Staging of the axilla in breast cancer: accurate in vivo assessment using positron emission tomography with 2-(fluorine-18)-fluoro-2-deoxy-D-glucose.

OBJECTIVE: To evaluate the ability of positron emission tomography (PET) with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) to determine noninvasively axillary lymph node status in patients with breast cancer. BACKGROUND: The presence of axillary lymph node metastasis is the most important prognostic factor in women with breast cancer. It signifies the presence of occult metastatic disease and indicates the need for adjuvant therapy. The only reliable way in which this important prognostic information may be obtained is by performing axillary dissection, which may be associated with significant complications and delay in discharge from the hospital. PET with 18F-FDG can visualize primary cancers in the breast and metastatic tumor deposits. METHODS: Fifty patients with untreated breast cancer had clinical examination of their axilla performed (graded as positive or negative), followed by PET of the axilla and midthorax. PET data were analyzed blindly and graded as positive or negative, depending on the presence or absence of axillary nodal metastases. Cytopathologic assessment of the axillary nodes was carried out within 1 week of PET, by fine-needle aspiration cytology in 5 patients and axillary dissection in 45; the excised specimens were examined by a single pathologist. RESULTS: The overall sensitivity of PET in 50 patients was 90% and the specificity was 97%. Clinical examination of the same patients had an overall sensitivity of 57% and a specificity of 90%. In the 24 patients with locally advanced breast cancer (T3, T4, TxN2), PET had a sensitivity of 93% and a specificity of 100%. In T1 tumors (seven patients), the sensitivity and specificity were 100%. PET had a high predictive value (>90%) and accuracy (94%) in staging the axilla. CONCLUSIONS: PET is a sensitive and specific method of staging the axilla in patients with breast cancer. It may obviate the need for axillary surgery in women with small primary tumors, define the women likely to benefit from axillary dissection, or allow radiotherapy to be substituted for surgery, particularly in post-menopausal women.     

Smoking cue reactivity in schizophrenia: effects of a nicotinic receptor antagonist.

BACKGROUND: Rates of cigarette smoking in schizophrenia are higher than in the general population. To investigate differences in sensitivity to smoking cues between schizophrenia and control subjects, we compared smoking cue reactivity (CR) in schizophrenia versus control smokers with and without pretreatment with the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (MEC). METHODS: Smoking CR in schizophrenia (n = 22) and nonpsychiatric control (n = 20) smokers was determined using exposure to smoking pictures. Three doses of MEC (0, 5, and 10 mg/day) were administered during the 3 test weeks to determine the role of nAChRs in mediating the smoking CR response. RESULTS: Eleven of 22 (50%) schizophrenia and 10 of 20 (50%) control smokers displayed smoking CR. Smoking CR was not significantly different between schizophrenia and control smokers in the placebo (0 mg/day) condition. However, MEC pretreatment produced a dose-dependent reduction of CR in schizophrenia smokers compared with placebo. There was no significant effect of MEC on CR in control smokers. CONCLUSIONS: Our findings suggest that blockade of CR by MEC may be more robust in schizophrenia versus control smokers, possibly due to reduced nAChR levels in the brains of patients with schizophrenia.     

Plasma coagulation markers in patients with solid tumors and venous thromboembolic disease receiving oral anticoagulation therapy.

PURPOSE: To correlate the concentration of plasma coagulation markers at baseline and during follow-up in patients with solid tumors and venous thromboembolic disease with the risk of recurrence and death. EXPERIMENTAL DESIGN: Patients (N = 223) with first episode of venous thromboembolic disease received oral anticoagulation with warfarin for a target international normalized ratio of 2 to 3. Plasma coagulation markers were measured before instituting warfarin and at 3 monthly intervals, thereafter. RESULTS: The median duration of oral anticoagulation was 6.7 months (range 2 weeks to 11 months). Major bleeding episodes occurred in 18 patients (8%), and minor hemorrhagic events occurred in 15 (6.7%) patients. Patients with advanced malignancy (P = 0.032), history of surgery (P = 0.057), and those with poor performance status (P = 0.001) were more likely to encounter major bleeding episodes. Recurrence of venous thromboembolic disease was diagnosed in 31 patients (14%). At univariate analysis, advanced stage of cancer (P = 0.03), performance status > 1 (P = 0.001), treatment with chemotherapy (P = 0.01), the presence of metastatic liver disease (P = 0.03), higher d-dimer (P = 0.001), and thrombin antithrombin complex levels (P = 0.01) were features predictive of recurrent venous thromboembolic disease. At multivariate analysis, poor performance status (P = 0.01) and d-dimer levels (P = 0.001) were predictors of recurrent venous thromboembolic disease. Persistent activation of coagulation as indicated by an upward trend in d-dimer (P = 0.001) and antithrombin (P = 0.001) was observed in patients who developed recurrent thrombosis. Similar upward trends in d-dimer (P = 0.001), antithrombin (P = 0.001), and prothrombin fragment F1 + 2 (P = 0.001) was observed in the 76 patients who died during the study period and in the patients who received chemotherapy. CONCLUSIONS: Successful oral anticoagulation with warfarin in patients with cancer and venous thromboembolic disease is more likely to be achieved in patients with early stage tumors and good performance status. The persistence of activation of hemostasis as shown by plasma coagulation markers is a strong predictor of recurrence and poor outcome.     

Coagulation inhibitors and fibrinolytic parameters in patients on peritoneal dialysis and haemodialysis

Coagulation inhibitors and fibrinolytic parameters were studied in twelve patients on continuous ambulatory peritoneal dialysis (CAPD) and ten patients on haemodialysis (HD). Patients on CAPD exhibited higher levels of ATIII and proteins C and S than those on HD. No significant differences were noted in tPA and PAI levels. Both groups of patients showed higher levels of tPA than controls. Besides, patients on HD had significantly lower levels of ATIII and protein C than controls. PAI levels in both patients groups were similar to those of the controls, but tPA levels were higher in patients than in controls. These results indicate that HD is associated with marked diminution in the circulating levels of coagulation inhibitors. This is in contrast to CAPD patients who showed elevated levels of these inhibitors, despite their significant loss in the dialysate. The finding of enhanced fibrinolysis in both patient groups may be a natural protective mechanism against the development of a thrombotic tendency.     

Frontalis suspension for upper eyelid ptosis: evaluation of different surgical designs and suture material

PURPOSE: To compare two sling designs (single loop or double pentagon) and a variety of suture material that was used in frontalis suspension surgery for correction of upper eyelid ptosis. DESIGN: Retrospective, nonrandomized, comparative interventional case series. METHODS: Medical record review of 99 patients (164 surgeries) who underwent frontalis suspension surgery for upper eyelid ptosis was conducted at the Jules Stein Eye Institute in 1996 to 2002. Functional and cosmetic success, margin reflex distance (MRD) and lagophthalmos were evaluated. RESULTS: MRD increased an average of 1.1 mm after the operation (P < .001). Ptosis recurrence was noticed in 42 cases (26%); polytetrafluoroethylene achieved the lowest recurrence rate (15%), although not statistically significant. No difference in functional success, ptosis recurrence, or change in MRD was noticed between single loop and double pentagon design. A better cosmetic outcome was noted in cases in which nylon suture was used. Complications included four cases (2.4%) of over-correction, three cases (1.8%) of suture infection (all in polytetrafluoroethylene), two cases of pyogenic granuloma (1.2%), and two cases (1.2%) of suture exposure. CONCLUSION: Frontalis suspension for upper eyelid ptosis resulted in 26% ptosis recurrence after a mean of 12 months from first surgery. Polytetrafluoroethylene showed the lowest incidence of ptosis recurrence. No statistically significant difference was found between different suture materials or loop shape that was used in the surgical technique. A better cosmetic outcome, as graded by different observers, was noted in cases in which a nylon sling was used.     

Environmental heme-based sensor proteins: implications for understanding bacterial pathogenesis

Abstract Significance: Heme is an important prosthetic group required in a wide array of functions, including respiration, photosynthesis, metabolism, O(2) transport, xenobiotic detoxification, and peroxide production and destruction, and is an essential cofactor in proteins such as catalases, peroxidases, and members of the cytochrome P450 superfamily. Importantly, bacterial heme-based sensor proteins exploit the redox chemistry of heme to sense environmental gases and the intracellular redox state of the cell. Recent Advances: The bacterial proteins FixL (Rhizobium ssp.), CooA (Rhodospirillum rubrum), EcDos (Escherichia. coli), RcoM (Burkholderia xenovorans), and particularly Mycobacterium tuberculosis (Mtb) DosS and DosT have emerged as model paradigms of environmental heme-based sensors capable of detecting multiple gases including NO, CO, and O(2). Critical Issues: How the diatomic gases NO, CO, or O(2) bind to heme iron to generate Fe-NO, Fe-CO, and Fe-O(2) bonds, respectively, and how the oxidation of heme iron by O(2) serves as a sensing mechanism that controls the activity of key proteins is complex and largely unclear. This is particularly important as many bacterial pathogens, including Mtb, encounters three overlapping host gases (NO, CO, and O(2)) during human infection. Future Directions: Heme is an important prosthetic group that monitors the microbe's internal and external surroundings to alter signal transduction or enzymatic activation. Modern expression, metabolomic and biochemical technologies combined with in vivo pathogenesis studies should provide fresh insights into the mechanism of action of heme-based redox sensors. Antioxid. Redox Signal. 17, 1232-1245.     

Comparison of high and low dose of cyclophosphamide in lupus nephritis patients: a long-term randomized controlled trial

To evaluate the outcome of low doses of cyclophosphamide (Cyclo) therapy in lupus nephritis (LN) patients, we studied 117 biopsy-proven, de novo LN WHO class IV patients double-blinded and randomized in December 1997 to receive Cyclo in different doses; Group I (n=73) received Cyclo 10 mg/kg monthly for six months then every two months for 12 months. Group II (n=44) received Cyclo 5 mg/kg monthly for six months then every two months for 36 months. The patients were followed-up till January 2007. Six months post-induction values for creatinine clearance were significantly higher in Group I (67.7 ± 28.6 mL/min) compared with Group II (55.1 ± 30.1 mL/min), P = 0.026. Serum C4 and ANA were not significantly different between the groups (P > 0.05). At the mean follow-up of 6.77 ± 3.3 years, the mean creatinine clearance was 44.74 ± 31.7 mL/min in Group I vs. 49.3 ± 38.8 in Group II. Urinary protein was 1.65 ± 1.8 g/dL in Group I vs. 1.02 ± 1.01 in Group II (P = 0.03). The survival curve showed that kidney survival overtime was comparable in both groups (P = 0.2). Complete remission was observed in 25 (34.2%) patients in Group I vs. 11 (25%) in Group II (P = 0.288), while partial remission was similar in both groups; 43 (58.9%) patients in Group I vs. 26 (59%) patients in Group II. End-stage renal disease was observed in 10 (13.7%) patients in Group I vs. 9 (20.4%) patients in Group II (P = 0.359). Side-effects were more frequent in Group I patients than in Group II patients; gonadal toxicity and malignancy were lower in Group II patients (P = 0.0000). Moreover, different infections occurred in 23 (31.3%) patients vs. six (13.6%), digital infarcts occurred in 1.35% vs. 0%, diabetes in 4.1% vs. 2.27%, and vasculitis in 4.1% vs. 2.27% in Group I vs. Group II, respectively. Sustained amenorrhea without pregnancy was observed in both groups; however, significantly more in Group I patients, P ≤ 0.05. We conclude that low-dose Cyclo therapy is sufficiently effective for WHO class IV LN patients with lower side-effects compared with standard dose.     

Comparative analysis of the effects of hubble-bubble (Sheesha) and cigarette smoking on respiratory and metabolic parameters in hubble-bubble and cigarette smokers

OBJECTIVES AND BACKGROUND: Hazard of smoking tobacco is believed to be minimized by smoking hubble-bubble (HB) instead of cigarettes. Our aims were to (i) develop an assay for estimating nicotine and cotinine; and (ii) evaluate the effect of smoking on respiratory and metabolic parameters in cigarette and HB smokers. METHODS: Urine samples were collected from 152 volunteer smokers (75 cigarette and 77 HB) as well as from 16 healthy controls. We optimized an HPLC method for the determination of nicotine and cotinine. Subjects were asked to complete a chronic respiratory symptoms questionnaire and to undergo spirometry. Fasting blood samples were collected for the determination of their lipid profile. RESULTS: The intra-assay coefficients of variation for nicotine and cotinine were 16.6% and 6.6%, respectively. The mean of cotinine in cigarette smokers (1321.4 ng/mL) was significantly (P = 0.008) higher than the mean cotinine (677.6 ng/mL) in HB smokers. The mean nicotine level in cigarette smokers (1487.3 ng/mL) was significantly (P < 0.0001) higher than the mean nicotine (440.5 ng/mL) in HB smoker. The urinary cotinine and nicotine levels of the control subjects were lower than the detection levels of the assay. The mean high-density lipoprotein cholesterol was lower in cigarette smokers (0.99 mmol/L) compared with HB smoker smokers (1.02 mmol/L) but this was not significant (P = 0.28). Spirometric values were comparable among the three groups but the chronic respiratory symptoms in the smoking groups appeared at an earlier age in the HB smokers compared with the cigarettes smokers (P < 0.05). CONCLUSION: Smoking HB does not reduce the risk of tobacco exposure and it's potentially harmful metabolites on health.     

A thermally targeted elastin-like polypeptide-doxorubicin conjugate overcomes drug resistance

The ability of cancer cells to become simultaneously resistant to different drugs, a trait known as multidrug resistance, remains a major obstacle for successful anticancer therapy. One major mechanism of resistance involves cellular drug efflux by expression of P-glycoprotein (P-gp), a membrane transporter with a wide variety of substrates. Anthracyclines are especially prone to induction of resistance by the P-gp mechanism. P-gp mediated resistance is often confronted by use of P-gp inhibitors, synthesis of novel analogs, or conjugating drugs to macromolecular carriers in order to circumvent the efflux mechanism. In this report, the effect of free and Elastin-like polypeptide (ELP) bound doxorubicin (Dox) on the viability of sensitive (MES-SA and MCF-7) and multidrug resistant (MES-SA/Dx5 and NCI/ADR-RES) human carcinoma cells was studied in vitro. The resistant MES-SA/Dx5 cells demonstrated about 70 times higher resistance to free Dox than the sensitive MES-SA cells, and the NCI/ADR-RES cells were about 30 fold more resistant than the MCF-7 cells. However, the ELP-bound Dox was equally cytotoxic in both sensitive and resistant cell lines. The ELP-bound Dox was shown to accumulate in MES-SA/Dx5 cells, as opposed to free Dox, which was rapidly pumped out by the P-gp transporter. Since ELP is a thermally responsive carrier, the effect of hyperthermia on the cytotoxicity of the ELP-Dox conjugate was investigated. Both cytotoxicity and apoptosis were enhanced by hyperthermia in the Dox resistant cells. The results suggest that ELP-Dox conjugates may provide a means to thermally target solid tumors and to overcome drug resistance in cancer cells.