Immunocryosurgery for basal cell carcinoma: results of a pilot, prospective, open-label study of cryosurgery during continued imiquimod application

Background/aim  Theoretical considerations support the combination of cryosurgery and topical imiquimod to treat basal cell carcinomas (BCC). The aim of the present study was to test the feasibility and efficacy of 'cryosurgery during continued imiquimod application' ('immunocryosurgery') to treat 'high-risk-for-recurrence' BCCs.
Methods  Thirteen patients with 21 biopsy-proven tumours (4 of 21 relapses after prior surgery) were included. After 2–5 weeks (median, 3) of daily 5% imiquimod cream application, the tumours were treated by liquid N₂ cryosurgery (spray, two cycles, 10–20 s) and imiquimod was continued for additional 2–12 weeks (median, 4). The outcome after at least 18 months of follow-up (18–24 months) is currently reported.
Results  Nineteen of 21 tumours responded promptly to immunocryosurgery; two tumours required additional treatment cycles to clear. Thus, the clinical clearance rate was 100%. Only 1 of 21(5%) tumour relapsed after at least 18 months of follow-up (cumulative efficacy: 95%).
Conclusions  'Immunocryosurgery' is a promising non-surgical combination modality to treat 'high-risk-for-recurrence BCCs'. Initial evidence is suggestive of an at least additive effect of the two combined modalities. Further studies comparing immunocryosurgery directly with cryosurgery and imiquimod monotherapies will confirm the reported results.     

FEASIBILITY OF CONDUCTING CARDIOVASCULAR OUTCOME RESEARCH IN AUSTRALIAN GENERAL PRACTICE: RESULTS FROM THE ANBP2 PILOT STUDY

1. The present study aimed to determine the feasibility of conducting a 5 year cardiovascular outcome trial of the treatment of 6000 elderly hypertensive patients in Australian general practices. 2. General practitioners (GPs) were invited to participate by mail and personal follow-up. Patient records were reviewed to identify subjects for a blood pressure (BP) screening programme. Blood pressure was measured on three occasions and eligible subjects were included if the average BP was 160 mmHg systolic or 90 mmHg diastolic if systolic BP was 140 mmHg. 3. Seven hundred and forty-one GPs were approached and 89 were enrolled in the study (12% of mail invites and 75% of those receiving a personal contact). In 16 practices where screening was completed, 82 000 records were reviewed to identify 4% patients eligible for screening. Twenty-two per cent of eligible subjects attended screening. Of 1938 subjects screened, 180 (9%) had BP 5=160/90 mmHg. Forty-seven percent of subjects (n = 916) were receiving antihypertensive therapy and 184 (20%) were withdrawn from therapy. One hundred and sixteen (63%) of these subjects had BP return to study entry levels within 6 weeks. Fifty-seven newly diagnosed and 81 previously treated subjects were randomized (7% of the screened population). 4. Based on the high participation rate of GPs, the response rate of patients to attend a BP screening programme and the 7% randomization to screening ratio for entry into the study, the ANBP2 pilot study has demonstrated that it is feasible to recruit subjects from Australian general practices to a cardiovascular outcome trial.     

GGA1 acts as a spatial switch altering amyloid precursor protein trafficking and processing

The beta-amyloid (Abeta) precursor protein (APP) is cleaved sequentially by beta-site of APP-cleaving enzyme (BACE) and gamma-secretase to release the Abeta peptides that accumulate in plaques in Alzheimer's disease (AD). GGA1, a member of the Golgi-localized gamma-ear-containing ARF-binding (GGA) protein family, interacts with BACE and influences its subcellular distribution. We now report that overexpression of GGA1 in cells increased the APP C-terminal fragment resulting from beta-cleavage but surprisingly reduced Abeta. GGA1 confined APP to the Golgi, in which fluorescence resonance energy transfer analyses suggest that the proteins come into close proximity. GGA1 blunted only APP but not notch intracellular domain release. These results suggest that GGA1 prevented APP beta-cleavage products from becoming substrates for gamma-secretase. Direct binding of GGA1 to BACE was not required for these effects, but the integrity of the GAT (GGA1 and TOM) domain of GGA1 was. GGA1 may act as a specific spatial switch influencing APP trafficking and processing, so that APP-GGA1 interactions may have pathophysiological relevance in AD.     

Heterogeneity of calcium channels in mast cells and basophils and the possible relevance to pathophysiology of lung diseases: A review

Calcium plays a critical role in the formation and secretion of a wide variety of chemical mediators. Calcium slow-channel blockers,e.g. nifedipine and verapamil, have been shown to inhibit the synthesis of SRS (SRS-A, leukotrienes) in human and guinea pig lung tissue, thromboxane A₂ formation in rat lung and platelet activating factor in human neutrophils. Verapamil and nifedipine also prevent the release of lysosomal enzymes from rabbit and human polymorphonuclear neutrophils. Calcium-channel blockers produce variable inhibitory effects on allergic and nonallergic histamine secretion. Ca⁺⁺-entry blockers also inhibit the Ca⁺⁺ uptake (influx) into mast cells. Many of these inhibitory effects of Ca⁺⁺ antagonists are antagonized by an increased extracellular Ca⁺⁺ ion concentration. The magnitude of the inhibitory influences of Ca⁺⁺-channel blockers on allergic and nonallergic release of chemical mediators appears to depend on the cell source, species, nature and the concentration of the secretory stimuli as well as on the composition and pH of buffers and the concentration of Ca⁺⁺-entry blockers used. The data summarized in this review suggest the existence of a functional heterogeneity of Ca⁺⁺ channels in leukocytes, mast cells and basophils. Interference with the Ca⁺⁺-dependent steps involved in the formation and/or release of chemical mediators appears to be the primary mode of action for Ca⁺⁺-channel blockers in these cells.The differential effects of Ca⁺⁺ antagonists on Ca⁺⁺-dependent activation of phospholipase A₂, 5-lipoxygenase, and calmodulin (or other intracellular Ca⁺⁺-binding proteins) in different cell types (mast cells, basophils, leukocytes, lung tissue, etc.) may explain the variation of their effectiveness in inhibiting the synthesis/release of chemical mediators and antagonizing bronchoconstriction in response to diverse stimuli.During the process of hypersensitization and in immediate hypersensitivity diseases, Ca⁺⁺ homeostasis (uptake, mobilization, distribution, relocation, etc.) may be altered in leukocytes (mast cells, basophils) and lung tissues. The altered Ca⁺⁺ homeostasis could be responsible for the induction of airway hyperreactivity in asthmatics and for hyperreleasability of chemical mediators from leukocytes, mast cells and other cell types.The development of drugs (Ca⁺⁺-channel blockers, antiallergic agents) that are capable of selectively altering Ca⁺⁺-dependent functions in leukocytes (mast cells, basophils, macrophages) and lung tissue in disease staes would offer an attractive alternative and an effective therapeutic approach for obstructive respiratory diseases,e.g. allergic asthma, exercise-induced asthma and a variety of other mediator-dependent allergic disorders.     

Aeroallergen-induced immediate asthmatic responses and late-phase associated pulmonary eosinophilia in the guinea pig: effect of methylprednisolone and mepyramine

Guinea pigs were sensitized by intraperitoneal injection of ovalbumin, 10 micrograms mixed with 100 mg A1(OH)3 in saline. On days 15-30 sensitized guinea pigs were challenged with ovalbumin aerosol (0.5 mg/ml, 30 s, 15 psi) which produced immediate asthmatic responses characterized by dyspnea, convulsions, and some deaths during the first 14 min. Twenty to 24 h later the animals were sacrificed with an overdose of pentobarbital, and lungs, bronchi, and lower trachea were dissected and fixed in 10% neutral buffered formalin. Histopathological examination of randomly coded tissues of the respiratory tract revealed a pulmonary eosinophilic cellular infiltrate in the epithelium/subepithelium of trachea, bronchi, and bronchioles as well as the peribronchial, peribronchiolar, and perivascular areas of the lungs. Oral administration of mepyramine (10 mg/kg) 2 h before aeroallergen challenge provided complete protection against immediate asthmatic responses and prevented deaths during the first 14 min without influencing the late phase associated lung eosinophilic cellular infiltrate. The immediate asthmatic responses were not influenced by methylprednisolone (30 mg/kg) administered orally 24 and 2 h before aeroallergen challenge. Following an additional dose of methylprednisolone 4 h after challenge, there was a significant inhibition of pulmonary eosinophilia (30 mg/kg; -24 h, -2 h, and +4 h). These observations suggest that histamine is the principal mediator of immediate asthma attacks in guinea pigs. Methylprednisolone may be acting by inhibiting the production of eosinophil chemotactic factor of anaphylaxis (platelet-activating factor or leukotriene B4) from the alveolar macrophages, T lymphocytes, and perhaps other cells, thus preventing pulmonary eosinophilia.     

Inhibition of aeroallergen-induced bronchial eosinophilia by azelastine in guinea pigs.

The ability of azelastine to influence allergic bronchial eosinophil infiltration in guinea pigs was studied. Aeroallergen challenge of actively sensitized guinea pigs produces eosinophil infiltration in bronchoalveolar lavage fluid collected 20-24 h after aeroallergen exposure. Azelastine and methylprednisolone, administered orally 2 h before challenge, inhibited eosinophilic infiltration yielding the ED50s of 1.55 and 4.48 mg/kg, respectively. WEB-2086, a platelet-activating factor antagonist (3 mg/kg), and theophylline, a phosphodiesterase inhibitor (30 mg/kg), also suppressed allergic bronchial infiltration of eosinophils by 44%. The data obtained in this study demonstrate that azelastine exerts direct bronchial anti-inflammatory activity in guinea pigs.     

The association of Hospital Medicare beneficiary payer-mix,national quality rankings and outcomes following hepatopancreatic surgery

IntroductionWe sought to determine the impact of payer-mix on post-operative outcomes among Medicare beneficiaries following hepatopancreatic surgery.MethodsMedicare beneficiaries who underwent hepatopancreatic surgery were identified. Hospital quality markers were obtained from the Hospital General Information dataset. Hospitals were dichotomized (low/average vs. high) based on Medicare patient days versus all patient days irrespective of payer type.ResultsHigh Medicare patient-mix hospitals were more likely to be ranked higher than the national average relative to safety of care (29.4% vs. 38.1%) and timeliness of care (15.4% vs. 26.3%) versus low burden Medicare hospitals (both p < 0.001). However, Medicare beneficiaries who had hepatopancreatic surgery at a high Medicare patient-mix hospital were at higher risk of a complication (OR = 1.13, 95%CI 1.04–1.22), and death within 30-days (OR = 1.37, 95%CI 1.23–1.53) following surgery.ConclusionWhile hospitals caring for higher numbers of Medicare beneficiaries generally performed better on CMS quality indicators, these rankings did not equate to improved post-operative outcomes.     

Disparities in NCCN Guideline Compliant Care for Resectable Cholangiocarcinoma at Minority-Serving Versus Non-Minority-Serving Hospitals

Annals of Surgical Oncology - Racial/ethnic disparities in cancer outcomes may relate to variations in receipt of National Comprehensive Cancer Network (NCCN)&nbsp;guideline&nbsp;compliant...     

ASO Visual Abstract: Impact of Race/Ethnicity and County-Level Vulnerability on Receipt of Surgery Among Older Medicare Beneficiaries Diagnosed with Early Pancreatic Cancer

Annals of Surgical Oncology -