Immunotherapy for urothelial carcinoma: Metastatic disease and beyond

For advanced and metastatic urothelial carcinomas (UCs), platinum (preferably cisplatin)‐based chemotherapy has been the standard treatment for many years. However, many patients are ineligible for cisplatin‐based chemotherapy because of poor performance status and/or other age‐related conditions. At the other end of the spectrum, patients with localized non‐muscle–invasive bladder cancer who are unresponsive to intravesical Bacillus Calmette‐Guérin (BCG) treatment often face radical cystectomy as the only option. In recent years, the application of immunotherapy in the form of immune‐checkpoint inhibitors has provided viable alternatives in the second‐line postplatinum and first‐line cisplatin‐ineligible settings. Recent and ongoing clinical trials are also assessing the safety and efficacy of immunotherapy for neoadjuvant and adjuvant uses before/after cystectomy, for BCG‐unresponsive cases, and for combination treatments that include the newer indoleamine 2,3‐dioxygenase‐1 inhibitors and/or BCG. This review summarizes recent developments in immunotherapy for UCs.     

Ischemia-reperfusion of small liver remnant promotes liver tumor growth and metastases--activation of cell invasion and migration pathways.

Elucidating the mechanism of liver tumor growth and metastasis after hepatic ischemia-reperfusion (I/R) injury of a small liver remnant will lay the foundation for the development of therapeutic strategies to target small liver remnant injury, and will reduce the likelihood of tumor recurrence after major hepatectomy or liver transplantation for liver cancer patients. In the current study, we aimed to investigate the effect of hepatic I/R injury of a small liver remnant on liver tumor development and metastases, and to explore the precise molecular mechanisms. A rat liver tumor model that underwent partial hepatic I/R injury with or without major hepatectomy was investigated. Liver tumor growth and metastases were compared among the groups with different surgical stress. An orthotopic liver tumor nude mice model was used to further confirm the invasiveness of the tumor cells from the above rat liver tumor model. Significant tumor growth and intrahepatic metastasis (5 of 6 vs. 0 of 6, P=0.015), and lung metastasis (5 of 6 vs. 0 of 6, P=0.015) were found in rats undergoing I/R and major hepatectomy compared with the control group, and was accompanied by upregulation of mRNA levels for Cdc42, ROCK (Rho kinase), and vascular endothelial growth factor, as well as activation of hepatic stellate cells. Most of the nude mice implanted with liver tumor from rats under I/R injury and major hepatectomy developed intrahepatic and lung metastases. In conclusion, hepatic I/R injury of a small liver remnant exacerbated liver tumor growth and metastasis by marked activation of cell adhesion, invasion, and angiogenesis pathways.     

Excitation of rat hippocampal interneurons via modulation of endogenous agonist activity at the α7 nicotinic ACh receptor

The α7 subtype of the nicotinic acetylcholine receptor (α7 nAChR) is prominently expressed in the hippocampus where it is thought to play a role in the regulation of cognitive function. In this study, we have investigated the effects of 5-hydroxyindole (5-HI), a positive modulator of the α7 nAChR, on GABAergic activity in hippocampal CA1 stratum radiatum interneurons in acute rat brain slices. Superfusion of 5-HI (100 μ m ) increased the mean frequency and amplitude of spontaneous IPSCs (sIPSCs). The potentiation was occluded by pretreatment of slices with: (1) a high concentration of the broad-spectrum agonist nicotine to desensitize the α7 receptor, (2) an α7 nAChR antagonist, and (3) tetrodotoxin to block action potential firing. These results indicate that facilitation by 5-HI was mediated by the α7 nAChR and required neuronal excitation. In contrast, 5-HI had no effect on sIPSCs recorded in hippocampal slices from younger animals, even though the expression of functional α7 nAChRs was confirmed by agonist application experiments. In these slices, 5-HI only enhanced sIPSCs after pretreatment with the acetylcholinesterase inhibitor Bw284c51. Taken together, our results suggest that 5-HI facilitates GABAergic transmission via excitation of the α7 nAChR, and that this effect requires the presence of the endogenous agonist ACh in the extracellular environment of the receptor.     

Setting targets: a three-stage model for determining priorities for health promotion

This paper describes a three-stage model for setting targets for health promotion. The model was developed in 1992 in response to the need to identify priority areas for health promotion for women in the Hunter Region of New South Wales. The approach enabled epidemiological data and views from the community to be synthesised and integrated with those of experts from health and social services (key informants), using a nominal group process. The reliability of the method was investigated by replicating the process with two groups of key informants. There was considerable commonality in the targets generated by the two groups. The process resulted in the identification of seven targets that reflected the concerns of the community and local experts as well as the health priorities suggested by local epidemiological data. The model used could be adapted for determining priorities in a wide range of health and health care settings, where available resources restrict the range of services or activities which can be offered. (Aust J Public Health 1995; 19: 263–9)     

Features of pediatric head injury in Hong Kong

Head injury in children causes special concern in most communities. From 1989 to 1994, 2,785 children younger than 16 years old were admitted to our neurosurgical service because of head injury. Fall from a height was the major cause of head injury leading to admission in infants and children in preschool age groups, whereas traffic-related or bicycle-related accidents were more likely to be the cause of head injury for those aged 11–15 years. In all age groups there was a male preponderance. The overall mortality was 0.6%. Traffic-ralated accidents caused more severe injury and accounted for 67% of all fatalities. For patients under 6 years old, about 40% of head injuries occurred at home. Preventive measures for pediatric head injury in Hong Kong are suggested.     

Angioedema due to angiotensin-converting enzyme inhibitor use: Radiographic findings in 3 patients

Angioedema of the oropharynx and hypopharynx due to oral angiotensin-converting enzyme (ACE) inhibitors is a potentially life-threatening event and has not been well described in the radiology literature. A retrospective review of the clinical and radiologic findings in three patients with angioedema due to ACE inhibitor use was performed.Our subgroup of patients treated with ACE inhibitors presented with varying degrees of dysphagia, dyspnea, and facial swelling. Plain radiographic findings included enlargement of the epiglottis, aryepiglottic folds, and prevertebral and submental soft tissue. Computed tomography confirmed extensive retropharyngeal and subcutaneous edema. Clinical symptoms resolved in each case in 24–48 hours with cessation of the ACE inhibitor and concomitant steriod therapy.Our cases demonstrate the typical clinical and radiographic presentation of neck angioedema in the setting of ACE inhibitor use. As ACE inhibitors are increasingly being used as first-line agents in the treatment of hypertension, we caution that neck angioedema may be encountered with increased frequency in adults. Early recognition and immediate intervention result in rapid resolution of this potentially life-threatening event.     

Proximal gastric vagotomy. The preferred operation for perforations in acute duodenal ulcer.

Simple closure, the conventional operation for perforated acute duodenal ulcers, is associated with symptomatic relapse in a large proportion of patients. In order to assess the role of immediate definitive surgery, 78 fit patients with perforated acute ulcers were prospectively randomized to undergo either closure alone or proximal gastric vagotomy with closure (PGV). Patients taking potentially ulcerogenic drugs or who had severe stress were excluded from the study. Both groups were comparable with respect to age, sex, general medical health, duration of perforation, length of ulcer history, and presence of duodenal scarring. There was no hospital mortality. Minor complications occurred in 7.3% after closure and 10.8% after PGV. At 3 years follow-up, the cumulative recurrence rates were 36.6% and 10.6% after closure and PGV, respectively (p = 0.001). Eighty-five per cent of recurrences after closure were symptomatic, and half of them required reoperation. Duodenal scarring itself did not appear to influence the outcome after closure. PGV was not associated with dumping, diarrhea or other unwanted side effects. Although less than that in chronic ulcers, there is a substantial risk of symptomatic relapse after closure of perforated acute duodenal ulcers. With judicious patient selection, PGV effectively reduces this risk without incurring disabling side effects associated with other ulcer operations.