Citations

We report the results of a phase 2 trial using lenalidomide plus dexamethasone (Rev/Dex) as initial therapy for myeloma. Thirtyfour patients were enrolled. Lenalidomide was given orally 25 mg daily on days 1 to 21 of a 28-day cycle. Dexamethasone was given orally 40 mg daily on days 1 to 4, 9 to 12, and 17 to 20 of each cycle. Objective response was defined as a decrease in serum monoclonal protein level by 50% or greater and a decrease in urine M protein level by at least 90% or to a level less than 200 mg/24 hours, confirmed by 2 consecutive determinations at least 4 weeks apart. Thirty-one of 34 patients achieved an objective response, including 2 (6%) achieving complete response (CR) and 11 (32%) meeting criteria for both very good partial response and near complete response, resulting in an overall objective response rate of 91%. Of the 3 remaining patients not achieving an objective response, 2 had minor response (MR) and one had stable disease. Fortyseven percent of patients experienced grade III or higher nonhematologic toxicity, most commonly fatigue (15%), muscle weakness (6%), anxiety (6%), pneumonitis (6%), and rash (6%). Rev/Dex is a highly active regimen with manageable side effects in the treatment of newly diagnosed myeloma.

Purpose Monoclonal gammopathy of undetermined significance (MGUS) progresses to multiple myeloma or another related plasma cell disorder (PCD) at a rate of approximately 1% per year. Identification of patients with MGUS at high risk of progression will allow development of preventive strategies. We studied the prognostic value of circulating plasma cells (PCs) in patients with MGUS to predict progression. Patients and Methods Patients were eligible for this retrospective analysis if they were seen at the Mayo Clinic between 1984 and 1997, were diagnosed with MGUS, and had an analysis of the peripheral blood for circulating PCs by the slide-based immunofluorescence method. Patients were observed for progression to another PCD. Results Three hundred twenty-five patients were eligible and 63 (19%) had circulating PCs. Patients with circulating PCs were twice as likely (hazard ratio, 2.1) to experience progression to another PCD (most commonly myeloma), compared with those without circulating PCs (95% CI, 1.1 to 4.3; P = .03). In patients with circulating PCs, the median progression-free survival was 138 months compared with a median not yet reached for those without circulating PCs (P = .028). The median overall survival also was shorter for those with circulating PCs. Other factors with prognostic value were high levels of M protein and non–immunoglobulin G heavy-chain type. Conclusion The presence of circulating PCs, especially when combined with other known prognostic factors such as M protein concentration and immunoglobulin isotype, identify a group of individuals with MGUS at higher risk of progression to overt multiple myeloma.

Background— Most studies that are the basis of recommended volume thresholds for percutaneous coronary interventions (PCIs) predate the routine use of stent placement. Methods and Results— Data from New York’s Percutaneous Coronary Interventions Reporting System in 1998 to 2000 (n=107 713) were used to examine the impact of annual hospital volume and annual operator volume on in-hospital mortality, same-day coronary artery bypass graft (CABG) surgery, and same-stay CABG surgery after adjustment for differences in patients’ severity of illness. For a hospital-volume threshold of 400, the odds ratios for low-volume hospitals versus high-volume hospitals were 1.98 (95% CI, 1.17, 3.35) for in-hospital mortality, 2.07 (95% CI, 1.36, 3.15) for same-day CABG surgery, and 1.51 (95% CI, 1.03, 2.21) for same-stay CABG surgery. For an operator-volume threshold of 75, the odds ratios for low-volume versus high-volume operators were 1.65 (95% CI, 1.05, 2.60) for same-day CABG surgery and 1.55 (95% CI, 1.10, 2.18) for same-stay CABG surgery. Operator volume was not significantly associated with mortality. Also, for hospital volumes below 400 and operator volumes below 75, the respective odds of mortality, same-day CABG surgery, and same-stay CABG surgery were 5.92, 4.02, and 3.92 times the odds for hospital volumes of 400 or higher and operator volumes of 75 or higher. Conclusions— Higher-volume operators and hospitals continue to experience lower risk-adjusted PCI outcome rates.

AbstractThe latest World Health Organization International Classification defines papillary thyroid carcinoma by its “follicular cell differentiation. .. as well as characteristic nuclear changes”. However the oxyphilic (Hürthle cell) papillary carcinoma have nuclei which generally resemble the nuclei seen in oxyphilic follicular carcinomas, and such oxyphilic papillary tumors may behave more aggressively than typical papillary cancers. To further characterize these rare tumors, we identified during a 32‐year period 22 patients with oxyphilic papillary cancer and compared them with 1,084 patients with typical papillary cancers and 57 patients with oxyphilic follicular cancers treated by the Mayo surgical group during the same time period. Although typical papillary and oxyphilic papillary cancers were comparable with regards to patient age, tumor size and extent, TNM stage, and prognostic score (AGES), there were significant differences. Compared to typical papillary tumors, oxyphilic papillary cancers had fewer neck nodal metastases at primary diagnosis (5% vs 40%,p<0.0001), were more often DNA non‐diploid (71% vs 21%,p<0.001), and after 10 postoperative years had higher rates of both tumor recurrence (28% vs 11%,p<0.0001) and cause‐specific mortality (1.7% vs 4%,p<0.0005). In these four important respects the oxyphilic papillary cancers more resembled the oxyphilic follicular cancers. For oxyphilic follicular cancers, the frequency of initial neck nodal metastases was 7% (cf 5%); 83% of the oxyphilic follicular tumors were non‐diploid (cf 71%), and at 10 years postoperatively the tumor recurrence and cause‐specific mortality rates were 28% and 18%, insignificantly different from 28% and 17% seen with the oxyphilic papillary cancers. These results demonstrate that oxyphilic papillary tumors are more similar to oxyphilic follicular than typical papillary cancers, and suggest that in a differentiated follicular cell‐derived carcinoma a predominance of oxyphilic cells may be a prognostically more relevant feature than the individual tumor's predominant papillary or follicular morphologic pattern. Perhaps in future Histologic Classifications the World Health Organization should group the oxyphilic papillary cancers with the oxyphilic follicular rather than the typical papillary carcinomas.

AbstractAmong 971 patients with chronic ulcerative colitis who underwent ilealpouch anal anastomosis during an 8‐year period from January, 1982 to December 1989, 30 patients were randomly selected from each year (total = 240 patients) for an assessment of their long‐term functional results and quality of life as of 1990. Patients undergoing cholecystectomy during each of the same years served as “controls” (20 patients/year, total = 160 patients). All 400 patients completed a written questionnaire that measured bowel habits, overall quality of life, general health, and performance in sports/recreation, travel, sex life, family relationship, occupational work, social activities, and household activities. Ileo‐anal patients had more frequent stools (median, 6 stools/day) and more fecal spotting (68% of patients had episodes) than cholecystectomy patients (median, 1 stool/day, 13% had episodes,p<0.05). In spite of the altered bowel habits, 90% of ileo‐anal patients had an excellent overall quality of life, 76% enjoyed good health, and 91% had good performance scores in the areas examined. In fact, quality of life and performance were similar among ileo‐anal patients and cholecystectomy patients. Moreover, quality of life and bowel habits remained steady in both groups of patients during the 8‐year follow‐up. In conclusion, functional results were satisfactory and quality of life was excellent after ileal pouch‐anal anastomosis; neither deteriorated as patients aged over an 8‐year period after operation.

AbstractThe ileal pouch‐anal operation is the procedure of choice for those suitable patients requiring surgery for chronic ulcerative colitis or familial adenomatous polyposis. The functional results are generally good but pouchitis remains a significant and poorly understood complication. This review encompasses factors relating to pouchitis, e.g., bacteriological, functional and histological changes, with emphasis on its biology and treatment, and the long‐term implications.

The tau (MAPT) locus exists as two distinct clades, H1 and H2. The H1 clade has a normal linkage disequilibrium structure and is the only haplotype found in all populations except those derived from Caucasians. The H2 haplotype is the minor haplotype in Caucasian populations and is not found in other populations. It shows no recombination over a region of 2 Mb with the more common H1 haplotype. The distribution of the haplotype and analysis of the slippage of dinucleotide repeat markers within the haplotype suggest that it entered Homo sapiens populations between approx. 10000 and 30000 years ago. However, sequence comparison of the H2 haplotype with the H1 haplotype and with the chimp sequence suggests that the common founder of the H1 and H2 haplotypes was far earlier than this. We suggest that the H2 haplotype is derived from Homo neanderthalensis and entered H. sapiens populations during the co-existence of these species in Europe from approx. 45000 to 18000 years ago and that the H2 haplotype has been under selection pressure since that time, possibly because of the role of this H1 haplotype in neurodegenerative disease.

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, safety, dosage, and administration of alvimopan, a peripherally acting μ-opioid receptor antagonist, in the management of postoperative ileus (POI). DATA SOURCES: A literature search (1980–October 2004%) applying the terms alvimopan, ADL 8–2698, and LY246736 was conducted using MEDLINE. Information was also obtained from scientific congress abstracts and data on file with the manufacturer. STUDY SELECTION AND DATA EXTRACTION: Studies and abstracts investigating alvimopan and POI were considered for inclusion; however, they were restricted to English-language articles. DATA SYNTHESIS: Alvimopan is a novel, peripherally acting μ-opioid receptor antagonist that is currently under evaluation for the management of POI. POI presents significant clinical challenges that can delay patient recovery and contribute to increased morbidity and prolonged hospitalization after surgery. Clinical trials have demonstrated that alvimopan, at oral doses of 6 and 12 mg, can accelerate time to recovery of gastrointestinal (GI) function and time to hospital discharge following abdominal surgery. The incidence of adverse events with alvimopan therapy was shown to be similar to that of placebo. CONCLUSIONS: Alvimopan is well tolerated and effective at accelerating GI recovery and time to discharge in patients who have undergone bowel resection or hysterectomy when administered prior to surgery and twice daily thereafter until discharge or for up to 7 days. Alvimopan potentially offers significant benefits for patients with POI over currently available treatments.

Background— The objective of this study was to address the feasibility and the biological activity of orally administered human brain natriuretic peptide (hBNP). Proprietary technology has been developed in which short, amphiphilic oligomers are covalently attached to peptides. The conjugated peptides are intended to have an improved pharmacokinetic profile and to enable oral administration. We hypothesized that novel oral conjugated hBNP (CONJ-hBNP) increases plasma hBNP, activates cGMP, and reduces mean arterial pressure (MAP). Methods and Results— This randomized crossover-designed study tested the biological activity of oral CONJ-hBNP compared with oral native hBNP in normal conscious dogs. Measurements of MAP, plasma hBNP, and cGMP were made at baseline (BL) and repeated at 10, 30, 60, 120, 180, and 240 minutes after oral administration. Plasma hBNP was not detectable in dogs at BL. Plasma hBNP was detected after native hBNP and CONJ-HBNP administration. However, plasma hBNP concentration was significantly higher after CONJ-hBNP than after native hBNP administration ( P =0.0374 between groups). Plasma cGMP increased after CONJ-hBNP for 60 minutes (from 10.8±3 to 36.8±26 pmol/mL; P <0.05), whereas it did not change after native hBNP ( P =0.001 between groups). MAP decreased at 10 minutes and remained decreased for 60 minutes after CONJ-hBNP (from 113±8 to 101±12 mm Hg after 10 minutes to 97.5±10 mm Hg after 30 minutes to 99±13 mm Hg after 60 minutes) while remaining unchanged after native hBNP ( P =0.0387 between groups). Conclusions— This study reports for the first time that novel conjugated oral BNP activates cGMP and significantly reduces MAP, thus implying an efficacious coupling of CONJ-hBNP to the natriuretic receptor-A. These data advance a new concept of orally administered chronic BNP therapy for cardiovascular diseases.