PCOM Library / Hot Topics in Research / Archive for "Internal Medicine"

Category: Internal Medicine

Hot Topics: Ultrasound Therapy Reduces Parkinson’s Tremors

katheride Central Nervous System Disorders, Hot Topics in Research, Neurology

Safety and Efficacy of Focused Ultrasound Thalamotomy for Patients With Medication-Refractory, Tremor-Dominant Parkinson Disease: A Randomized Clinical Trial
Bond, A. E., Shah, B. B., Huss, D. S., et al. (2017). Safety and efficacy of focused ultrasound thalamotomy for patients with medication-refractory, tremor-dominant parkinson disease: A randomized clinical trial. JAMA Neurology. doi:10.1001/jamaneurol.2017.3098
Importance  Clinical trials have confirmed the efficacy of focused ultrasound (FUS) thalamotomy in essential tremor, but its effectiveness and safety for managing tremor-dominant Parkinson disease (TDPD) is unknown.
Objective  To assess safety and efficacy at 12-month follow-up, accounting for placebo response, of unilateral FUS thalamotomy for patients with TDPD.
Design, Setting, and Participants  Of the 326 patients identified from an in-house database, 53 patients consented to be screened. Twenty-six were ineligible, and 27 were randomized (2:1) to FUS thalamotomy or a sham procedure at 2 centers from October18, 2012, to January 8, 2015. The most common reasons for disqualification were withdrawal (8 persons [31%]), and not being medication refractory (8 persons [31%]). Data were analyzed using intention-to-treat analysis, and assessments were double-blinded through the primary outcome.
Interventions  Twenty patients were randomized to unilateral FUS thalamotomy, and 7 to sham procedure. The sham group was offered open-label treatment after unblinding.
Main Outcomes and Measures  The predefined primary outcomes were safety and difference in improvement between groups at 3 months in the on-medication treated hand tremor subscore from the Clinical Rating Scale for Tremor (CRST). Secondary outcomes included descriptive results of Unified Parkinson’s Disease Rating Scale (UPDRS) scores and quality of life measures.
Results  Of the 27 patients, 26 (96%) were male and the median age was 67.8 years (interquartile range [IQR], 62.1-73.8 years). On-medication median tremor scores improved 62% (IQR, 22%-79%) from a baseline of 17 points (IQR, 10.5-27.5) following FUS thalamotomy and 22% (IQR, −11% to 29%) from a baseline of 23 points (IQR, 14.0-27.0) after sham procedures; the between-group difference was significant (Wilcoxon P = .04). On-medication median UPDRS motor scores improved 8 points (IQR, 0.5-11.0) from a baseline of 23 points (IQR, 15.5-34.0) following FUS thalamotomy and 1 point (IQR, −5.0 to 9.0) from a baseline of 25 points (IQR, 15.0-33.0) after sham procedures. Early in the study, heating of the internal capsule resulted in 2 cases (8%) of mild hemiparesis, which improved and prompted monitoring of an additional axis during magnetic resonance thermometry. Other persistent adverse events were orofacial paresthesia (4 events [20%]), finger paresthesia (1 event [5%]), and ataxia (1 event [5%]).
Conclusions and Relevance  Focused ultrasound thalamotomy for patients with TDPD demonstrated improvements in medication-refractory tremor by CRST assessments, even in the setting of a placebo response.

Hot Topics: Atrial Fibrillation May Be Commonly Undiganosed

katheride Cardiology, Hot Topics in Research

Incidence of Previously Undiagnosed Atrial Fibrillation Using Insertable Cardiac Monitors in a High-Risk Population: The REVEAL AF Study
Reiffel JA, Verma A, Kowey PR, al e. Incidence of previously undiagnosed atrial fibrillation using insertable cardiac monitors in a high-risk population: The reveal af study. JAMA Cardiology. 2017. http://dx.doi.org/10.1001/jamacardio.2017.3180.
Importance  In approximately 20% of atrial fibrillation (AF)–related ischemic strokes, stroke is the first clinical manifestation of AF. Strategies are needed to identify and therapeutically address previously undetected AF.
Objective  To quantify the incidence of AF in patients at high risk for but without previously known AF using an insertable cardiac monitor.
Design, Setting, and Participants  This prospective, single-arm, multicenter study was conducted from November 2012 to January 2017. Visits took place at 57 centers in the United States and Europe. Patients with a CHADS2 score of 3 or greater (or 2 with at least 1 additional risk factor) were enrolled. Approximately 90% had nonspecific symptoms potentially compatible with AF, such as fatigue, dyspnea, and/or palpitations.
Exposures  Patients underwent monitoring with an insertable cardiac monitor for 18 to 30 months.
Main Outcomes and Measures  The primary end point was adjudicated AF lasting 6 or more minutes and was assessed at 18 months. Other analyses included detection rates at points from 30 days to 30 months and among CHADS2 score subgroups. Median time from insertion to detection and the percentage of patients subsequently prescribed oral anticoagulation therapy was also determined.
Results  A total of 446 patients were enrolled; 233 (52.2%) were male, and the mean (SD) age was 71.5 (9.9) years. A total of 385 patients (86.3%) received an insertable cardiac monitor, met the primary analysis cohort definition, and were observed for a mean (SD) period of 22.5 (7.7) months. The detection rate of AF lasting 6 or more minutes at 18 months was 29.3%. Detection rates at 30 days and 6, 12, 24, and 30 months were 6.2%, 20.4%, 27.1%, 33.6%, and 40.0%, respectively. At 18 months, AF incidence was similar among patients with CHADS2 scores of 2 (24.7%; 95% CI, 17.3-31.4), 3 (32.7%; 95% CI, 23.8-40.7), and 4 or greater (31.7%; 95% CI, 22.0-40.3) (P = .23). Median (interquartile) time from device insertion to first AF episode detection was 123 (41-330) days. Of patients meeting the primary end point, 13 (10.2%) had 1 or more episodes lasting 24 hours or longer, and oral anticoagulation therapy was prescribed for 72 patients (56.3%).
Conclusions and Relevance  The incidence of previously undiagnosed AF may be substantial in patients with risk factors for AF and stroke. Atrial fibrillation would have gone undetected in most patients had monitoring been limited to 30 days. Further trials regarding the value of detecting subclinical AF and of prophylactic therapies are warranted.

Hot Topics: Mass Spectroscopy “Cancer Pen” Could Quickly Detect Tumors

katheride Hot Topics in Research, Oncology, Uncategorized

Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system
Zhang J, Rector J, Lin JQ, et al. Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system. Science Translational Medicine. 2017;9(406). http://dx.doi.org/10.1126/scitranslmed.aan3968
Conventional methods for histopathologic tissue diagnosis are labor- and time-intensive and can delay decision-making during diagnostic and therapeutic procedures. We report the development of an automated and biocompatible handheld mass spectrometry device for rapid and nondestructive diagnosis of human cancer tissues. The device, named MasSpec Pen, enables controlled and automated delivery of a discrete water droplet to a tissue surface for efficient extraction of biomolecules. We used the MasSpec Pen for ex vivo molecular analysis of 20 human cancer thin tissue sections and 253 human patient tissue samples including normal and cancerous tissues from breast, lung, thyroid, and ovary. The mass spectra obtained presented rich molecular profiles characterized by a variety of potential cancer biomarkers identified as metabolites, lipids, and proteins. Statistical classifiers built from the histologically validated molecular database allowed cancer prediction with high sensitivity (96.4%), specificity (96.2%), and overall accuracy (96.3%), as well as prediction of benign and malignant thyroid tumors and different histologic subtypes of lung cancer. Notably, our classifier allowed accurate diagnosis of cancer in marginal tumor regions presenting mixed histologic composition. Last, we demonstrate that the MasSpec Pen is suited for in vivo cancer diagnosis during surgery performed in tumor-bearing mouse models, without causing any observable tissue harm or stress to the animal. Our results provide evidence that the MasSpec Pen could potentially be used as a clinical and intraoperative technology for ex vivo and in vivo cancer diagnosis.

Hot Topics: Cardiovascular Event Risk Lowered by Reducing Inflammation Alone

katheride Cardiology, Hot Topics in Research

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease
Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017. http://dx.doi.org/10.1056/NEJMoa1707914.

BACKGROUND

Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved.

METHODS

We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death.

RESULTS

At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31).

CONCLUSIONS

Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.)

Hot Topics: Combination of Traditional and New Drugs Effective for Esophageal Cancer

katheride Hot Topics in Research, Oncology

Inhibition of pRB pathway differentially modulates apoptosis in esophageal cancer cells
Soletti RC, Biasoli D, Rodrigues NALV, et al. Inhibition of pRB pathway differentially modulates apoptosis in esophageal cancer cells. Translational Oncology. 2017;10(5):726-733. doi: http://dx.doi.org/10.1016/j.tranon.2017.06.008.
Esophageal cancer is the sixth most common cause of cancer-related death worldwide. Current chemotherapy regimens include a combination of 5-fluorouracil (5-FU) and cisplatin, but more efficient therapy strategies are needed to increase 5-year survival. Alterations in the signaling pathway of the tumor suppressor gene Rb-1, which encodes a phosphoprotein (pRB) that negatively regulates the G1/S transition of the cell cycle, are present in 70% of all tumors, but its role in esophageal cancer is still unclear. Most of these are alterations leading to up-regulation of the activity of cyclin-dependent kinases (CDKs) to phosphorylate pRB, which suggests that keeping the wild type pRB phosphorylated might be advantageous. Besides proliferation, pRB also regulates apoptosis induced by tumor necrosis factor-alpha (TNF-α) and DNA-damage. We investigated the status of phosphorylation of pRB along esophageal tumorigenesis stages, as well as whether hyperphosphorylation of pRB could suppress apoptosis induced by cisplatin, 5-FU, or TNF-α in esophageal cancer cells. pRB phosphorylation increased progressively from normal esophageal tissue to metaplasia and adenocarcinoma, suggesting that pRB phosphorylation increases along esophageal tumor stages. When RB-1 was knocked down or CDK inhibitors reduced the levels of phosphorylated pRB, opposite apoptotic effects were observed, depending on the combination of drugs tested: whereas TNF-α- and cisplatin-induced apoptosis increased, 5-FU-induced apoptosis decreased. Taken together, these data suggest that pRB plays a role in esophageal adenocarcinoma and that, depending on the type of anti-cancer treatment, combining CDK inhibitors and chemotherapy has the potential to increase the sensitivity of esophageal cancer cells to cell death.

Hot Topic: Cannabis May Ease Neuropathic Pain

katheride Hot Topics in Research, Neurology

The effects of cannabis among adults with chronic pain and an overview of general harms: A systematic review
Nugent SM, Morasco BJ, O’Neil ME, al e. The effects of cannabis among adults with chronic pain and an overview of general harms: A systematic review. Annals of Internal Medicine. doi: 10.7326/M17-0155

Background: Cannabis is increasingly available for the treatment of chronic pain, yet its efficacy remains uncertain.
Purpose: To review the benefits of plant-based cannabis preparations for treating chronic pain in adults and the harms of cannabis use in chronic pain and general adult populations.
Data Sources: MEDLINE, Cochrane Database of Systematic Reviews, and several other sources from database inception to March 2017.
Study Selection: Intervention trials and observational studies, published in English, involving adults using plant-based cannabis preparations that reported pain, quality of life, or adverse effect outcomes.
Data Extraction: Two investigators independently abstracted study characteristics and assessed study quality, and the investigator group graded the overall strength of evidence using standard criteria.
Data Synthesis: From 27 chronic pain trials, there is low-strength evidence that cannabis alleviates neuropathic pain but insufficient evidence in other pain populations. According to 11 systematic reviews and 32 primary studies, harms in general population studies include increased risk for motor vehicle accidents, psychotic symptoms, and short-term cognitive impairment. Although adverse pulmonary effects were not seen in younger populations, evidence on most other long-term physical harms, in heavy or long-term cannabis users, or in older populations is insufficient.
Limitation: Few methodologically rigorous trials; the cannabis formulations studied may not reflect commercially available products; and limited applicability to older, chronically ill populations and patients who use cannabis heavily.
Conclusion: Limited evidence suggests that cannabis may alleviate neuropathic pain in some patients, but insufficient evidence exists for other types of chronic pain. Among general populations, limited evidence suggests that cannabis is associated with an increased risk for adverse mental health effects.

 

Hot Topic: Mind-Body Therapies Dramatically Reduce Pain in Hospital Patients

katheride Hot Topics in Research, Neurology, Psychology and Psychiatry

Randomized Controlled Trial of Brief Mindfulness Training and Hypnotic Suggestion for Acute Pain Relief in the Hospital Setting
Garland EL, Baker AK, Larsen P, et al. Randomized controlled trial of brief mindfulness training and hypnotic suggestion for acute pain relief in the hospital setting. Journal of General Internal Medicine. 2017. https://doi.org/10.1007/s11606-017-4116-9.
Background
Medical management of acute pain among hospital inpatients may be enhanced by mind-body interventions.
Objective
We hypothesized that a single, scripted session of mindfulness training focused on acceptance of pain or hypnotic suggestion focused on changing pain sensations through imagery would significantly reduce acute pain intensity and unpleasantness compared to a psychoeducation pain coping control. We also hypothesized that mindfulness and suggestion would produce significant improvements in secondary outcomes including relaxation, pleasant body sensations, anxiety, and desire for opioids, compared to the control condition.
Methods
This three-arm, parallel-group randomized controlled trial conducted at a university-based hospital examined the acute effects of 15-min psychosocial interventions (mindfulness, hypnotic suggestion, psychoeducation) on adult inpatients reporting “intolerable pain” or “inadequate pain control.” Participants (N = 244) were assigned to one of three intervention conditions: mindfulness (n = 86), suggestion (n = 73), or psychoeducation (n = 85).
Key Results
Participants in the mind-body interventions reported significantly lower baseline-adjusted pain intensity post-intervention than those assigned to psychoeducation (p < 0.001, percentage pain reduction: mindfulness = 23%, suggestion = 29%, education = 9%), and lower baseline-adjusted pain unpleasantness (p < 0.001). Intervention conditions differed significantly with regard to relaxation (p < 0.001), pleasurable body sensations (p = 0.001), and desire for opioids (p = 0.015), but all three interventions were associated with a significant reduction in anxiety (p < 0.001).
Conclusions
Brief, single-session mind-body interventions delivered by hospital social workers led to clinically significant improvements in pain and related outcomes, suggesting that such interventions may be useful adjuncts to medical pain management.

Hot Topics: Anti-Statin Internet Trend Could Threaten Lives

katheride Cardiology, Hot Topics in Research

Statin Denial: An Internet-Driven Cult With Deadly Consequences
Nissen SE. Statin Denial: An Internet-Driven Cult With Deadly Consequences. Ann Intern Med. doi: 10.7326/M17-1566
The reduction in cardiovascular morbidity and mortality during the past 3 decades represents one of the great triumphs of contemporary medicine. In 1987, the age-adjusted mortality rate in the U.S. population for cardiovascular disease was 357 in 100 000, decreasing to 167 in 100 000 by 2014 (1). Although precisely gauging the relative contributions of various public health measures to the decline in cardiovascular morbidity and mortality is impossible, most critical observers consider the introduction of statins in 1987 to be one of the keys to this success. According to the Centers for Disease Control and Prevention, the prevalence of elevated low-density lipoprotein cholesterol levels (>4.1 mmol/L [160 mg/dL], >3.4 mmol/L [130 mg/dL], and >2.6 mmol/L [100 mg/dL] for low-, medium-, and high-risk persons, respectively) declined from 59% to 28% between 1980 and 2010 (2). Average low-density lipoprotein cholesterol levels decreased from 3.3 mmol/L (129 mg/dL) in 1988 to 1994 to 3.0 mmol/L (116 mg/dL) in 2007 to 2010.

Hot Topics: Monthly Injections Could Replace Pills for HIV Treatment

katheride Hot Topics in Research, Infectious Disease

Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial
Margolis DA, Gonzalez-Garcia J, Stellbrink H, et al. Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. The Lancet. http://dx.doi.org/10.1016/S0140-6736(17)31917-7.
Summary
Background
Cabotegravir and rilpivirine are antiretroviral drugs in development as long-acting injectable formulations. The LATTE-2 study evaluated long-acting cabotegravir plus rilpivirine for maintenance of HIV-1 viral suppression through 96 weeks.
Methods
In this randomised, phase 2b, open-label study, treatment-naive adults infected with HIV-1 initially received oral cabotegravir 30 mg plus abacavir–lamivudine 600–300 mg once daily. The objective of this study was to select an intramuscular dosing regimen based on a comparison of the antiviral activity, tolerability, and safety of the two intramuscular dosing regimens relative to oral cabotegravir plus abacavir–lamivudine. After a 20-week induction period on oral cabotegravir plus abacavir–lamivudine, patients with viral suppression (plasma HIV-1 RNA <50 copies per mL) were randomly assigned (2:2:1) to intramuscular long-acting cabotegravir plus rilpivirine at 4-week intervals (long-acting cabotegravir 400 mg plus rilpivirine 600 mg; two 2 mL injections) or 8-week intervals (long-acting cabotegravir 600 mg plus rilpivirine 900 mg; two 3 mL injections) or continued oral cabotegravir plus abacavir–lamivudine. Randomisation was computer-generated with stratification by HIV-1 RNA (<50 copies per mL, yes or no) during the first 12 weeks of the induction period. The primary endpoints were the proportion of patients with viral suppression at week 32 (as defined by the US Food and Drug Administration snapshot algorithm), protocol-defined virological failures, and safety events through 96 weeks. All randomly assigned patients who received at least one dose of study drug during the maintenance period were included in the primary efficacy and safety analyses. The primary analysis used a Bayesian approach to evaluate the hypothesis that the proportion with viral suppression for each long-acting regimen is not worse than the oral regimen proportion by more than 10% (denoted comparable) according to a prespecified decision rule (ie, posterior probability for comparability >90%). Difference in proportions and associated 95% CIs were supportive to the primary analysis. The trial is registered at ClinicalTrials.gov, number NCT02120352.
Findings
Among 309 enrolled patients, 286 were randomly assigned to the maintenance period (115 to each of the 4-week and 8-week groups and 56 to the oral treatment group). This study is currently ongoing. At 32 weeks following randomisation, both long-acting regimens met primary criteria for comparability in viral suppression relative to the oral comparator group. Viral suppression was maintained at 32 weeks in 51 (91%) of 56 patients in the oral treatment group, 108 (94%) of 115 patients in the 4-week group (difference 2·8% [95% CI −5·8 to 11·5] vs oral treatment), and 109 (95%) of 115 patients in the 8-week group (difference 3·7% [−4·8 to 12·2] vs oral treatment). At week 96, viral suppression was maintained in 47 (84%) of 56 patients receiving oral treatment, 100 (87%) of 115 patients in the 4-week group, and 108 (94%) of 115 patients in the 8-week group. Three patients (1%) experienced protocol-defined virological failure (two in the 8-week group; one in the oral treatment group). Injection-site reactions were mild (3648 [84%] of 4360 injections) or moderate (673 [15%] of 4360 injections) in intensity and rarely resulted in discontinuation (two [<1%] of 230 patients); injection-site pain was reported most frequently. Serious adverse events during maintenance were reported in 22 (10%) of 230 patients in the intramuscular groups (4-week and 8-week groups) and seven (13%) of 56 patients in the oral treatment group; none were drug related.
Interpretation
The two-drug combination of all-injectable, long-acting cabotegravir plus rilpivirine every 4 weeks or every 8 weeks was as effective as daily three-drug oral therapy at maintaining HIV-1 viral suppression through 96 weeks and was well accepted and tolerated.

Hot Topics: Unnecessary Antibiotics in Hospitals Can Cause Adverse Events

katheride Hot Topics in Research, Internal Medicine, Pharmaceutical Sciences

Association of Adverse Events With Antibiotic Use in Hospitalized Patients
Tamma PD, Avdic E, Li DX, Dzintars K, Cosgrove SE. Association of Adverse Events With Antibiotic Use in Hospitalized Patients. JAMA Intern Med. Published online June 12, 2017. doi:10.1001/jamainternmed.2017.1938
Importance  Estimates of the incidence of overall antibiotic-associated adverse drug events (ADEs) in hospitalized patients are generally unavailable.
Objective  To describe the incidence of antibiotic-associated ADEs for adult inpatients receiving systemic antibiotic therapy.
Design, Setting, and Participants  Retrospective cohort of adult inpatients admitted to general medicine wards at an academic medical center.
Exposures  At least 24 hours of any parenteral or oral antibiotic therapy.
Main Outcomes and Measures  Medical records of 1488 patients were examined for 30 days after antibiotic initiation for the development of the following antibiotic-associated ADEs: gastrointestinal, dermatologic, musculoskeletal, hematologic, hepatobiliary, renal, cardiac, and neurologic; and 90 days for the development of Clostridium difficile infection or incident multidrug-resistant organism infection, based on adjudication by 2 infectious diseases trained clinicians.
Results  In 1488 patients, the median age was 59 years (interquartile range, 49-69 years), and 758 (51%) participants were female. A total of 298 (20%) patients experienced at least 1 antibiotic-associated ADE. Furthermore, 56 (20%) non–clinically indicated antibiotic regimens were associated with an ADE, including 7 cases of C difficile infection. Every additional 10 days of antibiotic therapy conferred a 3% increased risk of an ADE. The most common ADEs were gastrointestinal, renal, and hematologic abnormalities, accounting for 78 (42%), 45 (24%), and 28 (15%) 30-day ADEs, respectively. Notable differences were identified between the incidence of ADEs associated with specific antibiotics.
Conclusions and Relevance  Although antibiotics may play a critical role when used appropriately, our findings underscore the importance of judicious antibiotic prescribing to reduce the harm that can result from antibiotic-associated ADEs.