Citations

AbstractOBJECTIVE:Olfaction is often sacrificed to gain access to the cranial base in anterior craniofacial surgery. We describe the long-term results of olfactory function in patients who underwent anterior craniofacial surgery and a cribriform plate osteotomy to preserve olfaction.METHODS:Between 1992 and 2004, 28 patients underwent 29 cribriform plate osteotomies in an attempt to preserve olfaction during anterior craniofacial surgery performed through modified extended transbasal approaches. Patients' charts and office notes were reviewed retrospectively. Formal olfactory testing was available in 5 patients, but most data were based on patients' subjective reports of olfaction. Olfactory preservation was defined by the subjective ability to detect fumes such as coffee, chocolate, roses, and orange juice regardless of the intensity of the sensation. Follow-up was based on phone calls to patients.RESULTS:Four patients were lost to follow-up and excluded. Therefore, follow-up was available in 24 patients after 25 procedures. On the basis of patients' subjective reports, olfaction was spared in 22 patients after 23 procedures (92%) and was confirmed objectively in the five patients formally tested. After surgery, only two patients were anosmic.CONCLUSION:Olfaction can be preserved in selected patients undergoing anterior craniofacial surgery. At least 1 cm of nasal mucosa should remain attached to the cribriform plate, which can be achieved by including the nasal bone in the osteotomy of the orbital bar. A medial orbital canthopexy is therefore necessary after these procedures.

PurposeAlthough rare overall, marginal zone B-cell lymphoma (MZBCL) is the most common primary low-grade CNS lymphoma reported in the literature. The aim of this study is to elucidate the biology and genetic features of this unusual tumor.Patients and MethodsFifteen CNS MZBCLs were studied clinically, pathologically, and genetically, including fluorescent in situ hybridization analyses with commercially available MALT1 and IgH break-apart and centromere 3, 7, 12, and 18 probes.ResultsCNS MZBCLs preferentially affect middle-aged women (female-to-male ratio, 4:1), with 93% presenting as dural-based masses mimicking meningioma. Ten patients with 1 to 7.6 years of follow-up after diagnosis showed no evidence of disease after radiation and/or chemotherapy. Like MZBCLs outside of the CNS, they consisted of CD20+, CD3−small B lymphocytes with varying degrees of plasmacytic differentiation and predominantly κ light-chain restriction (78%). Lymphoid follicles with follicular colonization were seen in three patients and deposition of amyloid was noted in samples from two patients, one of which was tumefactive. Neither Bcl-6 protein nor Epstein-Barr virus–encoded RNA was expressed. Trisomy 3 was detected in six of 12 patients, with no rearrangements of MALT1 or IgH and no trisomies of 7, 12, or 18 detected.ConclusionOur data suggest that intracranial MZBCL is an indolent primary CNS lymphoma that typically presents as a meningioma-like dural-based mass. Trisomy 3, but not MALT1 or IgH translocation, is a common genetic abnormality that may contribute to the pathogenesis of this CNS lymphoma.

PurposeMantle cell lymphoma (MCL) is characterized by a t(11;14) resulting in overexpression of cyclin D1 messenger RNA. This study tested whether temsirolimus (previously known as CCI-779), an inhibitor of the mammalian target of rapamycin kinase that regulates cyclin D1 translation, could produce tumor responses in patients with MCL.Patients and MethodsPatients with relapsed or refractory MCL were eligible to receive temsirolimus 250 mg intravenously every week as a single agent. Patients with a tumor response after six cycles were eligible to continue drug for a total of 12 cycles or two cycles after complete remission, and were then observed without maintenance.ResultsThirty-five patients were enrolled and were assessable for toxicity; one patient had MCL by histology but was cyclin D1 negative and was ineligible for efficacy. The median age was 70 years (range, 38 to 89 years), 91% were stage 4, and 69% had two or more extranodal sites. Patients had received a median of three prior therapies (range, one to 11), and 54% were refractory to the last treatment. The overall response rate was 38% (13 of 34 patients; 90% CI, 24% to 54%) with one complete response (3%) and 12 partial responses (35%). The median time-to-progression in all patients was 6.5 months (95% CI, 2.9 to 8.3 months), and the duration of response for the 13 responders was 6.9 months (95% CI, 5.2 to 12.4 months). Hematologic toxicities were the most common, with 71% (25 of 35 patients) having grade 3 and 11% (four of 35 patients) having grade 4 toxicities observed. Thrombocytopenia was the most frequent cause of dose reductions but was of short duration, typically resolving within 1 week.ConclusionsSingle-agent temsirolimus has substantial antitumor activity in relapsed MCL. This study demonstrates that agents that selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. Further studies of this agent in MCL and other lymphoid malignancies are warranted.

Background— Rheumatic heart disease is the most common cause of valvular disease in developing countries. Despite the high prevalence of this disease, the cellular mechanisms are not well known. We hypothesized that rheumatic valve calcification is associated with an osteoblast bone formation and neoangiogenesis. Methods and Results— To test this hypothesis, we examined human rheumatic valves replaced at surgery (n=23), normal human valves (n=20) removed at cardiac transplantation, and degenerative mitral valve leaflets removed during surgical valve repair (n=15). Microcomputed tomography was used to assess mineralization fronts to reconstruct the extents of mineralization. Immunohistochemistry was used to localize osteopontin protein, α-actin, osteocalcin, vascular endothelial growth factor, von Willebrand factor, and CD68 (human macrophage). Microcomputed tomography demonstrated complex calcification developing within the heavily calcified rheumatic valves, not in the degenerative mitral valves and control valves. Immunohistochemistry localized osteopontin and osteocalcin to areas of smooth muscle cells within microvessels and proliferating myofibroblasts. Vascular endothelial growth factor was present in areas of inflammation and colocalized with the CD68 stain primarily in the calcified rheumatic valves. Alizarin red, osteopontin, and osteocalcin protein expression was upregulated in the calcified rheumatic valves and was present at low levels in the degenerative mitral valves. Conclusions— These findings support the concept that rheumatic valve calcification is not a random passive process but a regulated, inflammatory cellular process associated with the expression of osteoblast markers and neoangiogenesis.

Dynamic membrane protrusions such as lamellipodia and filopodia are driven by actin polymerization and often hijacked by intracellular microbes to enter host cells. The overall rate of membrane protrusion depends on the actin polymerization rate and the increase of localized cell volume. Although the signaling pathways involving actin polymerization are well characterized, the molecular mechanisms regulating local cell volume associated with membrane protrusion are unclear. Cryptosporidium parvum , an intracellular parasite, depends on host-cell membrane protrusion to accomplish cell entry and form the parasitophorous vacuole. Here, we report that C. parvum infection of cholangiocytes recruits host-cell SGLT1, a Na + /glucose cotransporter, and aquaporin 1 (AQP1), a water channel, to the attachment site. SGLT1-dependent glucose uptake occurs at the attachment site. Concordantly, the region of attachment displays localized water influx that is inhibited by either suppression of AQP1 by means of AQP1-small interfering RNA (siRNA) or inhibition of SGLT1 by a specific pharmacologic inhibitor, phlorizin. Inhibition of SGLT1 does not affect actin accumulation but decreases the membrane protrusion at the attachment site. Moreover, functional inhibition of host-cell AQP1 and SGLT1 hampers C. parvum invasion of cholangiocytes. Thus, glucose-driven, AQP-mediated localized water influx is involved in the membrane protrusion during C. parvum cellular invasion, phenomena that may also be relevant to the mechanisms of cell membrane protrusion in general.

AbstractReoperation for persistent or recurrent hyperparathyroidism is more hazardous than is primary cervical exploration and is also much less likely to result in cure of the disease. Only 21 of 34 reoperations (62%) were successful during the period 1970 through 1972 at the Mayo Clinic, compared with success in 312 of 327 primary operations (95%). In 9 patients who had their initial exploration at this institution, the most common cause of failure at the first operation was inadequate treatment of multiglandular disease; in 25 patients who were first operated on elsewhere, missed adenomas were far more common.Parathyroid arteriography and selective venous sampling with parathyroid hormone assays should improve the results of reoperation by providing preoperative localization of hyperfunctioning parathyroid glands in difficult cases. These procedures, however, are expensive and technically difficult, and they are not always successful. They are also associated with a definite morbidity, which must be weighed against any anticipated benefits. The systematic evaluation and treatment of patients facing reoperation for hyperparathyroidism should be undertaken in special centers accustomed to dealing with these difficult problems.

Background— Obesity is associated with coronary artery calcification (CAC), a marker of the presence and extent of subclinical coronary atherosclerosis. Obesity adds incremental information in identifying those at higher risk of coronary heart disease to traditional risk factor assessment. The present study examined associations between obesity measures and progression of CAC in those at higher (≥10%) and lower (<10%) 10-year coronary heart disease risk according to the Framingham risk equation. Methods and Results— In this study, 443 asymptomatic white individuals >30 years of age (243 men) had baseline and follow-up CAC measurements an average of 8.9 years apart. Multivariable linear regression models were fit to determine associations of obesity measures at baseline with progression of CAC defined as log e of the difference between follow-up and baseline CAC area plus 1 divided by time (in years) between examinations, adjusting for baseline CAC quantity, age, sex, baseline hypertension status, and baseline cholesterol level. Among 329 participants (74.3%) in the lower-risk group, waist circumference ( P =0.024), waist-to-hip ratio ( P <0.001), body mass index ( P =0.036), and being overweight compared with being underweight or of normal weight ( P =0.008) were each significantly positively associated with progression of CAC. Among those at higher coronary heart disease risk, no baseline obesity measures were associated with CAC progression. Conclusions— Various measures of obesity were associated with increased progression of CAC in those at lower risk of coronary heart disease. Future studies examining the effectiveness of weight reduction strategies in reducing CAC progression among those with an otherwise favorable risk factor profile may be warranted.

Purpose To describe the demographic and tumor related characteristics and outcomes for patients with primary T-cell CNS lymphoma (TPCNSL). Patients and Methods A retrospective series of patients with TPCNSL was compiled from twelve cancer centers in seven countries. Results We identified 45 patients with a median age of 60 years (range, 3 to 84 years). Twenty (44%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Twenty-six (58%) had involvement of a cerebral hemisphere and sixteen (36%) had lesions of deeper sites in the brain. Serum lactate dehydrogenase was elevated in 7 (32%) of 22 patients, and CSF protein was elevated in 19 of 24 patients (79%) with available data. The median disease-specific survival (DSS) was 25 months (95% CI, 11 to 38 months). The 2- and 5-year DSS were 51% (95% CI, 35% to 66%) and 17% (95% CI, 6% to 34%), respectively. Univariate and multivariate analyses were conducted for age (≤ 60 v > 60 years), PS (0 or 1 v 2, 3, or 4), involvement of deep structures of the CNS (no v yes), and methotrexate (MTX) use in the primary treatment (yes v no). Only PS and MTX use were significantly associated with better outcome with hazard ratios of 0.2 (95% CI, 0.1 to 0.4) and 0.4 (95% CI, 0.2 to 0.8), respectively. Conclusion This is the largest series ever assembled of TPCNSL. The presentation and outcome appear similar to that of B cell PCNSL. PS 0 or 1 and administration of MTX are associated with better survival.

Purpose Patients with newly diagnosed, advanced-stage, follicular grade 1 non-Hodgkin's lymphoma (NHL) are often asymptomatic and can be observed without immediate chemotherapy. The goals of this study were to assess the overall response rate (ORR) to rituximab in this patient population and to determine the time-to-progression (TTP) and time-to-subsequent-chemotherapy (TTSC). Patients and Methods Eligible patients had untreated follicular grade 1 NHL, and measurable stage III/IV disease. Patients received rituximab 375 mg/m2 intravenous weekly × 4 doses and were then followed for response and progression; no maintenance therapy was provided. Results Thirty-seven patients were accrued; one patient was ineligible. The median age was 59 years (range, 29 to 83 years). Six patients (18%) had elevated lactate dehydrogenase levels. The ORR was 72%, with 36% complete remissions. Fourteen (39%) of 36 patients remain in unmaintained remission, two died without disease progression, and three died with disease progression. Twenty (56%) of 36 patients have disease progression. The median TTP was 2.2 years (95% CI, 1.3 to not yet reached). Eighteen patients have subsequently been treated with chemotherapy, with a median TTSC of 2.3 years (95% CI, 1.6 to not yet reached). Patients with a high lactate dehydrogenase level had a lower ORR of 33% and a short TTP of only 6 months. Conclusion Rituximab can be safely administered to patients with advanced-stage follicular grade 1 NHL with efficacy and minimal toxicity. This therapy is highly active and offers an acceptable alternative to observation in this patient population. Patients with high LDH should not be considered for rituximab monotherapy.

Background— Coronary bypass surgery (CABG) and angioplasty (PTCA) have been compared in several randomized trials, but data about long-term economic and quality-of-life outcomes are limited. Methods and Results— Cost and quality-of-life data were collected prospectively from 934 patients who were randomized in the Bypass Angioplasty Revascularization Investigation (BARI) and followed up for 10 to12 years. CABG had 53% higher costs initially, but the gap closed to <5% during the first 2 years; after 12 years, the mean cumulative cost of CABG patients was $123 000 versus $120 750 for PTCA, yielding a cost-effectiveness ratio of $14 300/life-year added. CABG patients experienced significantly greater improvement in their physical functioning for the first 3 years but not in later follow-up. Recurrent angina substantially reduced all quality-of-life measures throughout follow-up. Cumulative costs were significantly higher among patients with diabetes, heart failure, and comorbid conditions and among women; costs also were increased by angina, by the number of revascularization procedures, and among patients who died. Conclusion— Early differences between CABG and PTCA in costs and quality of life were no longer significant at 10 to 12 years of follow-up. CABG was cost-effective as compared with PTCA for multivessel disease.