Prognostic Significance of Cavitary Lung Nodules in Granulomatosis With Polyangiitis (Wegener's): A Clinical Imaging Study of 225 Patients

Objective

Granulomatosis with polyangiitis (Wegener's) (GPA) is a systemic necrotizing vasculitis in which pulmonary nodules are a common manifestation. Our study examined whether pulmonary nodules, and nodule type (solid versus cavitary), are associated with different disease manifestations and outcomes.

Methods

Demographic, clinical, biologic, and radiologic data at diagnosis and during followup and treatments of GPA patients followed at the Mount Sinai Hospital (Canada) Vasculitis Clinic were analyzed. Patients were separated by the absence of lung nodules, presence of solid nodules only, and presence of cavitary nodules (+/? solid nodules). The study outcomes included followup lung imaging, relapses, and deaths.

Results

Of 225 patients with GPA, 46 had solid nodules only and 44 had cavitary nodules at diagnosis. Demographic and clinical manifestations were similar in the patient subgroups at diagnosis. Cyclophosphamide (CYC) was used for induction after diagnosis in 76.7% of patients with cavitary nodules, compared with 64.7% of patients without nodules and 51.1% of patients with solid nodules (P = 0.04). The mean ± SD followup after diagnosis was 106.6 ± 92.6 months, and 6 of the patients died. In multivariable analysis, diagnosis before 2000 or pulmonary nodule cavitation at diagnosis were associated with relapse, with a hazard ratio of 0.38 (95% confidence interval [95% CI] 0.22–0.65; P < 0.001) and 1.53 (95% CI 1.00–2.33; P = 0.05), respectively, after adjustment for CYC use.

Conclusion

The presence of cavitary nodules led to increased use of CYC but had no impact on survival. Relapse occurred more often, however, in patients with cavitary nodules than in those with solid nodules or no nodules, and should be studied in other cohorts.

     

Systemic therapy for advanced uterine sarcoma: a systematic review of the literature

OBJECTIVE: To conduct a systematic review of the literature regarding the systemic treatment of advanced uterine sarcoma and provide an evidence-based summary of the available literature. METHODS: MEDLINE, EMBASE, and the Cochrane Library databases were searched. "Uterine sarcoma," "leiomyosarcoma," "mixed mesodermal tumor," "chemotherapy," and "systemic therapy" were combined with the search terms for study designs. RESULTS: Three randomized controlled trials and 24 prospective phase II trials were included in the systematic review. In a randomized trial of doxorubicin versus doxorubicin plus cyclophosphamide for advanced or recurrent uterine sarcoma, doxorubicin produced an overall response rate (RR) of 19% and median survival of 11.6 months, which was similar to the response with combination chemotherapy (RR 19%, median survival 10.9 months). A randomized trial comparing ifosfamide plus cisplatin versus ifosfamide alone in mixed mesodermal tumors showed a significant improvement in RR and progression-free survival with the combination compared with ifosfamide alone, however, the combination was associated with increased toxicity including death. A randomized trial comparing doxorubicin to doxorubicin with dacarbazine in women with advanced or recurrent uterine sarcoma demonstrated a significantly higher RR with the combination (P < 0.05), but no significant difference in survival. CONCLUSIONS: Offering palliative chemotherapy to patients with advanced, unresectable uterine sarcoma who are symptomatic from this disease is a reasonable decision. Doxorubicin is an option for women with advanced uterine sarcoma. The combination of cisplatinum and ifosfamide is also an option for women with metastatic mixed mesodermal tumors; however, this combination is associated with significant toxicity when compared to ifosfamide alone.     

Effects of Socioeconomic Status on Colon Cancer Treatment Accessibility and Survival in Toronto,Ontario, and San Francisco,California, 1996–2006

Objectives. We examined the differential effects of socioeconomic status on colon cancer care and survival in Toronto, Ontario, Canada, and San Francisco, California.Methods. We analyzed registry data for colon cancer patients from Ontario (n = 930) and California (n = 1014), diagnosed between 1996 and 2000 and followed until 2006, on stage, surgery, adjuvant chemotherapy, and survival. We obtained socioeconomic data for individuals’ residences from population censuses.Results. Income was directly associated with lymph node evaluation, chemotherapy, and survival in San Francisco but not in Toronto. High-income persons had better survival rates in San Francisco than in Toronto. After adjustment for stage, survival was better for low-income residents of Toronto than for those of San Francisco. Middle- to low-income patients were more likely to receive indicated chemotherapy in Toronto than in San Francisco.Conclusions. Socioeconomic factors appear to mediate colon cancer care in urban areas of the United States but not in Canada. Improvements are needed in screening, diagnostic investigations, and treatment access among low-income Americans.A study of cancer survival in low-income areas of Toronto, Ontario, and Detroit, Michigan, during the 1980s found advantages among Canadians for common cancers.¹ The Toronto survival advantage was replicated for breast cancer across diverse low-income Canadian and US contexts through the 1990s.² Studies of that era, however, were not able to account for differences in stage of disease at diagnosis. More recent studies that accounted for breast cancer stage again found Canadian advantages.^3–6 In the United States, women with breast cancer who lived in low-income areas waited longer for surgery and adjuvant radiation therapy and were less likely to receive radiation therapy or to survive. Similar disparities between high- and low-income women with breast cancer did not exist in Canada; thus low-income Canadians fared better across most breast cancer care indices than their US counterparts. More inclusive health insurance in Canada was advanced as the most plausible explanation.Colon cancer care may be an even more important health care performance indicator. The second most frequent cause of cancer death in North America, its prognosis can be excellent with early diagnosis and treatment.^7,8 For several reasons, colon cancer seems particularly instructive for Canada–US cancer care comparisons. First, research on income and colon cancer survival has found moderate to strong inverse associations in the United States but only modest to null associations in Canada.^1,9–13 Second, colon cancer screening is important, but implementation is at an early stage in both countries.^14,15 Third, effective chemotherapies proliferated during the 1990s for stage III colon cancer and more recently for stage II disease.^16–18 Fourth, screening, diagnosis, and treatment of colon cancer are more accessible to persons with higher socioeconomic status in the United States.^18–22 Colon cancer screening is more prevalent among higher-income persons in Canada,²³ but no previous study has examined associations of socioeconomic status with colon cancer treatment in that country.Because past studies have not observed associations between socioeconomic status and breast cancer treatment in Canada,^3–5 we hypothesized that we would also find no significant correlation. Previous comparisons of colon cancer survival in Canada and the United States showed a significant advantage for Canadians only for low-income and not for middle- or high-income patients.^1,9,24 These international studies of colon cancer survival, however, did not account for differences in stage at the time of diagnosis between countries, as ours did. Because of Canada''s broad health insurance coverage, we expected to find an interaction between income and country for survival. We hypothesized that a direct income–survival gradient would exist in an urban California cohort but not in an urban Ontario cohort and that low-income persons in Ontario would have a survival advantage over those in urban California.     

Exploiting protein fluctuations at the active-site gorge of human cholinesterases: further optimization of the design strategy to develop extremely potent inhibitors

Protein conformational fluctuations are critical for biological functions, although the relationship between protein motion and function has yet to be fully explored. By a thorough bioinformatics analysis of cholinesterases (ChEs), we identified specific hot spots, responsible for protein fluctuations and functions, and those active-site residues that play a role in modulating the cooperative network among the key substructures. This drew the optimization of our design strategy to discover potent and reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase (hAChE and hBuChE) that selectively interact with specific protein substructures. Accordingly, two tricyclic moieties differently spaced by functionalized linkers were investigated as molecular yardsticks to probe the finest interactions with specific hot spots in the hChE gorge. A number of SAR trends were identified, and the multisite inhibitors 3a and 3d were found to be the most potent inhibitors of hBuChE and hAChE known to date.     

Myopathy and parkinsonism in phosphoglycerate kinase deficiency

A 25‐year‐old man with exertional myoglobinuria had no evidence of hemolytic anemia, but he had severe parkinsonism that was responsive to levodopa. Phosphoglycerate kinase (PGK) activity was markedly decreased in muscle, and molecular analysis of the PGK1 gene identified the p.T378P mutation that was recently reported in a patient with isolated myopathy. This case reinforces the concept that PGK deficiency is a clinically heterogeneous disorder and raises the question of a relationship between PGK deficiency and idiopathic juvenile Parkinson disease. Muscle Nerve, 2010     

Membrane glycoprotein changes associated with anthracycline resistance in HL-60 cells

Summary The glycoproteins on the surface of HL-60/S wild-type, drug-sensitive human leukemia cells and HL-60/AR anthracycline-resistant cells which do not overexpress the P-glycoprotein, were characterized by labeling with [³⁵S]-methionine, NaB[³H₄], phosphorus 32, or sodium iodide I 125. HL-60/S and HL-60/AR cell lysates and membrane fractions tagged with [³⁵S]-methionine or phosphorus 32 showed no significant differences in their protein patterns as analyzed by sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE) and by autoradiography. HL-60/S cells labeled with NaB[³H₄] yielded glycoproteins that were smeared predominantly in the molecular-weight range of 210,000 and 160,000 Da, with pI values ranging between pH 4 and pH 4.4. In contrast, NaB[³H₄]-labeled HL-60/AR cells showed 7–8 discrete glycoproteins within a molecular-weight range of 170,000 and 140,000 Da, with pI values also ranging between pH 4 and pH 4.4. In addition, [³H]-glucosamine incorporation into HL-60/S and HL-60/AR cells revealed that the latter showed lower uptake of [³H]-glucosamine than did the former. Following treatment with tunicamycin, [³H]-glucosamine uptake in HL-60/S cells decreased, whereas that in HL-60/AR cells remained unchanged. Surface-membrane radioiodination of HL-60/S and HL-60/AR cells showed two distinct protein electrophoretic patterns, with differences being observed in both the high-(220–95 kDa) and low-molecular-weight ranges (21 kDa). Flow cytometric analysis of HL-60/S and HL-60/AR cells using myeloid and lymphoid antigen-specific antibodies demonstrated no antigenic differences between HL-60/S and HL-60/AR cells. HL-60/S cells incubated in the presence of tunicamycin, an inhibitor ofN-linked glycosylation, or the protein kinase C agonist phorbol 12-myristate 13-acetate (PMA) developed a glycoprotein pattern similar to that observed in HL-60/AR cells. In addition, tunicamycin treatment of HL-60/S cells decreased daunorubicin (DNR) retention and altered its intracellular distribution as compared with that in HL-60/AR cells. These data indicate that HL-60/AR cells do not possess either de novo or amplified high-molecular-weight surface-membrane proteins; instead, existing proteins are hypoglycosylated. These results also show that HL-60/AR cells exhibit the multidrug-resistant phenotype in association with altered membrane glycoproteins of both high (220–95 kDa) and low molecular weight (21 kDa), but without overexpression of the P-glycoprotein. Furthermore, in HL-60/S cells, the multidrug-resistant phenotype is partially inducible by inhibition ofN-linked glycosylation of cell-surfac proteins.Abbreviations HL-60/AR anthracycline-resistant cells - HL-60/S parental HL-60 cells - DNR daunorubicin - RA retinoic acid - PBS phosphatebuffered saline (Hanks' Balanced Salt Solution) - PMA phorbol 12-myristate, 13-acetate - DVFM digitized video fluorescence microscopy - DFP diisopropylfluorophosphate - SDS-PAGE sodium dodecyl sulfatepolyacrylamide gel electrophoresis - MDR multidrug resistance - 6GT 6-thioguanine - NP-40 Nonidet-40 detergent Supported by grants ACS CH-357, CA-31 761, CA-42 450, CA-40 188, the, William J. Matheson Foundation, the Medical Research Council of Canada, and the National Cancer Institute of Canada     

Design, synthesis, and structure-activity relationship studies of 4-quinolinyl- and 9-acrydinylhydrazones as potent antimalarial agents

Malaria is a major health problem in poverty-stricken regions where new antiparasitic drugs are urgently required at an affordable price. We report herein the design, synthesis, and biological investigation of novel antimalarial agents with low potential to develop resistance and structurally based on a highly conjugated scaffold. Starting from a new hit, the designed modifications were performed hypothesizing a specific interaction with free heme and generation of radical intermediates. This approach provided antimalarials with improved potency against chloroquine-resistant plasmodia over known drugs. A number of structure-activity relationship (SAR) trends were identified and among the analogues synthesized, the pyrrolidinylmethylarylidene and the imidazole derivatives 5r, 5t, and 8b were found as the most potent antimalarial agents of the new series. The mechanism of action of the novel compounds was investigated and their in vivo activity was assessed.