Renal cell carcinoma in the Canadian Indigenous population.

Background: Diagnosis and treatment of renal cell carcinoma (rcc) might be different in Indigenous Canadians than in non-Indigenous Canadians. In this cohort study, we compared rcc presentation and treatments in Indigenous and non-Indigenous Canadians. Methods: Patients registered in the Canadian Kidney Cancer Information System treated at 16 institutions between 2011 and 2018 were included. Baseline patient, tumour, and treatment characteristics were compared between Indigenous and non-Indigenous Canadians. The primary objective was to determine if differences in rcc stage at diagnosis were evident between the groups. The secondary objective was to determine if treatments and outcomes were different between the groups. Results: During the study period, 105 of the 4529 registered patients self-identified as Indigenous. Those patients were significantly younger at the time of clinical diagnosis (57.9 ± 11.3 years vs. 62.0 ± 12.1 years, p = 0.0006) and had a family history prevalence of rcc that was double the prevalence in the non-Indigenous patients (14% vs. 7%, p = 0.004). Clinical stage at diagnosis was similar in the two groups (p = 0.61). The disease was metastatic at presentation in 11 Indigenous Canadians (10%) and in 355 non-Indigenous Canadians (8%). Comorbid conditions that could affect the management of rcc-such as obesity, renal disease, diabetes mellitus, and smoking-were more common in Indigenous Canadians (p < 0.05). Indigenous Canadians experienced a lower rate of active surveillance (p = 0.01). Treatments and median time to treatments were similar in the two groups. Conclusions: Compared with their non-Indigenous counterparts, Indigenous Canadian patients with rcc are diagnosed at an earlier age and at a similar clinical stage. Despite higher baseline comorbid conditions, clinical outcomes are not worse for Indigenous Canadians than for non-Indigenous Canadians.

A loop of cancer-stroma-cancer interaction promotes peritoneal metastasis of ovarian cancer via TNFα-TGFα-EGFR.

Peritoneum is the most common site for ovarian cancer metastasis. Here we investigate how cancer epigenetics regulates reciprocal tumor-stromal interactions in peritoneal metastasis of ovarian cancer. Firstly, we find that omental stromal fibroblasts enhance colony formation of metastatic ovarian cancer cells, and de novo expression of transforming growth factor-alpha (TGF-α) is induced in stromal fibroblasts co-cultured with ovarian cancer cells. We also observed an over-expression of tumor necrosis factor-alpha (TNF-α) in ovarian cancer cells, which is regulated by promoter DNA hypomethylation as well as chromatin remodeling. Interestingly, this ovarian cancer-derived TNF-α induces TGF-α transcription in stromal fibroblasts through nuclear factor-κB (NF-κB). We further show that TGF-α secreted by stromal fibroblasts in turn promotes peritoneal metastasis of ovarian cancer through epidermal growth factor receptor (EGFR) signaling. Finally, we identify a TNFα-TGFα-EGFR interacting loop between tumor and stromal compartments of human omental metastases. Our results therefore demonstrate cancer epigenetics induces a loop of cancer-stroma-cancer interaction in omental microenvironment that promotes peritoneal metastasis of ovarian cancer cells via TNFα-TGFα-EGFR.

Diurnal blood pressure and urine production in acute spinal cord injury compared with controls.

STUDY DESIGN: This is a prospective observational study. OBJECTIVES: The objective of this study was to determine time-dependent changes in diurnal blood pressure (BP) and urine production in acute spinal cord injury (SCI). SETTING: This study was conducted in a specialist, state-based spinal cord service in Victoria, Australia. METHODS: Consenting patients admitted consecutively with acute SCI were compared with patients confined to bed rest while awaiting surgery and with mobilising able-bodied controls. Participants underwent ambulatory BP monitoring (ABPM), measurement of diurnal urine production and rated orthostatic symptoms over 1 year. Participants with night:day systolic BP (SBP) <90% were classified as dippers, 90-100% as non-dippers and >100% as reverse dippers. RESULTS: Participants comprised tetraplegics (n=47, 40.0±17.3 years), paraplegics (n=35, 34.4±13.9 years), immobilised (n=18, 30.9±11.3 years) and mobilising (n=44, 33.1±13.5 years) controls. At baseline, 24-h BP was significantly lower in tetraplegics (111.8±1.9/62.1±1.1 mm Hg) but not in paraplegics (116.7± 1.4/66.0±1.1 mm Hg), compared with controls (117.1 ±1.3/69.1±1.1 mm Hg), adjusting for gender. This difference was not observed at 1 year. The average night:day SBP in mobilising controls was 86.1±0.7%, differing from paraplegics (94.0±1.5%, P<0.001) and tetraplegics (101.5±1.5%, P<0.001). Urine production in tetraplegics and paraplegics did not fall at night compared with the day. Abnormal diurnal BP and orthostatic symptoms in tetraplegics persisted throughout the study. Nocturnal hypertension was observed in 27% (n=9) of tetraplegics, of whom only 2 had day hypertension. All mobilising controls with nocturnal hypertension (n=6, 14%) had day hypertension. CONCLUSION: People with SCI have a high prevalence of isolated nocturnal hypertension, reverse dipping, orthostatic intolerance and nocturnal polyuria. Cardiovascular risk management and assessment of orthostatic symptoms should include ABPM.

Unusual serological findings associated with ceftriaxone-induced immune hemolytic anemia in a child with disseminated low-grade glioma.

Ceftriaxone-induced immune hemolytic anemia (CIHA) is the second most common cause of drug-induced hemolytic anemia. Prompt recognition of this drug reaction is essential because brisk hemolysis can be deadly. The extent to which ceftriaxone antibodies persist after CIHA is unknown; rechallenging patients who have experienced CIHA is not recommended. We report a case of CIHA in a neurooncology patient, which is the first to show anticeftriaxone antibodies with Rh specificity and persisted for 8 months after the drug reaction. These findings have implications for understanding the mechanism of CIHA.

Infant hearing screening: effects of timeline.

OBJECTIVES: Universal infant hearing screening using otoacoustic emission and auditory brain-stem response audiometry is widely administered to attain the goals of early identification of, and intervention for hearing impairment. Concerns regarding screening specificity have, however, been raised. False positives may result from vernix occlusion in the ear canal or transient middle ear effusion, and can result in substantial costs to health care systems. The current study investigates the effects of age and time interval between tests on hearing assessment results. SETTING & PARTICIPANTS: Three hundred and seventeen positive screens from a 2-stage distortion product otoacoustic emission (DPOAE) screening programme in Hong Kong, who subsequently received diagnostic auditory brainstem response (ABR) assessment and monitoring, were investigated. MAIN OUTCOME MEASURES: Differences in diagnostic ABR results were compared among infants of different ages at tests, and with different time lapses after DPOAE screening. The proportion of those having persistent hearing impairment, conductive loss and impairment of moderate degree or above, were also compared. RESULTS: A significantly higher rate of normal ABR thresholds (60%versus 24%) was noted in infants assessed after age 50 days, and in infants diagnostically assessed with a time lapse of over 20 days post-DPOAE screening (65%versus 42%). CONCLUSIONS: Delaying diagnostic ABR assessment may reveal a higher percentage of normal thresholds, and hence probably higher specificity. Time delay may allow for spontaneous resolution of transient outer and middle ear conditions. However, the goals of early identification and intervention, as well as possible parental anxiety with delayed assessment, should also be considered when reviewing infant hearing screening schedules.

Development of a closed-system process for clinical-scale generation of DCs: evaluation of two monocyte-enrichment methods and two culture containers.

BACKGROUND: Clinical immunotherapy trials using DCs depend on large-scale methods for DC generation that fulfil current good manufacturing practice requirements. Our goal was to develop data on two variables, monocyte-enrichment method and culture container, which could be used to design a closed-system process for ex vivo generation of immature DCs. METHODS: Mononuclear cells were collected by leukapheresis and enriched for monocytes by either counterflow centrifugal elutriation, or immunomagnetic selection using Isolex, an automated closed-system device. Monocytes were cultured for 7 days in serum-free medium with GM-CSF and IL-4, using either plastic flasks or gas-permeable Stericell bags. Monocytes and cultured DCs were evaluated for yield, flow cytometric phenotype, and in vitro function in MLR, and autologous recall responses to tetanus toxoid and influenza virus. RESULTS: Enriched monocyte products from elutriation and immunomagnetic selection were equivalent in yield and purity, and were capable of generating immature DCs in either flasks or bags. DCs from all four culture conditions were equivalent in yield, phenotype, and in vitro function. Mean DC yield was 67-80% per seeding monocyte, and 11-13% per starting mononuclear cell (MNC). A leukapheresis product containing 5 x 10(9) MNCs processed by this method could therefore yield approximately 5 x 10(8) immature DCs. DISCUSSION: In this manufacturing process, the Isolex system was equivalent to elutriation, and Stericell bags were equivalent to flasks. Together, the Isolex system and Stericell bags can be incorporated into a closed-system process to generate immature DCs.

Development of a clinical-scale method for generation of dendritic cells from PBMC for use in cancer immunotherapy.

BACKGROUND: There is growing interest in the use of dendritic cells (DCs) for treatment of malignancy and infectious disease. Our goal was to develop a clinical scale method to prepare autologous DCs for cancer clinical trials. METHODS: PBMC were collected from normal donors or cancer patients by automated leukapheresis, purified by counterflow centrifugal elutriation and placed into culture in polystyrene flasks at 1 x 10(6) cells/mL for 5-7 days at 37 degrees C, with 5% CO(2), with IL-4 and GM-CSF. Conditions investigated included media formulation, supplementation with heat in activated allogeneic AB serum or autologous plasma and time to harvest (Day 5 or Day 7). DCs were evaluated for morphology, quantitative yield, viability, phenotype and function, including mixed leukocyte response and recall response to tetanus toxoid and influenza virus. RESULTS: DCs with a typical immature phenotype (CD14-negative, CD1a-positive, mannose receptor-positive, CD80-positive, CD83-negative) were generated most consistently in RPMI 1640 supplemented with 10% allogeneic AB serum or 10% autologous plasma. Cell yield was higher at Day 5 than Day 7, without detectable differences in phenotype or function. In pediatric sarcoma patients, autologous DCs had enhanced function compared with monocytes from which they were generated. In this patient group, starting with 8.0 +/- 3.7 x 10(8) fresh or cryopreserved autologous monocytes, DC yield was 2.1 +/- 1.0 x 10(8) cells, or 29% of the starting monocyte number. DISCUSSION: In the optimized clinical-scale method, purified peripheral monocytes are cultured for 5 days in flasks at 1 x 10(6) cells/mL in RPMI 1640, 10% allogeneic AB serum or autologous plasma, IL-4 and GM-CSF. This method avoids the use of FBS and results in immature DCs suitable for clinical trials.

Mapping the physiological parameters of articular cartilage with magnetic resonance imaging.

The ability of magnetic resonance imaging (MRI) to visualize the spatial distribution of parameters related to the physiological and structural properties of tissues makes it an ideal tool for the study of articular cartilage. A variety of ingenious MRI methods have been devised to probe the complex composition and biochemistry of normal and degenerate articular cartilage. In this article we review the current status of this research and pose some questions concerning the future directions of articular cartilage research and clinical applications.

A double-blind, randomized, parallel group study of omeprazole and ranitidine in Korean patients with gastric ulcer.

The efficacy of the proton pump inhibitor omeprazole, 20 mg every morning, was compared with that of the H2-receptor antagonist ranitidine, 150 mg every morning and at bedtime, in a double-blind randomized parallel group study in 250 patients with gastric or prepyloric ulcers. At both 4 and 8 weeks, significantly more patients had healed ulcers in the omeprazole group than the ranitidine group, whether the results were analysed on a per-protocol or an intention-to-treat basis. At 4 weeks, 74% of patients in the omeprazole group were healed compared with 51% in the ranitidine group (P = 0.001), and at 8 weeks the corresponding values were 99 and 82% (P = 0.001, per-protocol cohort). Omeprazole treatment and small ulcer size significantly increased the probability of healing, but smoking had no significant effect. Patients in the omeprazole group had significantly fewer occurrences of daytime epigastric pain during the first 4 weeks than the ranitidine group (P = 0.0037), as shown by their diary cards. Both treatments were well tolerated.

A meta-analysis comparing the efficacy of omeprazole with H2-receptor antagonists for acute treatment of duodenal ulcer in Asian patients.

A meta-analysis was performed on pooled data from five large double-blind studies (a total of 1057 patients), which were conducted in Asia to compare the effects of omeprazole with H2-receptor antagonists (H2-RA) in duodenal ulcer. As each study followed the same protocol and data evaluation procedures, a detailed analysis of ulcer healing, symptom relief and influence of prognostic factors across the data was possible. Patients received omeprazole 20 mg om or standard doses of H2-RA for a minimum of 2 and a maximum of 4 weeks, depending on healing (as verified by endoscopy). All efficacy analyses were based on per protocol data. The mean healing rates at 2 weeks were 72% for omeprazole and 42% for H2-RA (difference 30%; 95% CI: 24-36%; P < 0.0001) and at 4 weeks were 96% for omeprazole and 83% for H2-RA (difference 13%; 95% CI: 10-17%; P < 0.0001). In addition to treatment, ulcer size had a significant influence on healing, with large ulcers (diameter > 10 mm) taking longer to heal than small ulcers. There was no significant influence of smoking and alcohol drinking on ulcer healing. Patients on omeprazole experienced significantly less epigastric pain after 2 weeks than those on H2-RA, 79% of them being completely symptom-free on omeprazole compared with 65% on H2-RA. The incidence of adverse events was approximately 5% on each treatment and profiles were similar for each drug. It is concluded that omeprazole, even in the presence of adverse prognostic influences, results in significantly better healing of duodenal ulcer and relief from symptoms than H2-RA.

Association of calmodulin with isolated nuclei from rat hepatocytes.

Calmodulin plays an important role in regulating cell proliferation and intranuclear processes (J. Biol. Chem. 265: 18595, 1990). Therefore we studied the association of 125I-calmodulin with highly purified rat hepatocyte nuclear preparations which were characterized by marker enzymes and electron microscopy. Steady-state association of 125I-calmodulin was reached within 5 minutes. Half-maximal binding was achieved at approximately 7.1 microM. This association was partially Ca(2+)-dependent, but was not influenced by ATP, GTP or wheat germ agglutinin. Ultrastructural autoradiography showed specific association of 125I-calmodulin with peripheral and non-peripheral heterochromatin, nuclear membranes, and nucleoli. Specific binding (ratio of the grain density of 125I-calmodulin to Na125I) was greatest in the regions of the nucleoli and non-peripheral heterochromatin. The data indicate that exogenous calmodulin can associate with specific nuclear components in an energy-independent and Ca(2+)-dependent manner.

Omeprazole in acute and long-term treatment of Asian patients with peptic ulcer refractory to H2-antagonists.

Twenty-seven patients with peptic ulcer (19 with duodenal ulcer (DU) and eight with gastric ulcer (GU] refractory to H2-antagonists were treated with 40 mg of omeprazole once daily for 4-8 weeks, depending on the rate of ulcer healing. Clinical assessment, endoscopy and laboratory tests were performed at entry, after 2 and after 4 weeks, and if unhealed, also after 8 weeks' treatment. Ten healed patients were given a maintenance therapy of omeprazole 20 mg daily for up to 12 months during which the patients returned for endoscopy, gastric biopsy and laboratory tests at 3-monthly intervals. The initial treatment healed 15 of 19 (79%) DU patients in 2 weeks and all DU patients by 4 weeks. Seven of eight (87%) GU patients healed in 4 weeks and only one required 8 weeks' treatment. Symptom relief was rapid, with most patients being symptom-free within the first day of treatment. Six patients received 12 months' continuous maintenance therapy, one patient 9 months and three patients 6 months' treatment. All patients remained in remission whilst on omeprazole therapy. No adverse events were reported throughout the study. There were no clinically significant changes in haematology or blood chemistry after healing or during the long-term treatment. Biopsy samples revealed no histological changes in the gastric mucosa at any stage. Omeprazole 40 mg therefore was found to produce rapid healing and symptom relief in Asian patients with H2-antagonist-resistant peptic ulcers. Maintenance therapy with omeprazole 20 mg daily was shown to be safe and effective in preventing recurrence of peptic ulceration.