all patients who underwent surgical interventions for laparoscopic radical cystectomy‐specific complications were also reviewed. Kaplan–Meier curves were used to describe the time to surgical intervention. Results The 90‐day rates for overall complications, high‐grade complications (Clavien–Dindo classification III–V) and mortality were 53%, 17% and 1.4%, respectively. Gastrointestinal (25%), infectious (22%) and abdominal wall‐related (9%) complications were the most common. The late complication rate was 18%, and a total of 81 patients (19%) underwent surgical intervention during the median follow‐up period of 22 months. The reoperation rate was 25% at 5 years. Gastrointestinal complications in the early postoperative period and abdominal wall‐related complications in the late postoperative period were the main reasons for reoperation. Seven (7%) out of 100 female patients underwent emergent surgical reoperation for transvaginal bowel evisceration as a result of vaginal dehiscence. Conclusions Early and late postoperative complications and surgical reoperations are notable after laparoscopic radical cystectomy. Abdominal wall‐related complications including vaginal dehiscence are common, and they represent the main indication for reoperation during long‐term follow up.

In order to clarify whether or not the electronegative olfactory mueosal potentials (EOG) are generator potentials, the effects of changed ionic enviroment were studied. The EOG decreased in amplitude and in some cases nearly or completely disappeared, when Na + in the bathing Ringer solution was replaced .by sucrose, Li +, choline +, tetraethylammoninm + (TEA), or hydrazine. In the K+-free Ringer solution, the negative EOG's initially increased and then decreased in amplitude, In Ringer's solution with increased K +, the negative EOG's increased in amplitude. When K + was increased in exchange for Na + in Ringer's solution, the negative EOG's decreased, disappeared, and then reversed their polarity (Fig. 6). Next, when the K + was replaced by equimolar sucrose, Li +, choline +, TEA+, hydrazine, or Na +, the reversed potentials recovered completely only in Na+-Ringer's solution, but never in the other solutions, Thus, the essential role of Na + and K + in the negative EOG's was demonstrated. Ba ++ was found t ° depress selectively the electropositive EOG, but it hardly :decreased and never increased the negative EOG. Hence, it is concluded that Ba ++ interferes only with CI-influx, and that the negative EOG's are elicited by an increase in permeability of the olfactory receptive membrane to Na + and K +, but not to CA-. From the ionic mechanism it is inferred that the negative EOG's are in most eases composites of generator and positive potentials.Since the pioneer work by Hosoya and Yoshida (1937) in the dog, and by Ottoson (1954Ottoson ( , 1956 in the rabbit and frog, the electrical phenomena elicited in the olfactory epithelium by application of odors have been extensively studied and much new information has been obtained. Besides the electronegative slow potentials of the " o n " type found by the above workers, and named "electro-olfactogram ( E O G ) " by Ottoson (1956), electronegative po-

A 13-year-old girl with a pituitary abscess complained of continuous headache and bitemporal hemianopsia after a common cold. However, she had no inflammatory reactions on admission. Comput ed tomography showed a low-density sellar mass lesion extending to the suprasellar cistern with a peripheral low-density area, and ring enhancement of the capsule with a particularly thick region. Mag netic resonance imaging showed the mass lesion as a low and high-intensity area on the T₁-and T₂