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Patients with advanced non-small-cell lung cancer survive four months longer with fewer side effects on an immunotherapy drug called atezolizumab compared to chemotherapy, according to a phase 3 clinical trial published in The Lancet. The trial enrolled 1225 advanced non-small-cell lung cancer patients who have no more treatment options, but this study used an early analysis of the first 850 patients from the trial. Half of the group were given atezolizumab and the other half were given docetaxel chemotherapy, which is the standard treatment for advanced non-small-cell lung cancer. Patients given atezolizumab - a drug that blocks the programmed death ligand 1 (PD-L1) protein - survived for an average of 13.8 months, compared with 9.6 months for those on chemotherapy. As well as the benefits in survival, atezolizumab also had fewer side effects than chemotherapy with 14.8% (90 of 609) of those given the drug having grade three or four side effects compared with 42.7% (247 of 578) of those given chemotherapy. However, 46 (of 609, 7.6%) of the patients given atezolizumab still gave up treatment due to side effects, as well as 108 (of 578 patients, 18.7%) of those on chemotherapy. "Lung cancer is the most common cancer affecting 1.8 million people each year worldwide. It is also the leading cause of cancer death worldwide and survival remains stubbornly low. Recently, important advances in the treatment of the disease have come from immunotherapies that target the PD-L1 and PD-1 pathway," said Dr Achim Rittmeyer, lead author, University Goettingen, Germany. "Atezolizumab reinvigorates patients' immune systems against cancer, and our trial has shown that this has significant results for their survival." [1] In the trial the researchers also studied the amount of PD-L1 protein on the patients' cancer and immune cells and how long patients survived for on each treatment. They found that the drug worked best for patients with the highest levels of the PD-L1 protein on their cells - more than doubling survival compared with those given chemotherapy (20.5 months compared with 8.9 months overall survival) - but still increased survival for those with little to no levels of the protein by three and a half months (12.6 compared with 8.9 months overall survival). "This is the first phase 3 trial of a PD-L1-directed immunotherapy in lung cancer. The fact that it improves survival in patients with all categories of PD-L1 expression is highly encouraging and adds to the already known benefits of immunotherapy in lung cancer." said Dr David Gandara, senior author, UC Davis Comprehensive Cancer Center, USA. [1] Other immunotherapies for non-small-cell lung cancer, such as nivolumab and pembrolizumab, are designed to block PD-L1's counterpart, the programmed cell death protein 1 (PD-1) which is located on the immune cell surface. Normally the PD-L1 and PD-1 proteins signal to one another to activate the immune system to attack tumours. It's thought that the extra PD-L1 protein on some cancer cells' surfaces helps them hide from the immune system, meaning it cannot find and kill cancer cells as usual. But by blocking the extra PD-L1 protein, atezolizumab may unveil the cells to the immune system so they can be attacked and destroyed. The study is the first phase 3 trial of a PD-L1 inhibitor drug and has shown longer survival than trials of PD-1 inhibitors. The authors note that the trial was 'open label', meaning that patients and doctors knew whether or not they were being given immunotherapy. In addition, after the study treatment finished some (17%) of those given chemotherapy on the trial were prescribed another immunotherapy drug (mostly nivolumab) by their own doctor. This could have increased survival in the chemotherapy group, meaning that the difference between two groups may be greater than shown in this study. Writing in a linked Comment, Professor Elisabeth Quoix, Hôpitaux Universitaires de Strasbourg, France, said: "After decades of disappointments with non-specific vaccines or more recently tumor associated antigen specific vaccines, immunotherapy with antibodies that target the PD-L1 and PD-1 pathway have emerged as a major therapeutic breakthrough. This treatment improves the prognosis of patients with non-small-cell lung cancer that cannot benefit from targeted therapies... The time in which chemotherapy will no more be the mainstay of treatment of metastatic non-small-cell lung cancer is perhaps not so far away. Nevertheless... Several points need to be clarified, such as the optimum therapeutic schedule and the optimum duration of treatment, to limit treatment costs. Additionally combinations of different immunotherapies might be of interest." The study was funded by F. Hoffman-La Roche Ltd and Genentech Ltd.. It was conducted by scientists from Lungenfachklinik Immenhausen, Aix Marseille Universite, Sungkyunkwan University School of Medicine, Seconda Università degli Studi di Napoli, Asklepios Fachkliniken München-Gauting, Karmanos Cancer Institute/Wayne State University, Aichi Cancer Center Hospital, Institute M. Sklodowska-Curie, Hospital Regional Universitario Carlos Haya, AOU San Gerardo, Minnesota Oncology, Southern California Permanente Medical Group, PUCRS School of Medicine, University of California, Centro Internacional de Estudios Clinicos, European Institute of Oncology, Istanbul University Cerrahpasa Medical Faculty Hospital, Seoul National University Bundang Hospital, Genentech Inc. and UC Davis Comprehensive Cancer Center. A declaration of interests is available in the Article. [ 1] Quote direct from author and cannot be found in the text of the Article. IF YOU WISH TO PROVIDE A LINK FOR YOUR READERS, PLEASE USE THE FOLLOWING, WHICH WILL GO LIVE AT THE TIME THE EMBARGO LIFTS: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32517-X/fulltext


Five new JAMA and JAMA Internal Medicine studies published online compare a variety of health outcomes in men with low testosterone who used testosterone. Four of the five testosterone-related studies are from the Testosterone Trials, a group of placebo-controlled, coordinated trials designed to determine the efficacy of testosterone gel use by men 65 or older with low testosterone for no apparent reason other than age. The studies examined the health outcomes of memory and cognitive function, bone density, coronary artery plaque volume and anemia. A fifth study, which was not part of the Testosterone Trials, examined the association of testosterone replacement therapy with cardiovascular outcomes. In this study, researchers tested if treating older men with low testosterone with a testosterone gel for a year would slow the progression of coronary artery plaque volume compared with a placebo gel. The study included 138 men (73 who received testosterone gel and 65 who received placebo gel). Findings: Among the men, using testosterone gel for one year compared with placebo gel increased the amount of coronary artery noncalcified plaque, an early sign of increased risk of heart problems. Larger studies are needed to understand the clinical implications of this finding. Authors: Peter J. Snyder, M.D., of the University of Pennsylvania, Philadelphia, and colleagues as part of the Testosterone Trials. To place an electronic embedded link to this study in your story: This link will be live at the embargo time: http://jamanetwork. Researchers also wanted to know if older men with low testosterone who used testosterone gel for one year compared with placebo gel improved their memory and cognitive function. Among 493 men with age-associated memory impairment (AAMI), 247 received testosterone gel and 246 received placebo for one year. Findings: Using testosterone gel for one year compared with placebo gel was not associated with improved memory or cognitive function. Authors: Peter J. Snyder, M.D., of the University of Pennsylvania, Philadelphia, and colleagues as part of the Testosterone Trials. To place an electronic embedded link to this study in your story: This link will be live at the embargo time: http://jamanetwork. In this study, researchers wanted to determine if older men with low testosterone and mild anemia could improve their anemia by using testosterone gel for one year. Of the 788 men enrolled in the Testosterone Trials, 126 were anemic at the start and, of those, 62 had anemia of known causes. Findings: Testosterone gel increased hemoglobin levels and corrected the anemia (of both known and unknown causes) in older men with low testosterone more than placebo gel. Authors: Peter J. Snyder, M.D., of the University of Pennsylvania, Philadelphia, and coauthors as part of the Testosterone Trials. To place an electronic embedded link to this study in your story: This link will be live at the embargo time: http://jamanetwork. Another question researchers examined was whether using testosterone gel would help older men with low testosterone improve their bone density and strength. This study included 211 men, of whom 110 received testosterone gel and 101 got the placebo gel. Findings: Using testosterone gel for one year by older men with low testosterone increased bone density and strength compared with placebo, more so in the spine than hip and more so in trabecular bone than cortical-rich peripheral bone. Authors: Peter J. Snyder, M.D., of the University of Pennsylvania, Philadelphia, and coauthors as part of the Testosterone Trials. To place an electronic embedded link to this study in your story: This link will be live at the embargo time: http://jamanetwork. This study, which was not part of the Testosterone Trials, examined the association between testosterone replacement therapy (TRT) and cardiovascular outcomes in men 40 or older with low testosterone at Kaiser Permanente California. The study, which was observational, included 8,808 men who were ever prescribed TRT given by injection, orally or topically. Findings: Among men with low testosterone, dispensed testosterone prescriptions were associated with a lower risk of cardiovascular outcomes over a median follow-up of about three years. Authors: T. Craig Cheetham, Pharm.D., M.S., of the Southern California Permanente Medical Group, Pasadena, and coauthors. To place an electronic embedded link to this study in your story: This link will be live at the embargo time: http://jamanetwork. Editor's Note: Please see the articles for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc. Media Advisory: To contact Peter J. Snyder, M.D., email Abbey Anderson at Abbey.Anderson@uphs.upenn.edu or call 215-349-8369. To contact T. Craig Cheetham, Pharm.D. , M.S., email Vincent Staupe at vincent.p.staupe@kp.org or call 510-267-7364. Related video: There will be a JAMA Report video story on testosterone treatment and health outcomes for you to use in your report. Video will be available under embargo at this link and include broadcast-quality downloadable video files, B-roll, scripts and other images. Please contact JAMA Network Media Relations at mediarelations@jamanetwork.org if there are questions. Related materials: The JAMA editorial, "Testosterone and Male Aging," by David J. Handelsman, M.B.B.S., Ph.D., F.R.A.C.P., F.A.H.M.S., of the University of Sydney and Concord Hospital, Sydney, Australia; the JAMA Internal Medicine editorial, "Further Elucidation of the Potential Benefits of Testosterone Therapy in Older Men," by Eric Orwoll, M.D., of the Oregon Health & Science University, Portland; and the JAMA Internal Medicine editorial, "Addressing Ethical Lapses in Research," by Bernard Lo, M.D., of the Greenwell Foundation, New York, and JAMA Internal Medicine deputy editor Deborah Grady, M.D., M.P.H., of the University of California, San Francisco, also are available on the For The Media website


Wu B.U.,Southern California Permanente Medical Group | Pandol S.J.,Cedars Sinai Medical Center | Liu I.-L.A.,Kaiser Permanente
Gut | Year: 2015

Objective: To characterise the relationship between simvastatin and risk of acute pancreatitis (AP).Design: We conducted a retrospective cohort study (2006-2012) on data from an integrated healthcare system in southern California. Exposure to simvastatin was calculated from time of initial dispensation until 60 days following prescription termination. AP cases were defined by ICD-9 CM 577.0 and serum lipase≥3 times normal. Patients were censored at death, last follow-up, and onset of AP or end-of-study. Incidence rate of pancreatitis among simvastatin users was compared with the adult reference population. Robust Poisson regression was used to generate risk ratio (RR) estimates for simvastatin use adjusted for age, gender, race/ethnicity, gallstone-related disorders, hypertriglyceridaemia, smoking and alcohol dependence. Analysis was repeated for atorvastatin.Results: Among 3 967 859 adult patients (median duration of follow-up of 3.4 years), 6399 developed an initial episode of AP. A total of 707 236 patients received simvastatin during the study period. Patients that received simvastatin were more likely to have gallstone-related disorders, alcohol dependence or hypertriglyceridaemia compared with the reference population. Nevertheless, risk of AP was significantly reduced with simvastatin use, crude incidence rate ratio 0.626 (95% CL 0.588, 0.668), p<0.0001. In multivariate analysis, simvastatin was independently associated with reduced risk of pancreatitis, adjusted RR 0.29 (95% CL 0.27, 0.31) after adjusting for age, gender, race/ethnicity, gallstone disorders, alcohol dependence, smoking and hypertriglyceridaemia. Similar results were noted with atorvastatin, adjusted RR 0.33 (0.29, 0.38).Conclusions: Use of simvastatin was independently associated with reduced risk of AP in this integrated healthcare setting. Similar findings for atorvastatin suggest a possible class effect.


Macy E.,Southern California Permanente Medical Group | Ngor E.W.,Kaiser Permanente
Journal of Allergy and Clinical Immunology: In Practice | Year: 2013

Background: Penicillin skin testing is rarely used to undiagnose penicillin "allergy" in the United States, partially because of concern that commercially available materials are inadequate. Objective: We determined whether skin testing with only commercially available penicilloyl-poly-lysine and penicillin followed by an oral amoxicillin challenge, if skin test-negative, can safely identify clinically significant penicillin allergy. Methods: Five hundred sequential persons with positive history of penicillin "allergy" were evaluated by skin testing with penicilloyl-poly-lysine and penicillin between June 8, 2010, and March 29, 2012. All persons with negative skin tests were given an oral amoxicillin challenge and observed for 1 hour. Results: Persons undergoing penicillin allergy testing were representative of all health plan members with penicillin allergy. Only 4 persons (0.8%; 95% CI, 0.32%-2.03%) had a positive skin test result. Only 4 persons (0.8%; 95% CI, 0.32%-2.03%) had an acute objective oral amoxicillin challenge reaction. Fifteen persons (3.0%; 95% CI, 1.83%-4.98%) had subjective oral challenge reactions, either acute transient itching or dizziness. All were women and 11 (73.3%) had multiple drug intolerance syndrome. None had severe reactions or objective signs. These were not considered to be positive challenge reactions. Sixty-eight subjects (13.6%) who were negative on testing were exposed to 88 courses of penicillins during 90 days of follow-up. New reactions were reported after 4 courses (4.5%), 3 (75%) occurring in subjects with multiple drug intolerance syndrome. Conclusions: Penicillin skin testing, using only penicilloyl-poly-lysine and penicillin, followed by oral amoxicillin challenge, if negative, can safely identify clinically significant IgE-mediated penicillin allergy in patients who use health care in the United States at this time. © 2013 American Academy of Allergy, Asthma & Immunology.


Encapsulated follicular variant of papillary thyroid carcinoma is a common thyroid gland cancer, with a highly indolent behavior. Recently, reclassification as a non-malignant neoplasm has been proposed. There is no comprehensive, community hospital based longitudinal evaluation of encapsulated follicular variant of papillary thyroid carcinoma. Ninety-four cases of encapsulated follicular variant of papillary thyroid carcinoma were identified in a review of all thyroid gland surgeries performed in 2002 within the Southern California Permanente Medical Group. All histology slides were reviewed and follow-up obtained. Seventy-five women and nineteen men, aged 20-80 years (mean 45.6 years), had a single (n=61), multiple (same lobe; n=20), or bilateral (n=13) tumor(s), ranging in size from 0.7 to 9.5 cm in diameter (mean 3.3 cm). Histologically, all cases demonstrated a well-formed tumor capsule, with capsular and/or lymphovascular invasion in 17 and no invasion in 77 cases. Lymph node metastases were not identified. The tumors had a follicular architecture, without necrosis or >3 mitoses/10 high-power fields (HPFs). Classical papillary thyroid carcinoma nuclear features were seen in at least three HPFs per 3 mm of tumor diameter, including enlarged, elongated, crowded, and overlapping nuclei, irregular nuclear contours, nuclear grooves, and nuclear chromatin clearing. Lobectomy alone (n=41), thyroidectomy alone (n=34), or completion thyroidectomy (n=19) was the initial treatment combined with post-op radioablative iodine in 25 patients. All patients were without evidence of disease after a median follow-up of 11.8 years. Encapsulated follicular variant of papillary thyroid carcinoma showed benign behavior, supporting conservative surgery alone and reclassification of these tumors to Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP). © 2016 USCAP, Inc All rights reserved.


Macy E.,Southern California Permanente Medical Group
Current allergy and asthma reports | Year: 2014

Penicillin is the most common beta-lactam antibiotic allergy and the most common drug class allergy, reported in about 8% of individuals using health care in the USA. Only about 1% of individuals using health care in the USA have a cephalosporin allergy noted in their medical record, and other specific non-penicillin, non-cephalosporin beta-lactam allergies are even rarer. Most reported penicillin allergy is not associated with clinically significant IgE-mediated reactions after penicillin rechallenge. Un-verified penicillin allergy is a significant and growing public health problem. Clinically significant IgE-mediated penicillin allergy can be safely confirmed or refuted using skin testing with penicilloyl-poly-lysine and native penicillin G and, if skin test is negative, an oral amoxicillin challenge. Acute tolerance of an oral therapeutic dose of a penicillin class antibiotic is the current gold standard test for a lack of clinically significant IgE-mediated penicillin allergy. Cephalosporins and other non-penicillin beta-lactams are widely, safely, and appropriately used in individuals, even with confirmed penicillin allergy. There is little, if any, clinically significant immunologic cross-reactivity between penicillins and other beta-lactams. Routine cephalosporin skin testing should be restricted to research settings. It is rarely needed clinically to safely manage patients and has unclear predictive value at this time. The use of alternative cephalosporins, with different side chains, is acceptable in the setting of a specific cephalosporin allergy. Carbapenems and monobactams are also safely used in individuals with confirmed penicillin allergy. A certain predictable, but low, rate of adverse reactions will occur with all beta-lactam antibiotic use both pre- and post-beta-lactam allergy evaluations.


Macy E.,Southern California Permanente Medical Group | Contreras R.,Kaiser Permanente
Journal of Allergy and Clinical Immunology | Year: 2015

Background Few studies have provided population-based, route-specific data on allergy to cephalosporin or incidence of serious adverse drug reactions (ADRs).Objective We investigated the incidence of new reports of cephalosporin-associated "allergy" and serious ADRs.Methods We identified all members of the Kaiser Permanente Southern California health plan given cephalosporins (from January 1, 2010, through December 31, 2012), all new reports of cephalosporin-associated allergy, and all serious ADRs.Results There were 622,456 health plan members exposed to 901,908 courses of oral cephalosporins and 326,867 members exposed to 487,630 courses of parenteral cephalosporins over the 3-year study period. New reports of allergy to cephalosporin were more frequent among women (0.56%; 95% CI, 0.54% to 0.57%) than among men (0.43%; 95% CI, 0.41% to 0.44%) per course (P <.0001). The most frequent serious cephalosporin-associated ADRs were Clostridium difficile infection within 90 days (0.91%), nephropathy within 30 days (0.15%), and all-cause death within 1 day (0.10%). None correlated with history of drug allergy. Physician-documented cephalosporin-associated anaphylaxis occurred with 5 oral exposures (95% CI, 1/1,428,571-1/96,154) and 8 parenteral exposures (95% CI, 1/200,000-1/35,971) (P =.0761). There were 3 documented cephalosporin-associated serious cutaneous adverse reactions (95% CI, 0-1 in 217,291). All were associated with the use of another antibiotic at the same time as cephalosporin.Conclusions Cephalosporins are widely and safely used, even in individuals with a history of penicillin allergy. Physician-documented cephalosporin-associated anaphylaxis and serious cutaneous adverse reactions are rare compared with C difficile infection within 90 days, nephropathy within 30 days, and all-cause death within 1 day. © 2014 American Academy of Allergy, Asthma & Immunology.


Macy E.,Southern California Permanente Medical Group | Contreras R.,Kaiser Permanente
Journal of Allergy and Clinical Immunology | Year: 2014

Background Penicillin is the most common drug "allergy" noted at hospital admission, although it is often inaccurate. Objective We sought to determine total hospital days, antibiotic exposures, and the prevalence rates of Clostridium difficile, methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE) in patients with and without penicillin "allergy" at hospital admission. Methods We performed a retrospective, matched cohort study of subjects admitted to Kaiser Foundation hospitals in Southern California during 2010 through 2012. Results It was possible to match 51,582 (99.6% of all possible cases) unique hospitalized subjects with penicillin "allergy" to 2 unique discharge diagnosis category-matched, sex-matched, age-matched, and date of admission-matched control subjects each. Cases with penicillin "allergy" averaged 0.59 (9.9%; 95% CI, 0.47-0.71) more total hospital days during 20.1 ± 10.5 months of follow-up compared with control subjects. Cases were treated with significantly more fluoroquinolones, clindamycin, and vancomycin (P <.0001) for each antibiotic compared with control subjects. Cases had 23.4% (95% CI, 15.6% to 31.7%) more C difficile, 14.1% (95% CI, 7.1% to 21.6%) more MRSA, and 30.1% (95% CI, 12.5% to 50.4%) more VRE infections than expected compared with control subjects. Conclusions A penicillin "allergy" history, although often inaccurate, is not a benign finding at hospital admission. Subjects with a penicillin "allergy" history spend significantly more time in the hospital. Subjects with a penicillin "allergy" history are exposed to significantly more antibiotics previously associated with C difficile and VRE. Drug "allergies" in general, but most those notably to penicillin, are associated with increased hospital use and increased C difficile, MRSA, and VRE prevalence. © 2013 American Academy of Allergy, Asthma and Immunology.


Macy E.,Southern California Permanente Medical Group
Current Opinion in Allergy and Clinical Immunology | Year: 2015

Purpose of review Unverified penicillin allergy is being increasingly recognized as a public health concern. The ideal protocol for verifying true clinically significant IgE-mediated penicillin allergy needs to use only commercially available materials, be well tolerated and easy to perform in both the inpatient and outpatient settings, and minimize false-positive determinations. This review concentrates on articles published in 2013 and 2014 that present new data relating to the diagnosis and management of penicillin allergy. Recent findings Penicillin allergy can be safely evaluated at this time, in patients with an appropriate clinical history of penicillin allergy, using only penicilloyl-poly-lysine and native penicillin G as skin test reagents, if an oral challenge with amoxicillin 250mg, followed by 1 h of observation, is given to all skin test negative individuals. Summary Millions of individuals falsely labeled with penicillin allergy need to be evaluated to safely allow them to use penicillin-class antibiotics and avoid morbidity associated with penicillin avoidance. Further research is needed to determine optimal protocol(s). There will still be a 1-2% rate of adverse reactions reported with all future therapeutic penicillin-class antibiotic use, even with optimal methods used to determine acute penicillin tolerance. Only a small minority of these new reactions will be IgE-mediated. © 2015 Wolters Kluwer Health, Inc.


Csintalan R.P.,Southern California Permanente Medical Group
The journal of knee surgery | Year: 2013

Both nonoperative and operative treatments for anterior cruciate ligament (ACL) deficient knees in skeletally immature patients have reported potentially negative outcomes. This study describes primary ACL reconstruction patients with open physes and their concurrent injuries and evaluates whether these patients are at a higher early risk of revision and reoperation than closed physes patients. A retrospective analysis of prospectively collected data was performed. Patients were identified using an ACL Reconstruction Registry. Summary statistics comparing open and closed physes patients of similar ages in regard to patient characteristics and incidence of early revision and reoperation are provided. Adjusted Cox regression models assessed risk of early revision and reoperation for open physes patients. Of 1,867 patients identified, 232 (12.4%) patients had open physes and 1,635 (87.6%) patients had closed physes. Patients with open physes were younger, less likely to be women, and had less medial meniscal injuries than closed physes patients. No significant differences were observed in cartilage injury, overall menisci injury and repair, and early revision and reoperation rate. According to the our results, no significant differences in risk of early revision or early reoperation in open physes compared with closed physes patients when adjusting for age were observed, nor were there any reoperations for physeal closure. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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