Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively managed needle biopsy cohort.

BACKGROUND: The natural history of prostate cancer is highly variable and it is difficult to predict. We showed previously that a cell cycle progression (CCP) score was a robust predictor of outcome in a conservatively managed cohort diagnosed by transurethral resection of the prostate. A greater need is to predict outcome in patients diagnosed by needle biopsy. METHODS: Total RNA was extracted from paraffin specimens. A CCP score was calculated from expression levels of 31 genes. Clinical variables consisted of centrally re-reviewed Gleason score, baseline prostate-specific antigen level, age, clinical stage, and extent of disease. The primary endpoint was death from prostate cancer. RESULTS: In univariate analysis (n=349), the hazard ratio (HR) for death from prostate cancer was 2.02 (95% CI (1.62, 2.53), P<10(-9)) for a one-unit increase in CCP score. The CCP score was only weakly correlated with standard prognostic factors and in a multivariate analysis, CCP score dominated (HR for one-unit increase=1.65, 95% CI (1.31, 2.09), P=3 × 10(-5)), with Gleason score (P=5 × 10(-4)) and prostate-specific antigen (PSA) (P=0.017) providing significant additional contributions. CONCLUSION: For conservatively managed patients, the CCP score is the strongest independent predictor of cancer death outcome yet described and may prove valuable in managing clinically localised prostate cancer.

Importance of TURP in diagnosing prostate cancer in men with multiple negative biopsies.

OBJECTIVE: Patients with persistently elevated PSA and multiple negative TRUS guided 12-core biopsies, present a clinical conundrum. We evaluated the efficacy of transurethral biopsy and/or resection in abetting prostate cancer diagnosis. PATIENTS AND METHODS: Eleven patients who had prostate cancer diagnosed only on TURP following TRUS guided (24-48 cores) negative biopsies, including five who underwent radical prostatectomy were assessed. Extent and site of tumour was analysed in relation to the TURP cavity. RESULTS: Mean age was 61.8 years (PSA range: 3.8-20.9 ng/ml.). Patients had TURP for worsening LUTS with chippings diagnosing invasive prostate cancer. Organ confined anterior prostate cancer was diagnosed in five who had radical prostatectomy. CONCLUSION: Anteriorly directed transurethral biopsies and/or TURP help in the diagnosis of prostate cancer in patients with multiple negative biopsies. Patients with anterior prostate cancer tend to have organ-confined disease even with higher PSA.

Treatment of ocular cicatricial pemphigoid with tacrolimus (FK 506).

PURPOSE: To evaluate the efficacy of tacrolimus (FK 506) therapy in patients with ocular cicatricial pemphigoid (OCP). METHODS: In a cohort study, six patients with OCP, in whom the disease was not controlled by conventional immunosuppressive agents administered in high doses for an appropriate period of time, were treated with FK 506. The FK 506 was administered orally at the daily dose of 8 mg. Final clinical response to FK 506 was divided into three categories based on the difference between severity of conjunctival inflammation before and after FK 506 therapy. "Total control" of disease activity was defined as residual inflammatory activity of 0.5 or less in the final examination and an inflammation decrement of at least 0.5 between initial and final examination. "Partial control" was defined as final disease activity 1.0 or 1.5 and at least 0.5 decrement of disease activity between initial and final examination. "Uncontrolled inflammation" was defined as final disease activity above 1.5 or no improvement between initial and final activity. RESULTS: The average age of the patients was 67.5 years (range 50-75 years). Male to female ratio was 1:1. The average duration of OCP prior to beginning of FK 506 treatment was 6.25 years (range 3-12.5 years). The average duration of treatment with FK 506 was 11 months (range 5-18 months). The average disease activity prior to the administration of FK 506 was 2.6 (range 2.0-3.0). The average disease activity at the time when FK 506 was stopped was 2.0 (range 1.0-2.5). In four patients (67%) FK 506 failed to control activity of OCP, and in two patients (33%) the activity was controlled partially. CONCLUSIONS: Although FK 506 was not used in a prospective randomized trial and although we used the drug only in patients with OCP refractory to conventional immunosuppressive agents, it is likely that FK 506 is incapable of controlling the activity of OCP and inducing a remission.

Linear IgA bullous disease limited to the eye: a diagnostic dilemma: response to intravenous immunoglobulin therapy.

PURPOSE: To report on a diagnostic dilemma and treatment challenge in a patient with chronic cicatrizing conjunctivitis without involvement of skin and other mucous membranes persisting for 6 years and not responding to topical and systemic steroids. DESIGN: Interventional case report. METHODS: We performed direct immunofluorescence of the conjunctiva with fluorescein-conjugated rabbit antihuman antibodies against immunoglobulin A, G, and M, complement 3 component, and fibrinogen. To investigate the presence of circulating antibodies in patient's serum, indirect immunofluorescence using normal human conjunctiva, normal human skin, and monkey esophagus as substrate was done. In addition, we did immunoblot analysis using normal human epidermis as substrate to determine the molecular weight of an antigen. The patient was treated with intravenous immunoglobulin (IVIg). The correlation between the titer of circulating antibodies and the activity of conjunctival inflammation at various intervals during the course of IVIg therapy was demonstrated by immunoblot assay with serial dilutions of the patient's serum. The highest dilution at which the binding was visible was considered the titer. RESULTS: Direct immunofluorescence of the conjunctiva and indirect immunofluorescence with both salt split skin and conjunctiva as substrate disclosed linear deposition of immunoglobulin A (IgA) at the epithelial basement membrane. Immunoblot analysis demonstrated the presence of IgA circulating antibodies in patient's serum directed against a 97kDa protein in human epidermis. A continuous decrease in the titer of these antibodies correlating to improvement of clinical symptoms was observed during IVIg therapy. CONCLUSIONS: Use of a nonconventional diagnostic tool (immunoblot analysis), in addition to conventional immunohistologic studies, might be helpful in establishing the diagnosis of patients with chronic cicatrizing conjunctivitis. On the basis of results of these laboratory tests and clinical presentation, we believe that this patient has linear IgA bullous disease limited to the eye. IVIg therapy decreased the titer of circulating antibodies and induced a remission in this patient.

Intravenous immunoglobulin therapy for ocular cicatricial pemphigoid: a preliminary study.

OBJECTIVE: To report the effects of intravenous immunoglobulin treatment of ten patients with progressive ocular cicatricial pemphigoid who did not respond to conventional immunomodulatory regimens. DESIGN: Noncomparative, interventional case series. PARTICIPANTS: Ten patients with biopsy-proven progressive cicatricial pemphigoid affecting the eyes who did not respond adequately to other local and systemic immunosuppressive treatment regimens. INTERVENTION: Intravenous infusions of pooled human immunoglobulin, 2 to 3 g/kg body weight/cycle, divided over 3 days, and repeated every 2 to 6 weeks. MAIN OUTCOME MEASURES: Reduction in conjunctival inflammation, prevention of progression of subepithelial conjunctival fibrosis, improvement in ocular symptoms (discomfort, photophobia), improved visual acuity, reduction in extraocular mucosal lesions. RESULTS: Clinical deterioration was arrested and resolution of chronic conjunctivitis was documented in all ten patients. Maximum therapeutic effect was observed and maintained after a minimum of 4 cycles of therapy; three patients required 12 cycles before disease control. The duration of therapy in these ten patients has been 16 to 23 months (mean, 19.3 months) with no treatment-induced side effects. Extraocular mucosal lesion resolution has occurred in all but one patient, Visual acuity has stabilized or improved in all ten patients, and subjective complaints of discomfort and photophobia have decreased in all patients. CONCLUSIONS: Intravenous immunoglobulin immunomodulatory therapy can be a safe and effective therapy for otherwise treatment-resistant ocular cicatricial pemphigoid.

Soluble P-selectin glycoprotein ligand 1 inhibits ocular inflammation in a murine model of allergy.

PURPOSE: To assess the anti-inflammatory modality of a soluble extracellular form of P-selectin glycoprotein ligand 1 (sPSGL-1) in a mouse model of ocular allergic response. METHODS: Potential anti-inflammatory effects of sPSGL-1 were investigated in SWR/J mice sensitized by topical application of short ragweed pollen to the nasal mucosa followed by a challenge of the ocular mucosa with the same allergen. Five experimental groups were included in these studies: A, mice neither sensitized nor challenged with pollen (control group 1); B, animals sensitized but not challenged (control group 2); C, animals not sensitized but challenged (control group 3); D, animals sensitized and challenged; and E, sensitized animals treated with sPSGL-1 before pollen challenge. All experimental groups were evaluated for gross morphologic ocular changes, and histologic assessments were made to determine the onset/progression of inflammatory reactions and to look for evidence of eosinophil infiltration. RESULTS: Mice sensitized and challenged with pollen developed clinical signs consistent with human allergic conjunctivitis. These signs correlate with histologic changes in the conjunctival epithelium and stroma (e.g., edema and extensive eosinophil infiltration). Moreover, the ocular changes also correlated with evidence of eosinophil degranulation. However, sensitized and challenged mice concurrently treated with sPSGL-1 displayed no inflammatory ocular changes associated with a ragweed-induced type-1 hypersensitivity reaction. The lack of ocular changes included the absence of histologic late-phase inflammatory changes of the conjunctiva and a 97% reduction in the induced eosinophil infiltrate. CONCLUSIONS: The antagonistic intervention of cell- cell interactions through the blockade of selectin-dependent leukocyte adhesion may offer novel therapeutic strategies to modulate inflammatory responses. The potent inhibitory effects on eosinophil recruitment and late-phase inflammation suggest a role for sPSGL-1 in the treatment of ocular allergic diseases.

Comparative effectiveness and molecular pharmacological mechanisms of antiallergic agents on experimental conjunctivitis in mice.

The purpose of this study was to determine the effectiveness of antiallergic agents in the treatment of experimental murine ragweed conjunctivitis. SWR/J mice were divided into eight groups: 1; normal controls (unmanipulated); 2, untreated; 3, lodoxamide; 4, cromolyn; 5, livocarbastine; 6, nedocromil; 7, buffer solution (BS); and 8, tetrandine (TDR). Groups 2-8 were exposed to ragweed pollen through topical application to conjunctival and nasal mucosa, followed by conjunctival challenge with the allergen. Allergic conjunctivitis was evaluated by scoring of the clinical signs and histopathology. mRNA gene expression of interleukin 1beta (IL-1beta), IL-6 and tumor necrosis factor alpha (TNF-alpha) in conjunctiva was analyzed by reverse transcription polymerase chain reaction techniques. Exposed mice developed allergic conjunctivitis clinically and histologically that was modulated by topical lodoxamide, cromolyn, livocarbastine, or nedocromil eye drops or TDR intraperitoneally injected. Histopathologic analysis demonstrated that the drugs and TDR significantly reduced conjunctival eosinophil infiltration and the number of intact and degranulating mast cells. IL-1beta and TNF-alpha mRNA gene expression in conjunctiva of treated mice was inhibited compared with untreated and BS-treated controls. No IL-6 mRNA expression was observed even on the conjunctiva of the untreated mice. The antiallergic drugs and TDR exerted a similar action on the murine model of allergic conjunctivitis and demonstrated pharmacologic effectiveness on the conjunctival mRNA expression of cytokines IL-1beta and TNF-alpha.

Potent inhibitory effect of tetrandrine on experimental allergic conjunctivitis in mice.

This study investigated the effectiveness of tetrandrine (TDR) on experimental allergic conjunctivitis secondary to ragweed pollen. SWR/J mice were divided as follows: group 1, normal controls; group 2, sensitized but untreated; group 3, sensitized, buffered saline (BS)-treated; and group 4, sensitized, TDR-treated. The last three groups were exposed to ragweed through topical contact on the nasal and conjunctival mucosae followed by challenge with the allergen on the conjunctiva. Groups 3 and 4 received doses of BS and TDR, respectively. The allergic conjunctivitis was evaluated by scoring of the clinical signs and histopathology. mRNA gene expression of interleukin 1 beta (IL-1 beta) and IL-5 in the conjunctiva was analyzed by polymerase chain reaction techniques. All mice exposed to ragweed developed allergic conjunctivitis clinically and histologically. The conjunctivitis was significantly modulated by intraperitoneal injection of a new anti-inflammatory agent, TDR. Histopathologic analysis demonstrated that TDR strikingly reduced the conjunctival eosinophil infiltration and the number of intact and degranulating mast cells. IL-1 beta and Il-5 mRNA gene expression in the conjunctiva of TDR-treated mice was dramatically down-regulated compared with untreated and BS-treated controls. The results indicate that TDR may have potential clinical use in the treatment of conjunctivitis.

Tetrandrine potently inhibits herpes simplex virus type-1-induced keratitis in BALB/c mice.

This study investigated the effect of tetrandrine (TDR) on experimental herpes simplex keratitis (HSK) in mice. BALB/c mice were divided as follows: Group 1, untreated; Group 2, acyclovir (ACV)-treated from day 0 postinfection; Group 3, ACV-treated from day 7; Group 4, TDR-treated from day 0; and Group 5, TDR-treated from day 7. All mice were infected in the right cornea with herpes simplex virus (HSV) type I. TDR 30 mg/kg and ACV 120 mg/kg were administered intraperitoneally daily. The mice were observed for 14 days postinfection. Clinical inflammatory reactions and ocular histopathology were analyzed. The herpes specific antibody response and the delayed type hypersensitivity (DTH) response were studied. Of the 22 untreated mice, 16 developed HSK (incidence, 72.7%). TDR given from day 7 reduced the HSK incidence to 8.5% (p < 0.01); the incidence of HSK was 45.4% in mice treated with TDR from day 0 (p > 0.05). Systemic ACV given from day 0 inhibited HSK development (p < 0.01); ACV given from day 7 resulted in an HSK incidence of 50% (p > 0.05). The specific anti-HSV antibody response in the serum of mice treated with TDR or ACV either from day 0 or day 7 was significantly less than that of untreated mice (p < 0.01 and p < 0.05, respectively), and TDR treatment suppressed DTH responses to HSV (p < 0.05). Systemic TDR administered after HSV inoculation of the cornea significantly modulates murine HSK development at least partly by modifying the host immune/inflammatory response to the virus.

Prevention of recurrence of oesophageal stricture, a comparison of lansoprazole and high-dose ranitidine.

OBJECTIVE: To determine the efficacy of lansoprazole 30 mg given in the morning compared with high-dose ranitidine 300 mg twice daily in the treatment of patients with oesophageal strictures. DESIGN: A multicentre, outpatient, double-blind, parallel group, prospectively randomized clinical trial. PATIENTS: One hundred and fifty-eight patients (lansoprazole 30 mg n = 78, ranitidine 600 mg n = 80) were enrolled from 19 centres in the UK over 23 months. INTERVENTIONS: Patients with an oesophageal stricture were randomized to receive either lansoprazole 30 mg once daily or high-dose ranitidine 300 mg twice daily for 12 months. Dilatation was performed at entry and repeat endoscopies were scheduled at 6 and 12 months and additionally at other times if there was symptomatic relapse. Redilatation was performed as required and according to a predefined scale. The patient's assessment of dysphagia over the previous 7 days was recorded by the investigator at 1, 3, 6, 9 and 12 months. Safety was assessed by laboratory tests, physical examination and all adverse events. MAIN OUTCOME MEASURES: Efficacy was assessed primarily by the time to redilatation, the proportion of patients requiring at least one redilatation, and the number of redilatations over 12 months. The relief of dysphagia and reduction in stricture grade were secondary efficacy measures. RESULTS: The time to redilatation was longer and the probability of no redilatation were higher in the lansoprazole group than in the ranitidine group; for all patients randomized (intention to treat principle), this difference was of borderline significance (life table, P = 0.053). The proportions of patients requiring at least one redilatation during the 12-month treatment period were 30.8% (24/78) with lansoprazole and 43.8% (35/80) with ranitidine (all patients randomized, chi 2 test, P = 0.092). Compared to ranitidine, patients receiving lansoprazole reported significantly lower dysphagia grades at 6 months (stratified Wilcoxon test, P = 0.0086) but not at 12 months (stratified Wilcoxon test, P = 0.074). A greater proportion of patients in the ranitidine group-33.8% (27/80)-withdrew prematurely compared to the lansoprazole group (26.9%, 21/78). The most frequent reasons for premature withdrawal were adverse events and protocol violations. There were no clinically significant differences in incidence or severity of adverse events between the two groups. The mean increase in gastrin levels after 12 months' treatment was significantly greater for patients in the lansoprazole group (124.2 pg/ml, P = 0.0056) than those in the ranitidine group (31.9 pg/ml). No significant changes in gastric mucosal histology were detected for patients in either group. CONCLUSION: It is concluded that lansoprazole 30 mg once daily is superior to ranitidine 300 mg twice daily in relieving dysphagia, and at least as effective in reducing the need for a repeat dilatation.

Experimental model of allergic conjunctivitis to ragweed in guinea pig.

An experimental model of ocular allergy was developed in the guinea pig by exposing these animals to ragweed through topical contact on nasal and conjunctival mucosae, followed by subsequent challenge with ragweed contact on the conjunctiva. Animals developed clinical and histological signs of allergy with and without the use of interleukin 4 as adjuvant. This model mimics human hay fever conjunctivitis more naturally than do animal models previously reported, and it may be subsequently more valuable in the study of the response of allergic conjunctivitis to different therapeutic approaches.

Effect of fish oil on cancer cachexia and host liver metabolism in rats with prostate tumors.

The aim of this study was to investigate whether tumor-induced cachexia and aberrations in host liver metabolism, induced by the MAT-LyLu variant of the Dunning prostate tumor, could be prevented by omega 3 fatty acids from fish oil. On day 0, adult Copenhagen-Fisher rats fed normal chow ad libitum were inoculated with 10(6) MAT-LyLu cells (n = 14) or saline (n = 9). On day 7, when tumors were palpable, four tumor-bearing (TB) and four nontumor-bearing (NTB) rats were put on isocaloric diets with 50% of total energy as fish oil. The introduction of fish oil-enriched diets caused a reduction in energy intake to less than half of the energy intake by animals fed normal diets during days 7-14 (difference by dietary group: NTB, P < 0.001; TB, P < 0.001). During days 14-21, energy intake in fish oil-fed animals returned to approximately 75% of energy intake by animals fed normal diets (difference by dietary group: NTB, P < 0.003; TB, P = 0.001). Carcass weight of animals on day 21, when the study was terminated, was significantly related to initial weight (P = 0.05) and mean food intake during the study (P = 0.01). When data were adjusted for these variables using analysis of covariance, with NTB animals on normal diets being the reference group, significant loss of carcass weight was observed in TB animals on normal diets only (mean +/- SEM 58 +/- 10 g loss, P < 0.001), but not in TB animals on fish oil diets (8 +/- 18 g loss, P = 0.67).(ABSTRACT TRUNCATED AT 250 WORDS)

Altered phosphorylation status, phospholipid metabolism and gluconeogenesis in the host liver of rats with prostate cancer: a 31P magnetic resonance spectroscopy study.

31P magnetic resonance spectroscopy (MRS) in vivo and in vitro was used to study modulation of host liver (HL) metabolism in rats bearing the MAT-LyLu variant of the Dunning prostate tumour. Animals were inoculated either with 10(6) or 10(7) MAT-LyLu cells, or with saline to serve as controls. Carcass weight in tumour-bearing (TB) animals decreased despite similar food and water intake in both groups. Absence of metastatic tumour cells from HL of all TB animals was confirmed by histological examination. Twenty-one days after inoculation, 31P MRS showed a 2.5-fold increase in [Pi]/[ATP] ratios in HL in vivo (P < 0.001) which was confirmed by 31P MRS of liver extracts in vitro (P < 0.005). Phosphodiester to ATP ratios were significantly increased (P < 0.05) in HL in vivo, but absolute PDE levels were similar in both groups. Phosphomonoester to ATP ratios did not change, although absolute phosphomonoester levels in HL were reduced by -41% (not significant). In HL extracts in vitro, sharp reductions in the levels of glucose-6-phosphate (P < 0.05), fructose-6-phosphate (P = 0.05), phosphocholine (P < 0.001), glycerophosphocholine (P < 0.001), and glycerophosphoethanolamine (P < 0.001) were observed. Electron microscopy revealed increased amounts and altered distribution of rough endoplasmic reticulum in HL. These findings show that experimental prostate cancer significantly affects hepatic phosphorylation status, phospholipid metabolism, and gluconeogenesis in the host animal, and demonstrate the value of combined MRS in vivo and in vitro in monitoring HL metabolism in cancer.

Immunohistopathologic features and therapy of conjunctival lichen planus.

Lichen planus is an autoimmune disease that typically involves skin and the mucosa of the genitalia and mouth. Conjunctival involvement is rare, and the microscopic abnormalities of affected conjunctivae are not well characterized. We treated two patients with cicatrizing conjunctivitis and extraocular conjunctival lichen planus confirmed by biopsy. We found irregular, thickened basement membrane with reduplications similar to the findings in oral mucosa affected by lichen planus. The absence of basement membrane immunoreactants excluded ocular cicatricial pemphigoid. Results of laboratory tests for collagen vascular diseases including sarcoidosis and lupus were also negative. Treatment with 2% cyclosporine eyedrops controlled inflammation and stopped cicatrization in one patient who was followed up for 12 months. The other patient, in whom lichen planus was recently diagnosed, responded favorably to topical cyclosporine. Lichen planus should be included in the differential diagnosis of cicatrizing conjunctivitis and its immunohistopathologic features should be studied in conjunctival biopsies. Topical cyclosporine may be used successfully for conjunctival lichen planus.

Long-term results of systemic chemotherapy for ocular cicatricial pemphigoid.

Ocular cicatricial pemphigoid (OCP) is a chronic, progressive, blinding, autoimmune disease that scars mucous membranes. We studied the long-term outcome in 104 consecutive patients (average follow-up: 4 years) to determine whether complete remission could be achieved following a course of treatment with immunosuppressive drugs. We found that prolonged periods of remission off therapy are maintained in about one third of OCP patients. Follow-up must be continued for life as relapse occurs in approximately one third of cases. Those who relapsed regained disease control readily upon reinstitution of therapy and did not deteriorate to more advanced cicatrization. Sex, age, initial degree of inflammation and the incidence of extraocular involvement did not bear a prognostic significance. The mechanism which underlies the differing responses to therapy is not yet known.

Systemic chemotherapy for ocular cicatricial pemphigoid.

The records of 105 patients treated with three different chemotherapeutic agents for ocular cicatricial pemphigoid (OCP) were reviewed to compare long-term efficacies, side effects, and tolerance of different regimens. For the entire group, OCP progressed in 6% of eyes in 10% of patients (follow-up 35 months). More than half of the treatment failures occurred in patients intolerant of chemotherapy. Diaminodiphenylsulfone (DAP), as initial agent, failed to control disease in 2% of patients, compared with 8% after cyclophosphamide (CYC) and 9% after azathioprine (AZA) (p less than 0.05). Stratification of results revealed that DAP was the most effective initial agent for modestly active OCP, whereas CYC was the most effective initial choice for highly active cases. In patients treated with a single agent exclusively for 10 months or more, failure to control disease occurred in 4% of DAP, 4% of CYC, and 15% of AZA patients (p less than 0.01). Recommendations for a sequential approach to chemotherapy for OCP are presented.