Penny Wise, Pound Foolish? Coverage Limits on Immunosuppression after Kidney Transplantation.

N Engl J Med. 2012 Feb 1;

Authors: Gill JS, Tonelli M

Abstract

As a treatment for end-stage renal disease (ESRD), kidney transplantation is superior to dialysis for improving patient survival rates and quality of life. Its long-term success, however, requires ongoing treatment with immunosuppressive drugs. Ironically, although many of the pivotal discoveries related to immunosuppression have been made in the United States, U.S. kidney-transplant recipients do not benefit from a coherent funding policy for these drugs, and thousands of such patients are therefore at risk for allograft failure and premature death. Ensuring lifetime access to these medications for all Americans with kidney transplants would save lives as well as reduce the total . . .

PMID: 22296029 [PubMed - as supplied by publisher]

Improving childhood vaccination rates.

N Engl J Med. 2012 Feb 2;366(5):391-3

Authors: Diekema DS

PMID: 22296072 [PubMed - in process]

Keeping score under a global payment system.

N Engl J Med. 2012 Feb 2;366(5):393-5

Authors: Landon BE

PMID: 22296073 [PubMed - in process]

Opportunity in austerity–a common agenda for medicine and public health.

N Engl J Med. 2012 Feb 2;366(5):395-7

Authors: Stine NW, Chokshi DA

PMID: 22296074 [PubMed - in process]

Ulipristal acetate versus placebo for fibroid treatment before surgery.

N Engl J Med. 2012 Feb 2;366(5):409-20

Authors: Donnez J, Tatarchuk TF, Bouchard P, Puscasiu L, Zakharenko NF, Ivanova T, Ugocsai G, Mara M, Jilla MP, Bestel E, Terrill P, Osterloh I, Loumaye E,

Abstract

BACKGROUND: The efficacy and safety of oral ulipristal acetate for the treatment of symptomatic uterine fibroids before surgery are uncertain.

METHODS: We randomly assigned women with symptomatic fibroids, excessive uterine bleeding (a score of >100 on the pictorial blood-loss assessment chart [PBAC, an objective assessment of blood loss, in which monthly scores range from 0 to >500, with higher numbers indicating more bleeding]) and anemia (hemoglobin level of ≤10.2 g per deciliter) to receive treatment for up to 13 weeks with oral ulipristal acetate at a dose of 5 mg per day (96 women) or 10 mg per day (98 women) or to receive placebo (48 women). All patients received iron supplementation. The coprimary efficacy end points were control of uterine bleeding (PBAC score of <75) and reduction of fibroid volume at week 13, after which patients could undergo surgery.

RESULTS: At 13 weeks, uterine bleeding was controlled in 91% of the women receiving 5 mg of ulipristal acetate, 92% of those receiving 10 mg of ulipristal acetate, and 19% of those receiving placebo (P<0.001 for the comparison of each dose of ulipristal acetate with placebo). The rates of amenorrhea were 73%, 82%, and 6%, respectively, with amenorrhea occurring within 10 days in the majority of patients receiving ulipristal acetate. The median changes in total fibroid volume were -21%, -12%, and +3% (P=0.002 for the comparison of 5 mg of ulipristal acetate with placebo, and P=0.006 for the comparison of 10 mg of ulipristal acetate with placebo). Ulipristal acetate induced benign histologic endometrial changes that had resolved by 6 months after the end of therapy. Serious adverse events occurred in one patient during treatment with 10 mg of ulipristal acetate (uterine hemorrhage) and in one patient during receipt of placebo (fibroid protruding through the cervix). Headache and breast tenderness were the most common adverse events associated with ulipristal acetate but did not occur significantly more frequently than with placebo.

CONCLUSIONS: Treatment with ulipristal acetate for 13 weeks effectively controlled excessive bleeding due to uterine fibroids and reduced the size of the fibroids. (Funded by PregLem; ClinicalTrials.gov number, NCT00755755.).

PMID: 22296075 [PubMed - in process]

Ulipristal acetate versus leuprolide acetate for uterine fibroids.

N Engl J Med. 2012 Feb 2;366(5):421-32

Authors: Donnez J, Tomaszewski J, Vázquez F, Bouchard P, Lemieszczuk B, Baró F, Nouri K, Selvaggi L, Sodowski K, Bestel E, Terrill P, Osterloh I, Loumaye E,

Abstract

BACKGROUND: The efficacy and side-effect profile of ulipristal acetate as compared with those of leuprolide acetate for the treatment of symptomatic uterine fibroids before surgery are unclear.

METHODS: In this double-blind noninferiority trial, we randomly assigned 307 patients with symptomatic fibroids and excessive uterine bleeding to receive 3 months of daily therapy with oral ulipristal acetate (at a dose of either 5 mg or 10 mg) or once-monthly intramuscular injections of leuprolide acetate (at a dose of 3.75 mg). The primary outcome was the proportion of patients with controlled bleeding at week 13, with a prespecified noninferiority margin of -20%.

RESULTS: Uterine bleeding was controlled in 90% of patients receiving 5 mg of ulipristal acetate, in 98% of those receiving 10 mg of ulipristal acetate, and in 89% of those receiving leuprolide acetate, for differences (as compared with leuprolide acetate) of 1.2 percentage points (95% confidence interval [CI], -9.3 to 11.8) for 5 mg of ulipristal acetate and 8.8 percentage points (95% CI, 0.4 to 18.3) for 10 mg of ulipristal acetate. Median times to amenorrhea were 7 days for patients receiving 5 mg of ulipristal acetate, 5 days for those receiving 10 mg of ulipristal acetate, and 21 days for those receiving leuprolide acetate. Moderate-to-severe hot flashes were reported for 11% of patients receiving 5 mg of ulipristal acetate, for 10% of those receiving 10 mg of ulipristal acetate, and for 40% of those receiving leuprolide acetate (P<0.001 for each dose of ulipristal acetate vs. leuprolide acetate).

CONCLUSIONS: Both the 5-mg and 10-mg daily doses of ulipristal acetate were noninferior to once-monthly leuprolide acetate in controlling uterine bleeding and were significantly less likely to cause hot flashes. (Funded by PregLem; ClinicalTrials.gov number, NCT00740831.).

PMID: 22296076 [PubMed - in process]

GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus.

N Engl J Med. 2012 Feb 2;366(5):433-42

Authors: Ludvigsson J, Krisky D, Casas R, Battelino T, Castaño L, Greening J, Kordonouri O, Otonkoski T, Pozzilli P, Robert JJ, Veeze HJ, Palmer J

Abstract

BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes.

METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels.

RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences.

CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.).

PMID: 22296077 [PubMed - in process]

Clinical practice. Delayed puberty.

N Engl J Med. 2012 Feb 2;366(5):443-53

Authors: Palmert MR, Dunkel L

PMID: 22296078 [PubMed - in process]

The perpetual challenge of infectious diseases.

N Engl J Med. 2012 Feb 2;366(5):454-61

Authors: Fauci AS, Morens DM

PMID: 22296079 [PubMed - in process]

Images in clinical medicine. Post-traumatic herniated cervical disk.

N Engl J Med. 2012 Feb 2;366(5):462

Authors: Diabira S, Morandi X

PMID: 22296080 [PubMed - in process]

Clinical problem-solving. Worth a second look.

N Engl J Med. 2012 Feb 2;366(5):463-8

Authors: Berzin TM, Greenberger NJ, Levy BD, Loscalzo J

PMID: 22296081 [PubMed - in process]

Uterine fibroids and evidence-based medicine–not an oxymoron.

N Engl J Med. 2012 Feb 2;366(5):471-3

Authors: Stewart EA

PMID: 22296082 [PubMed - in process]

Timing of antiretroviral therapy for HIV-1-associated tuberculosis.

N Engl J Med. 2012 Feb 2;366(5):474; author reply 475-6

Authors: Lawn SD, Wood R

PMID: 22296084 [PubMed - in process]

Timing of antiretroviral therapy for HIV-1-associated tuberculosis.

N Engl J Med. 2012 Feb 2;366(5):474-5; author reply 476

Authors: Boyles TH

PMID: 22296085 [PubMed - in process]

Glucocorticoids plus N-acetylcysteine in alcoholic hepatitis.

N Engl J Med. 2012 Feb 2;366(5):476-7; author reply 477

Authors: Lake-Bakaar G

PMID: 22296087 [PubMed - in process]

Early liver transplantation for severe alcoholic hepatitis.

N Engl J Med. 2012 Feb 2;366(5):477-8; author reply 479

Authors: Tamura S, Sugawara Y, Kukudo N

PMID: 22296089 [PubMed - in process]

Early liver transplantation for severe alcoholic hepatitis.

N Engl J Med. 2012 Feb 2;366(5):478; author reply 479

Authors: John S, Chung RT

PMID: 22296090 [PubMed - in process]

Early liver transplantation for severe alcoholic hepatitis.

N Engl J Med. 2012 Feb 2;366(5):478-9; author reply 479

Authors: Di Martino V, Sheppard F, Vanlemmens C

PMID: 22296091 [PubMed - in process]

Ultraviolet A and photosensitivity during vemurafenib therapy.

N Engl J Med. 2012 Feb 2;366(5):480-1

Authors: Dummer R, Rinderknecht J, Goldinger SM

PMID: 22296092 [PubMed - in process]

Staphylococcus aureus reactivation osteomyelitis after 75 years.

N Engl J Med. 2012 Feb 2;366(5):481-2

Authors: Libraty DH, Patkar C, Torres B

PMID: 22296093 [PubMed - in process]

Images in clinical medicine. Insulin-induced lipohypertrophy.

N Engl J Med. 2012 Feb 2;366(5):e9

Authors: Landau S

PMID: 22296094 [PubMed - in process]

Why Now Is Not the Time for Premium Support.

N Engl J Med. 2012 Jan 25;

Authors: Aaron HJ, Frakt AB

PMID: 22276779 [PubMed - as supplied by publisher]

Assessing Supplement Safety – The FDA’s Controversial Proposal.

N Engl J Med. 2012 Jan 25;

Authors: Cohen PA

PMID: 22276780 [PubMed - as supplied by publisher]

The Wyden-Ryan Proposal – A Foundation for Realistic Medicare Reform.

N Engl J Med. 2012 Jan 25;

Authors: Antos JR

PMID: 22276781 [PubMed - as supplied by publisher]

Time for a change–a new approach to ICD replacement.

N Engl J Med. 2012 Jan 26;366(4):291-3

Authors: Kramer DB, Buxton AE, Zimetbaum PJ

PMID: 22276818 [PubMed - in process]

Interpreting the coronary-artery calcium score.

N Engl J Med. 2012 Jan 26;366(4):294-6

Authors: Grayburn PA

PMID: 22276819 [PubMed - in process]

Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer.

N Engl J Med. 2012 Jan 26;366(4):299-309

Authors: von Minckwitz G, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, Schrader I, Kittel K, Hanusch C, Kreienberg R, Solbach C, Gerber B, Jackisch C, Kunz G, Blohmer JU, Huober J, Hauschild M, Fehm T, Müller BM, Denkert C, Loibl S, Nekljudova V, Untch M, ,

Abstract

BACKGROUND: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor A, has shown clinical efficacy in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. We evaluated the efficacy, measured according to the rate of pathological complete response (absence of invasive and intraductal disease in the breast and the axillary lymph nodes), and the safety of adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage breast cancer.

METHODS: We randomly assigned 1948 patients with a median tumor size of 40 mm on palpation to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel, with or without concomitant bevacizumab. Patients with untreated HER2-negative breast cancer were eligible if they had large tumors, hormone-receptor-negative disease, or hormone-receptor-positive disease with palpable nodes or positive findings on sentinel-node biopsy, and no increased cardiovascular or bleeding risk.

RESULTS: Overall, the rates of pathological complete response were 14.9% with epirubicin and cyclophosphamide followed by docetaxel and 18.4% with epirubicin and cyclophosphamide followed by docetaxel plus bevacizumab (odds ratio with addition of bevacizumab, 1.29; 95% confidence interval, 1.02 to 1.65; P=0.04); the corresponding rates of pathological complete response were 27.9% and 39.3% among 663 patients with triple-negative tumors (P=0.003) and 7.8% and 7.7% among 1262 patients with hormone-receptor-positive tumors (P=1.00). Breast-conserving surgery was possible in 66.6% of the patients in both groups. The addition of bevacizumab, as compared with neoadjuvant therapy alone, was associated with a higher incidence of grade 3 or 4 toxic effects (febrile neutropenia, mucositis, the hand-foot syndrome, infection, and hypertension) but with a similar incidence of surgical complications.

CONCLUSIONS: The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response among patients with HER2-negative early-stage breast cancer. Efficacy was restricted primarily to patients with triple-negative tumors, in whom the pathological complete response is considered to be a reliable predictor of long-term outcome. (Funded by Sanofi-Aventis and Roche, Germany; ClinicalTrials.gov number, NCT00567554.).

PMID: 22276820 [PubMed - in process]

Bevacizumab added to neoadjuvant chemotherapy for breast cancer.

N Engl J Med. 2012 Jan 26;366(4):310-20

Authors: Bear HD, Tang G, Rastogi P, Geyer CE, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N

Abstract

BACKGROUND: Bevacizumab and the antimetabolites capecitabine and gemcitabine have been shown to improve outcomes when added to taxanes in patients with metastatic breast cancer. The primary aims of this trial were to determine whether the addition of capecitabine or gemcitabine to neoadjuvant chemotherapy with docetaxel, followed by doxorubicin plus cyclophosphamide, would increase the rates of pathological complete response in the breast in women with operable, human epidermal growth factor receptor 2 (HER2)-negative breast cancer and whether adding bevacizumab to these chemotherapy regimens would increase the rates of pathological complete response.

METHODS: We randomly assigned 1206 patients to receive neoadjuvant therapy consisting of docetaxel (100 mg per square meter of body-surface area on day 1), docetaxel (75 mg per square meter on day 1) plus capecitabine (825 mg per square meter twice a day on days 1 to 14), or docetaxel (75 mg per square meter on day 1) plus gemcitabine (1000 mg per square meter on days 1 and for four cycles, with all regimens followed by treatment with doxorubicin-cyclophosphamide for four cycles. Patients were also randomly assigned to receive or not to receive bevacizumab (15 mg per kilogram of body weight) for the first six cycles of chemotherapy.

RESULTS: The addition of capecitabine or gemcitabine to docetaxel therapy, as compared with docetaxel therapy alone, did not significantly increase the rate of pathological complete response (29.7% and 31.8%, respectively, vs. 32.7%; P=0.69). Both capecitabine and gemcitabine were associated with increased toxic effects–specifically, the hand-foot syndrome, mucositis, and neutropenia. The addition of bevacizumab significantly increased the rate of pathological complete response (28.2% without bevacizumab vs. 34.5% with bevacizumab, P=0.02). The effect of bevacizumab on the rate of pathological complete response was not the same in the hormone-receptor-positive and hormone-receptor-negative subgroups. The addition of bevacizumab increased the rates of hypertension, left ventricular systolic dysfunction, the hand-foot syndrome, and mucositis.

CONCLUSIONS: The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response, which was the primary end point of this study. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00408408.).

PMID: 22276821 [PubMed - in process]

Lifetime risks of cardiovascular disease.

N Engl J Med. 2012 Jan 26;366(4):321-9

Authors: Berry JD, Dyer A, Cai X, Garside DB, Ning H, Thomas A, Greenland P, Van Horn L, Tracy RP, Lloyd-Jones DM

Abstract

BACKGROUND: The lifetime risks of cardiovascular disease have not been reported across the age spectrum in black adults and white adults.

METHODS: We conducted a meta-analysis at the individual level using data from 18 cohort studies involving a total of 257,384 black men and women and white men and women whose risk factors for cardiovascular disease were measured at the ages of 45, 55, 65, and 75 years. Blood pressure, cholesterol level, smoking status, and diabetes status were used to stratify participants according to risk factors into five mutually exclusive categories. The remaining lifetime risks of cardiovascular events were estimated for participants in each category at each age, with death free of cardiovascular disease treated as a competing event.

RESULTS: We observed marked differences in the lifetime risks of cardiovascular disease across risk-factor strata. Among participants who were 55 years of age, those with an optimal risk-factor profile (total cholesterol level, <180 mg per deciliter [4.7 mmol per liter]; blood pressure, <120 mm Hg systolic and 80 mm Hg diastolic; nonsmoking status; and nondiabetic status) had substantially lower risks of death from cardiovascular disease through the age of 80 years than participants with two or more major risk factors (4.7% vs. 29.6% among men, 6.4% vs. 20.5% among women). Those with an optimal risk-factor profile also had lower lifetime risks of fatal coronary heart disease or nonfatal myocardial infarction (3.6% vs. 37.5% among men, <1% vs. 18.3% among women) and fatal or nonfatal stroke (2.3% vs. 8.3% among men, 5.3% vs. 10.7% among women). Similar trends within risk-factor strata were observed among blacks and whites and across diverse birth cohorts.

CONCLUSIONS: Differences in risk-factor burden translate into marked differences in the lifetime risk of cardiovascular disease, and these differences are consistent across race and birth cohorts. (Funded by the National Heart, Lung, and Blood Institute.).

PMID: 22276822 [PubMed - in process]

Fingolimod for multiple sclerosis.

N Engl J Med. 2012 Jan 26;366(4):339-47

Authors: Pelletier D, Hafler DA

PMID: 22276823 [PubMed - in process]

Iron overload in human disease.

N Engl J Med. 2012 Jan 26;366(4):348-59

Authors: Fleming RE, Ponka P

PMID: 22276824 [PubMed - in process]

Images in clinical medicine. Hypertrophic pulmonary osteoarthropathy and tripe palms.

N Engl J Med. 2012 Jan 26;366(4):360

Authors: Saeed H, Massarweh S

PMID: 22276825 [PubMed - in process]

Case records of the Massachusetts General Hospital. Case 3-2012. A newborn boy with vomiting, diarrhea, and abdominal distention.

N Engl J Med. 2012 Jan 26;366(4):361-72

Authors: Melendez E, Goldstein AM, Sagar P, Badizadegan K

PMID: 22276826 [PubMed - in process]

Fighting fire with fire: rekindling the bevacizumab debate.

N Engl J Med. 2012 Jan 26;366(4):374-5

Authors: Montero AJ, Vogel C

PMID: 22276827 [PubMed - in process]

Closing the iron gate.

N Engl J Med. 2012 Jan 26;366(4):376-7

Authors: Andrews NC

PMID: 22276828 [PubMed - in process]

HPV vaccine against anal intraepithelial neoplasia.

N Engl J Med. 2012 Jan 26;366(4):378; author reply 378-9

Authors: Wieland U, Stuecker M, Kreuter A

PMID: 22276830 [PubMed - in process]

Briakinumab versus methotrexate for psoriasis.

N Engl J Med. 2012 Jan 26;366(4):379; author reply 380

Authors: Malgarini RB, Pimpinella G

PMID: 22276832 [PubMed - in process]

Briakinumab versus Methotrexate for Psoriasis.

N Engl J Med. 2012 Jan 26;366(4):379-80; author reply 380

Authors: Wu JJ

PMID: 22276833 [PubMed - in process]

Long-term hormonal adaptations to weight loss.

N Engl J Med. 2012 Jan 26;366(4):380-1; author reply 382

Authors: Cordido F, Sangiao-Alvarellos S, Perez-Fontán M

PMID: 22276835 [PubMed - in process]

Long-term hormonal adaptations to weight loss.

N Engl J Med. 2012 Jan 26;366(4):381; author reply 382

Authors: Wing RR, Strohacker K, McCaffery J

PMID: 22276836 [PubMed - in process]

Long-term hormonal adaptations to weight loss.

N Engl J Med. 2012 Jan 26;366(4):381-2; author reply 382

Authors: Mogul HR, Freeman R, Hantash FX

PMID: 22276837 [PubMed - in process]

Influenza vaccine in young children.

N Engl J Med. 2012 Jan 26;366(4):383; author reply 383-4

Authors: Ambrose CS, Belshe RB

PMID: 22276839 [PubMed - in process]

Influenza vaccine in young children.

N Engl J Med. 2012 Jan 26;366(4):383; author reply 383-4

Authors: Heikkinen T, Heinonen S

PMID: 22276840 [PubMed - in process]

Sildenafil for severe lymphatic malformations.

N Engl J Med. 2012 Jan 26;366(4):384-6

Authors: Swetman GL, Berk DR, Vasanawala SS, Feinstein JA, Lane AT, Bruckner AL

PMID: 22276841 [PubMed - in process]

Images in clinical medicine. Perilymph fistula test.

N Engl J Med. 2012 Jan 26;366(4):e8

Authors: Chu H, Chung WH

PMID: 22276842 [PubMed - in process]

Preparing for Precision Medicine.

N Engl J Med. 2012 Jan 18;

Authors: Mirnezami R, Nicholson J, Darzi A

Abstract

Ms. H. is a 35-year-old woman from Japan who has had a cough for 3 weeks. Her physician sends her for an x-ray and CT scan that reveal an advanced lesion, which a biopsy confirms to be non-small-cell lung cancer. She has never smoked. Can anything be done for her? Had Ms. H.’s cancer been diagnosed before 2004, her oncologist might have offered her a treatment to which about 10% of patients have a response, with the remainder gaining a negligible survival benefit and experiencing clinically significant side effects. But her diagnosis was made in 2011, when her biopsy tissue . . .

PMID: 22256780 [PubMed - as supplied by publisher]

Alleviating suffering 101–pain relief in the United States.

N Engl J Med. 2012 Jan 19;366(3):197-9

Authors: Pizzo PA, Clark NM

PMID: 22256802 [PubMed - in process]

Painful inequities–palliative care in developing countries.

N Engl J Med. 2012 Jan 19;366(3):199-201

Authors: Lamas D, Rosenbaum L

PMID: 22256803 [PubMed - in process]

RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors.

N Engl J Med. 2012 Jan 19;366(3):207-15

Authors: Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, Reis-Filho JS, Kong X, Koya RC, Flaherty KT, Chapman PB, Kim MJ, Hayward R, Martin M, Yang H, Wang Q, Hilton H, Hang JS, Noe J, Lambros M, Geyer F, Dhomen N, Niculescu-Duvaz I, Zambon A, Niculescu-Duvaz D, Preece N, Robert L, Otte NJ, Mok S, Kee D, Ma Y, Zhang C, Habets G, Burton EA, Wong B, Nguyen H, Kockx M, Andries L, Lestini B, Nolop KB, Lee RJ, Joe AK, Troy JL, Gonzalez R, Hutson TE, Puzanov I, Chmielowski B, Springer CJ, McArthur GA, Sosman JA, Lo RS, Ribas A, Marais R

Abstract

BACKGROUND: Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors.

METHODS: We performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib. An analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of the prevalent RAS mutation was also performed.

RESULTS: Among 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, 8 had RAS mutations (4 in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations, the most prevalent being HRAS Q61L. Increased proliferation of HRAS Q61L-mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)-pathway signaling and activation of ERK-mediated transcription. In a mouse model of HRAS Q61L-mediated skin carcinogenesis, the vemurafenib analogue PLX4720 was not an initiator or a promoter of carcinogenesis but accelerated growth of the lesions harboring HRAS mutations, and this growth was blocked by concomitant treatment with a MEK inhibitor.

CONCLUSIONS: Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous-cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib. The molecular mechanism is consistent with the paradoxical activation of MAPK signaling and leads to accelerated growth of these lesions. (Funded by Hoffmann-La Roche and others; ClinicalTrials.gov numbers, NCT00405587, NCT00949702, NCT01001299, and NCT01006980.).

PMID: 22256804 [PubMed - in process]

Preliminary study of two antiviral agents for hepatitis C genotype 1.

N Engl J Med. 2012 Jan 19;366(3):216-24

Authors: Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib R, Reindollar R, Rustgi V, McPhee F, Wind-Rotolo M, Persson A, Zhu K, Dimitrova DI, Eley T, Guo T, Grasela DM, Pasquinelli C

Abstract

BACKGROUND: Patients with chronic hepatitis C virus (HCV) infection who have not had a response to therapy with peginterferon and ribavirin may benefit from the addition of multiple direct-acting antiviral agents to their treatment regimen.

METHODS: This open-label, phase 2a study included an exploratory cohort of 21 patients with chronic HCV genotype 1 infection who had not had a response to previous therapy (i.e., had not had ≥2 log(10) decline in HCV RNA after ≥12 weeks of treatment with peginterferon and ribavirin). We randomly assigned patients to receive the NS5A replication complex inhibitor daclatasvir (60 mg once daily) and the NS3 protease inhibitor asunaprevir (600 mg twice daily) alone (group A, 11 patients) or in combination with peginterferon alfa-2a and ribavirin (group B, 10 patients) for 24 weeks. The primary end point was the percentage of patients with a sustained virologic response 12 weeks after the end of the treatment period.

RESULTS: A total of 4 patients in group A (36%; 2 of 9 with HCV genotype 1a and 2 of 2 with genotype 1b) had a sustained virologic response at 12 weeks after treatment and also at 24 weeks after treatment.. Six patients (all with HCV genotype 1a) had viral breakthrough while receiving therapy, and resistance mutations to both antiviral agents were found in all cases; 1 patient had a viral response at the end of treatment but had a relapse after the treatment period. All 10 patients in group B had a sustained virologic response at 12 weeks after treatment, and 9 had a sustained virologic response at 24 weeks after treatment. Diarrhea was the most common adverse event in both groups. Six patients had transient elevations of alanine aminotransferase levels to more than 3 times the upper limit of the normal range.

CONCLUSIONS: This preliminary study involving patients with HCV genotype 1 infection who had not had a response to prior therapy showed that a sustained virologic response can be achieved with two direct-acting antiviral agents only. In addition, a high rate of sustained virologic response was achieved when the two direct-acting antiviral agents were combined with peginterferon alfa-2a and ribavirin. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01012895.).

PMID: 22256805 [PubMed - in process]

Bone-density testing interval and transition to osteoporosis in older women.

N Engl J Med. 2012 Jan 19;366(3):225-33

Authors: Gourlay ML, Fine JP, Preisser JS, May RC, Li C, Lui LY, Ransohoff DF, Cauley JA, Ensrud KE,

Abstract

BACKGROUND: Although bone mineral density (BMD) testing to screen for osteoporosis (BMD T score, -2.50 or lower) is recommended for women 65 years of age or older, there are few data to guide decisions about the interval between BMD tests.

METHODS: We studied 4957 women, 67 years of age or older, with normal BMD (T score at the femoral neck and total hip, -1.00 or higher) or osteopenia (T score, -1.01 to -2.49) and with no history of hip or clinical vertebral fracture or of treatment for osteoporosis, followed prospectively for up to 15 years. The BMD testing interval was defined as the estimated time for 10% of women to make the transition to osteoporosis before having a hip or clinical vertebral fracture, with adjustment for estrogen use and clinical risk factors. Transitions from normal BMD and from three subgroups of osteopenia (mild, moderate, and advanced) were analyzed with the use of parametric cumulative incidence models. Incident hip and clinical vertebral fractures and initiation of treatment with bisphosphonates, calcitonin, or raloxifene were treated as competing risks.

RESULTS: The estimated BMD testing interval was 16.8 years (95% confidence interval [CI], 11.5 to 24.6) for women with normal BMD, 17.3 years (95% CI, 13.9 to 21.5) for women with mild osteopenia, 4.7 years (95% CI, 4.2 to 5.2) for women with moderate osteopenia, and 1.1 years (95% CI, 1.0 to 1.3) for women with advanced osteopenia.

CONCLUSIONS: Our data indicate that osteoporosis would develop in less than 10% of older, postmenopausal women during rescreening intervals of approximately 15 years for women with normal bone density or mild osteopenia, 5 years for women with moderate osteopenia, and 1 year for women with advanced osteopenia. (Funded by the National Institutes of Health.).

PMID: 22256806 [PubMed - in process]

Cognitive and neurologic outcomes after coronary-artery bypass surgery.

N Engl J Med. 2012 Jan 19;366(3):250-7

Authors: Selnes OA, Gottesman RF, Grega MA, Baumgartner WA, Zeger SL, McKhann GM

PMID: 22256807 [PubMed - in process]

Images in clinical medicine. Pulmonary cement embolism after vertebroplasty.

N Engl J Med. 2012 Jan 19;366(3):258

Authors: Tourtier JP, Cottez S

PMID: 22256808 [PubMed - in process]

Case records of the Massachusetts General Hospital. Case 2-2012. A 63-year-old woman with dyspnea and rapidly progressive respiratory failure.

N Engl J Med. 2012 Jan 19;366(3):259-69

Authors: Kotton DN, Muse VV, Nishino M

PMID: 22256809 [PubMed - in process]

RAF around the edges–the paradox of BRAF inhibitors.

N Engl J Med. 2012 Jan 19;366(3):271-3

Authors: Weeraratna AT

PMID: 22256810 [PubMed - in process]

A watershed moment in the treatment of hepatitis C.

N Engl J Med. 2012 Jan 19;366(3):273-5

Authors: Chung RT

PMID: 22256811 [PubMed - in process]

Clostridium difficile infection and colonization.

N Engl J Med. 2012 Jan 19;366(3):276; author reply 276-7

Authors: Lapane KL, Motzkus-Feagans C, Pakyz A

PMID: 22256813 [PubMed - in process]

Panretinal photocoagulation for diabetic retinopathy.

N Engl J Med. 2012 Jan 19;366(3):277; author reply 278-9

Authors: Trempe CL

PMID: 22256815 [PubMed - in process]

Panretinal photocoagulation for diabetic retinopathy.

N Engl J Med. 2012 Jan 19;366(3):277-8; author reply 278-9

Authors: Zhang ZY, Hoffman MR, Zhang XR

PMID: 22256816 [PubMed - in process]

Panretinal photocoagulation for diabetic retinopathy.

N Engl J Med. 2012 Jan 19;366(3):278; author reply 278-9

Authors: Zheng Y, Wong TY

PMID: 22256817 [PubMed - in process]

Restrictions on use of prescribing data for drug promotion.

N Engl J Med. 2012 Jan 19;366(3):279

Authors: Carmel PW

PMID: 22256818 [PubMed - in process]

More on hemophilia A induced by ipilimumab.

N Engl J Med. 2012 Jan 19;366(3):280-1; author reply 281

Authors: Lozier J

PMID: 22256820 [PubMed - in process]

Medical devices–balancing regulation and innovation.

N Engl J Med. 2012 Jan 19;366(3):280; author reply 280

Authors: Feder N

PMID: 22256822 [PubMed - in process]

Factor XIII in the treatment of hemophilia A.

N Engl J Med. 2012 Jan 19;366(3):281-3

Authors: Rea CJ, Foley JH, Sørensen B

PMID: 22256823 [PubMed - in process]

Images in clinical medicine. Tophaceous gout.

N Engl J Med. 2012 Jan 19;366(3):e6

Authors: Samaras N, Rossi C

PMID: 22256825 [PubMed - in process]

The irrelevance of the broccoli argument against the insurance mandate.

N Engl J Med. 2012 Jan 5;366(1):e1

Authors: Elhauge E

PMID: 22187959 [PubMed - indexed for MEDLINE]

Recurrent Somatic DICER1 Mutations in Nonepithelial Ovarian Cancers.

N Engl J Med. 2011 Dec 21;

Authors: Heravi-Moussavi A, Anglesio MS, Cheng SW, Senz J, Yang W, Prentice L, Fejes AP, Chow C, Tone A, Kalloger SE, Hamel N, Roth A, Ha G, Wan AN, Maines-Bandiera S, Salamanca C, Pasini B, Clarke BA, Lee AF, Lee CH, Zhao C, Young RH, Aparicio SA, Sorensen PH, Woo MM, Boyd N, Jones SJ, Hirst M, Marra MA, Gilks B, Shah SP, Foulkes WD, Morin GB, Huntsman DG

Abstract

Background Germline truncating mutations in DICER1, an endoribonuclease in the RNase III family that is essential for processing microRNAs, have been observed in families with the pleuropulmonary blastoma-family tumor and dysplasia syndrome. Mutation carriers are at risk for nonepithelial ovarian tumors, notably sex cord-stromal tumors. Methods We sequenced the whole transcriptomes or exomes of 14 nonepithelial ovarian tumors and noted closely clustered mutations in the region of DICER1 encoding the RNase IIIb domain of DICER1 in four samples. We then sequenced this region of DICER1 in additional ovarian tumors and in certain other tumors and queried the effect of the mutations on the enzymatic activity of DICER1 using in vitro RNA cleavage assays. Results DICER1 mutations in the RNase IIIb domain were found in 30 of 102 nonepithelial ovarian tumors (29%), predominantly in Sertoli-Leydig cell tumors (26 of 43, or 60%), including 4 tumors with additional germline DICER1 mutations. These mutations were restricted to codons encoding metal-binding sites within the RNase IIIb catalytic centers, which are critical for microRNA interaction and cleavage, and were somatic in all 16 samples in which germline DNA was available for testing. We also detected mutations in 1 of 14 nonseminomatous testicular germ-cell tumors, in 2 of 5 embryonal rhabdomyosarcomas, and in 1 of 266 epithelial ovarian and endometrial carcinomas. The mutant DICER1 proteins had reduced RNase IIIb activity but retained RNase IIIa activity. Conclusions Somatic missense mutations affecting the RNase IIIb domain of DICER1 are common in nonepithelial ovarian tumors. These mutations do not obliterate DICER1 function but alter it in specific cell types, a novel mechanism through which perturbation of microRNA processing may be oncogenic. (Funded by the Terry Fox Research Institute and others.).

PMID: 22187960 [PubMed - as supplied by publisher]

Selling Bone Marrow – Flynn v. Holder.

N Engl J Med. 2011 Dec 21;

Authors: Cohen IG

Abstract

On December 1, 2011, in Flynn v. Holder, the U.S. Court of Appeals for the Ninth Circuit held that the ban on selling “bone marrow” that is part of the National Organ Transplant Act (NOTA) of 1984(1) does not encompass “peripheral blood stem cells” obtained through apheresis. This ruling means that the sale of blood stem cells for transplantation will now be permitted.(2) The court based its holding solely on statutory interpretation of NOTA, not the plaintiffs’ more radical claim that the prohibition on selling bone marrow violates the Equal Protection Clause of the U.S. Constitution, which prohibits the federal . . .

PMID: 22187961 [PubMed - as supplied by publisher]

The Sources of the SGR “Hole”

N Engl J Med. 2011 Dec 21;

Authors: Alhassani A, Chandra A, Chernew ME

Abstract

Recently, the Centers for Medicaid and Medicare Services announced a scheduled cut in Medicare physician fees of 27.4% for 2012. This cut stems from the sustainable growth rate (SGR) formula used by the physician-payment system. Implemented in 1998 to curb the growth in expenditures on physicians’ services, the SGR formula is used to determine annual adjustments to payments for those services. The SGR system sets a target for aggregate nationwide expenditures on the basis of growth in the per capita gross domestic product, growth in the number of Medicare Part B enrollees, changes in physicians’ fees, and changes in laws . . .

PMID: 22187962 [PubMed - as supplied by publisher]

Stemming the brain drain–a WHO global code of practice on international recruitment of health personnel.

N Engl J Med. 2011 Dec 22;365(25):2348-51

Authors: Taylor AL, Hwenda L, Larsen BI, Daulaire N

PMID: 22187983 [PubMed - indexed for MEDLINE]

The emperor of all maladies–the beginning of the beginning.

N Engl J Med. 2011 Dec 22;365(25):2353-5

Authors: Schwartz R

PMID: 22187984 [PubMed - indexed for MEDLINE]

INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy.

N Engl J Med. 2011 Dec 22;365(25):2377-88

Authors: Boyer O, Nevo F, Plaisier E, Funalot B, Gribouval O, Benoit G, Cong EH, Arrondel C, Tête MJ, Montjean R, Richard L, Karras A, Pouteil-Noble C, Balafrej L, Bonnardeaux A, Canaud G, Charasse C, Dantal J, Deschenes G, Deteix P, Dubourg O, Petiot P, Pouthier D, Leguern E, Guiochon-Mantel A, Broutin I, Gubler MC, Saunier S, Ronco P, Vallat JM, Alonso MA, Antignac C, Mollet G

Abstract

BACKGROUND: Charcot-Marie-Tooth neuropathy has been reported to be associated with renal diseases, mostly focal segmental glomerulosclerosis (FSGS). However, the common mechanisms underlying the neuropathy and FSGS remain unknown. Mutations in INF2 were recently identified in patients with autosomal dominant FSGS. INF2 encodes a formin protein that interacts with the Rho-GTPase CDC42 and myelin and lymphocyte protein (MAL) that are implicated in essential steps of myelination and myelin maintenance. We therefore hypothesized that INF2 may be responsible for cases of Charcot-Marie-Tooth neuropathy associated with FSGS.

METHODS: We performed direct genotyping of INF2 in 16 index patients with Charcot-Marie-Tooth neuropathy and FSGS who did not have a mutation in PMP22 or MPZ, encoding peripheral myelin protein 22 and myelin protein zero, respectively. Histologic and functional studies were also conducted.

RESULTS: We identified nine new heterozygous mutations in 12 of the 16 index patients (75%), all located in exons 2 and 3, encoding the diaphanous-inhibitory domain of INF2. Patients presented with an intermediate form of Charcot-Marie-Tooth neuropathy as well as a glomerulopathy with FSGS on kidney biopsy. Immunohistochemical analysis revealed strong INF2 expression in Schwann-cell cytoplasm and podocytes. Moreover, we demonstrated that INF2 colocalizes and interacts with MAL in Schwann cells. The INF2 mutants perturbed the INF2-MAL-CDC42 pathway, resulting in cytoskeleton disorganization, enhanced INF2 binding to CDC42 and mislocalization of INF2, MAL, and CDC42.

CONCLUSIONS: INF2 mutations appear to cause many cases of FSGS-associated Charcot-Marie-Tooth neuropathy, showing that INF2 is involved in a disease affecting both the kidney glomerulus and the peripheral nervous system. These findings provide new insights into the pathophysiological mechanisms linking formin proteins to podocyte and Schwann-cell function. (Funded by the Agence Nationale de la Recherche and others.).

PMID: 22187985 [PubMed - indexed for MEDLINE]

Clinical practice. Primary hyperparathyroidism.

N Engl J Med. 2011 Dec 22;365(25):2389-97

Authors: Marcocci C, Cetani F

PMID: 22187986 [PubMed - indexed for MEDLINE]

Focal segmental glomerulosclerosis.

N Engl J Med. 2011 Dec 22;365(25):2398-411

Authors: D’Agati VD, Kaskel FJ, Falk RJ

PMID: 22187987 [PubMed - indexed for MEDLINE]

Images in clinical medicine. Pneumopericardium associated with a peptic ulcer.

N Engl J Med. 2011 Dec 22;365(25):2412

Authors: Andrianov A, Nissenbaum MA

PMID: 22187988 [PubMed - indexed for MEDLINE]

Case records of the Massachusetts General Hospital. Case 39-2011. A woman in her 90s with unilateral ptosis.

N Engl J Med. 2011 Dec 22;365(25):2413-22

Authors: Venna N, Gonzalez RG, Zukerberg LR

PMID: 22187989 [PubMed - indexed for MEDLINE]

Implementation of the federal health information technology initiative.

N Engl J Med. 2011 Dec 22;365(25):2426-31

Authors: Blumenthal D

PMID: 22187990 [PubMed - indexed for MEDLINE]

Lebrikizumab treatment in adults with asthma.

N Engl J Med. 2011 Dec 22;365(25):2432; author reply 2433-4

Authors: Zeskind B

PMID: 22187992 [PubMed - indexed for MEDLINE]

Lebrikizumab treatment in adults with asthma.

N Engl J Med. 2011 Dec 22;365(25):2432-3; author reply 2433-4

Authors: Dutt N, Mohapatra PR, Saini V

PMID: 22187993 [PubMed - indexed for MEDLINE]

Lebrikizumab treatment in adults with asthma.

N Engl J Med. 2011 Dec 22;365(25):2433; author reply 2433-4

Authors: Song CH, Lee JK

PMID: 22187994 [PubMed - indexed for MEDLINE]

Genetics of glucocorticoids in asthma.

N Engl J Med. 2011 Dec 22;365(25):2434-5; author reply 2435-6

Authors: van den Berge M, Hiemstra PS, Postma DS

PMID: 22187996 [PubMed - indexed for MEDLINE]

Genetics of glucocorticoids in asthma.

N Engl J Med. 2011 Dec 22;365(25):2435; author reply 2435-6

Authors: Gerber AN

PMID: 22187997 [PubMed - indexed for MEDLINE]

Long interdialytic interval and mortality.

N Engl J Med. 2011 Dec 22;365(25):2436-7; author reply 2437-8

Authors: Pazmiño PA

PMID: 22187999 [PubMed - indexed for MEDLINE]

Long interdialytic interval and mortality.

N Engl J Med. 2011 Dec 22;365(25):2437; author reply 2437-8

Authors: Doorenbos CJ

PMID: 22188000 [PubMed - indexed for MEDLINE]

Long interdialytic interval and mortality.

N Engl J Med. 2011 Dec 22;365(25):2437; author reply 2437-8

Authors: van Stralen KJ, Wanner C, Jager KJ

PMID: 22188001 [PubMed - indexed for MEDLINE]

Contraception in primary care–embracing the Institute of Medicine challenge.

N Engl J Med. 2011 Dec 22;365(25):2438-9

Authors: Pace LE, Cohen L, Schwarz EB

PMID: 22188002 [PubMed - indexed for MEDLINE]

Vemurafenib for melanoma metastases to the brain.

N Engl J Med. 2011 Dec 22;365(25):2439-41

Authors: Rochet NM, Kottschade LA, Markovic SN

PMID: 22188003 [PubMed - indexed for MEDLINE]

Images in clinical medicine. Ectopic Cushing’s syndrome.

N Engl J Med. 2011 Dec 22;365(25):e46

Authors: Flohr F, Geddert H

PMID: 22188007 [PubMed - indexed for MEDLINE]

Interactive medical case. Breathless.

N Engl J Med. 2011 Dec 22;365(25):e47

Authors: Ross JJ, Vaidya A, Gavin MC, Morse D, Partridge AH

PMID: 22188008 [PubMed - indexed for MEDLINE]

Three Patients with Full Facial Transplantation.

N Engl J Med. 2011 Dec 28;

Authors: Pomahac B, Pribaz J, Eriksson E, Bueno EM, Diaz-Siso JR, Rybicki FJ, Annino DJ, Orgill D, Caterson EJ, Caterson SA, Carty MJ, Chun YS, Sampson CE, Janis JE, Alam DS, Saavedra A, Molnar JA, Edrich T, Marty FM, Tullius SG

Abstract

Unlike conventional reconstruction, facial transplantation seeks to correct severe deformities in a single operation. We report on three patients who received full-face transplants at our institution in 2011 in operations that aimed for functional restoration by coaptation of all main available motor and sensory nerves. We enumerate the technical challenges and postoperative complications and their management, including single episodes of acute rejection in two patients. At 6 months of follow-up, all facial allografts were surviving, facial appearance and function were improved, and glucocorticoids were successfully withdrawn in all patients.

PMID: 22204672 [PubMed - as supplied by publisher]

Confirming the CMS Nominee – Overcoming Poisonous Politics.

N Engl J Med. 2011 Dec 28;

Authors: Iglehart JK

Abstract

Will Senate Republicans, who unanimously opposed the Affordable Care Act (ACA), declare a truce with Democrats long enough to confirm Marilyn Tavenner as administrator of the Centers for Medicare and Medicaid Services (CMS)? That question looms over President Barack Obama’s nomination of Tavenner, who, though widely considered well-qualified, has also been pivotal in implementing the ACA as the CMS’s principal deputy administrator since February 2010. If confirmed, Tavenner would succeed Donald Berwick, whose nomination never received a public hearing because of Republicans’ strong opposition. To sidestep an unwinnable battle (confirmation requires 60 Senate votes), Obama granted Berwick a “recess appointment” . . .

PMID: 22204673 [PubMed - as supplied by publisher]

Achieving accountable care–”It’s not about the bike”.

N Engl J Med. 2012 Jan 12;366(2):e4

Authors: Walker J, McKethan A

PMID: 22204674 [PubMed - in process]

Building the path to accountable care.

N Engl J Med. 2011 Dec 29;365(26):2445-7

Authors: Fisher ES, McClellan MB, Safran DG

PMID: 22204720 [PubMed - indexed for MEDLINE]

Copyright and open access at the bedside.

N Engl J Med. 2011 Dec 29;365(26):2447-9

Authors: Newman JC, Feldman R

PMID: 22204721 [PubMed - indexed for MEDLINE]

The road less traveled.

N Engl J Med. 2011 Dec 29;365(26):2449-51

Authors: Fingold DR

PMID: 22204722 [PubMed - indexed for MEDLINE]

Low-molecular-weight heparin and mortality in acutely ill medical patients.

N Engl J Med. 2011 Dec 29;365(26):2463-72

Authors: Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF,

Abstract

BACKGROUND: Although thromboprophylaxis reduces the incidence of venous thromboembolism in acutely ill medical patients, an associated reduction in the rate of death from any cause has not been shown.

METHODS: We conducted a double-blind, placebo-controlled, randomized trial to assess the effect of subcutaneous enoxaparin (40 mg daily) as compared with placebo–both administered for 10±4 days in patients who were wearing elastic stockings with graduated compression–on the rate of death from any cause among hospitalized, acutely ill medical patients at participating sites in China, India, Korea, Malaysia, Mexico, the Philippines, and Tunisia. Inclusion criteria were an age of at least 40 years and hospitalization for acute decompensated heart failure, severe systemic infection with at least one risk factor for venous thromboembolism, or active cancer. The primary efficacy outcome was the rate of death from any cause at 30 days after randomization. The primary safety outcome was the rate of major bleeding during and up to 48 hours after the treatment period.

RESULTS: A total of 8307 patients were randomly assigned to receive enoxaparin plus elastic stockings with graduated compression (4171 patients) or placebo plus elastic stockings with graduated compression (4136 patients) and were included in the intention-to-treat population. The rate of death from any cause at day 30 was 4.9% in the enoxaparin group as compared with 4.8% in the placebo group (risk ratio, 1.0; 95% confidence interval [CI], 0.8 to 1.2; P=0.83). The rate of major bleeding was 0.4% in the enoxaparin group and 0.3% in the placebo group (risk ratio, 1.4; 95% CI, 0.7 to 3.1; P=0.35).

CONCLUSIONS: The use of enoxaparin plus elastic stockings with graduated compression, as compared with elastic stockings with graduated compression alone, was not associated with a reduction in the rate of death from any cause among hospitalized, acutely ill medical patients. (Funded by Sanofi; LIFENOX ClinicalTrials.gov number, NCT00622648.).

PMID: 22204723 [PubMed - indexed for MEDLINE]

Incorporation of bevacizumab in the primary treatment of ovarian cancer.

N Engl J Med. 2011 Dec 29;365(26):2473-83

Authors: Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, Mannel RS, Homesley HD, Fowler J, Greer BE, Boente M, Birrer MJ, Liang SX,

Abstract

BACKGROUND: Vascular endothelial growth factor is a key promoter of angiogenesis and disease progression in epithelial ovarian cancer. Bevacizumab, a humanized anti-vascular endothelial growth factor monoclonal antibody, has shown single-agent activity in women with recurrent tumors. Thus, we aimed to evaluate the addition of bevacizumab to standard front-line therapy.

METHODS: In our double-blind, placebo-controlled, phase 3 trial, we randomly assigned eligible patients with newly diagnosed stage III (incompletely resectable) or stage IV epithelial ovarian cancer who had undergone debulking surgery to receive one of three treatments. All three included chemotherapy consisting of intravenous paclitaxel at a dose of 175 mg per square meter of body-surface area, plus carboplatin at an area under the curve of 6, for cycles 1 through 6, plus a study treatment for cycles 2 through 22, each cycle of 3 weeks’ duration. The control treatment was chemotherapy with placebo added in cycles 2 through 22; bevacizumab-initiation treatment was chemotherapy with bevacizumab (15 mg per kilogram of body weight) added in cycles 2 through 6 and placebo added in cycles 7 through 22. Bevacizumab-throughout treatment was chemotherapy with bevacizumab added in cycles 2 through 22. The primary end point was progression-free survival.

RESULTS: Overall, 1873 women were enrolled. The median progression-free survival was 10.3 months in the control group, 11.2 in the bevacizumab-initiation group, and 14.1 in the bevacizumab-throughout group. Relative to control treatment, the hazard ratio for progression or death was 0.908 (95% confidence interval [CI], 0.795 to 1.040; P=0.16) with bevacizumab initiation and 0.717 (95% CI, 0.625 to 0.824; P<0.001) with bevacizumab throughout. At the time of analysis, 76.3% of patients were alive, with no significant differences in overall survival among the three groups. The rate of hypertension requiring medical therapy was higher in the bevacizumab-initiation group (16.5%) and the bevacizumab-throughout group (22.9%) than in the control group (7.2%). Gastrointestinal-wall disruption requiring medical intervention occurred in 1.2%, 2.8%, and 2.6% of patients in the control group, the bevacizumab-initiation group, and the bevacizumab-throughout group, respectively.

CONCLUSIONS: The use of bevacizumab during and up to 10 months after carboplatin and paclitaxel chemotherapy prolongs the median progression-free survival by about 4 months in patients with advanced epithelial ovarian cancer. (Funded by the National Cancer Institute and Genentech; ClinicalTrials.gov number, NCT00262847.).

PMID: 22204724 [PubMed - indexed for MEDLINE]

A phase 3 trial of bevacizumab in ovarian cancer.

N Engl J Med. 2011 Dec 29;365(26):2484-96

Authors: Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, Carey MS, Beale P, Cervantes A, Kurzeder C, du Bois A, Sehouli J, Kimmig R, Stähle A, Collinson F, Essapen S, Gourley C, Lortholary A, Selle F, Mirza MR, Leminen A, Plante M, Stark D, Qian W, Parmar MK, Oza AM,

Abstract

BACKGROUND: Angiogenesis plays a role in the biology of ovarian cancer. We examined the effect of bevacizumab, the vascular endothelial growth factor inhibitor, on survival in women with this disease.

METHODS: We randomly assigned women with ovarian cancer to carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body-surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease. Outcome measures included progression-free survival, first analyzed per protocol and then updated, and interim overall survival.

RESULTS: A total of 1528 women from 11 countries were randomly assigned to one of the two treatment regimens. Their median age was 57 years; 90% had epithelial ovarian cancer, 69% had a serous histologic type, 9% had high-risk early-stage disease, 30% were at high risk for progression, and 70% had stage IIIC or IV ovarian cancer. Progression-free survival (restricted mean) at 36 months was 20.3 months with standard therapy, as compared with 21.8 months with standard therapy plus bevacizumab (hazard ratio for progression or death with bevacizumab added, 0.81; 95% confidence interval, 0.70 to 0.94; P=0.004 by the log-rank test). Nonproportional hazards were detected (i.e., the treatment effect was not consistent over time on the hazard function scale) (P<0.001), with a maximum effect at 12 months, coinciding with the end of planned bevacizumab treatment and diminishing by 24 months. Bevacizumab was associated with more toxic effects (most often hypertension of grade 2 or higher) (18%, vs. 2% with chemotherapy alone). In the updated analyses, progression-free survival (restricted mean) at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab (P=0.04 by log-rank test); in patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression-free survival (restricted mean) at 42 months of 14.5 months with standard therapy alone and 18.1 months with bevacizumab added, with respective median overall survival of 28.8 and 36.6 months.

CONCLUSIONS: Bevacizumab improved progression-free survival in women with ovarian cancer. The benefits with respect to both progression-free and overall survival were greater among those at high risk for disease progression. (Funded by Roche and others; ICON7 Controlled-Trials.com number, ISRCTN91273375.).

PMID: 22204725 [PubMed - indexed for MEDLINE]

Proprotein convertases in health and disease.

N Engl J Med. 2011 Dec 29;365(26):2507-18

Authors: Artenstein AW, Opal SM

PMID: 22204726 [PubMed - indexed for MEDLINE]

Images in clinical medicine. A head shot.

N Engl J Med. 2011 Dec 29;365(26):2519

Authors: Safarova MS, Ezhov MV

PMID: 22204727 [PubMed - indexed for MEDLINE]