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INTRODUCTION — This section highlights selected specific new recommendations and/or updates that we anticipate may change usual clinical practice. Practice Changing UpDates focus on changes that may have significant and broad impact on practice, and therefore do not represent all updates that affect practice. These Practice Changing UpDates, reflecting important changes to UpToDate over the past year, are presented chronologically, and are discussed in greater detail in the identified topic reviews.
OBSTETRICS, GYNECOLOGY AND WOMEN'S HEALTH (May 2017)
Tranexamic acid for management of postpartum hemorrhage
●For women with postpartum hemorrhage diagnosed within three hours of delivery, we recommend administration of tranexamic acid as a component of overall treatment (Grade 1B). When more than three hours have elapsed since delivery, we still suggest tranexamic acid (Grade 2C), but the benefit of treatment is less clear.
Tranexamic acid, an antifibrinolytic drug, reduces bleeding in surgical and trauma patients. In a pragmatic randomized trial involving over 20,000 women with postpartum hemorrhage in over 20 countries (World Maternal Antifibrinolytic Randomized Trial [WOMAN]), tranexamic acid, compared with placebo, reduced the relative risk of death due to bleeding by 20 to 30 percent, reduced the incidence of laparotomy to control bleeding, and was not associated with an increase in adverse effects . Overall mortality was not reduced. We now recommend administration of tranexamic acid as a component of the treatment for postpartum hemorrhage. (See "Management of postpartum hemorrhage at vaginal delivery".)
HEMATOLOGY (May 2017)
Eltrombopag for adults with acquired severe aplastic anemia unable to undergo HCT
●For adults with acquired severe aplastic anemia who are not candidates for allogeneic hematopoietic cell transplantation, we suggest eltrombopag plus standard immunosuppressive therapy (IST) rather than IST alone (Grade 2C).
Acquired aplastic anemia (AA) has a high morbidity, and allogeneic hematopoietic cell transplantation (HCT) is suggested as therapy for patients healthy enough to tolerate HCT who have a suitable donor. Immunosuppressive therapy (IST) is offered to those for whom HCT is not an option but is often ineffective in improving outcomes over the long term. A prospective cohort study in adults with acquired severe AA evaluated the effectiveness of IST plus eltrombopag, a thrombopoietin receptor agonist that acts on platelet precursors and hematopoietic stem cells . Eltrombopag plus IST produced higher rates of overall hematologic response at six months compared with responses in a historical cohort (80 to 94 percent versus 66 percent for the historical group). Based on these findings, we now suggest administration of eltrombopag plus IST for individuals with acquired severe AA who are not candidates for allogeneic HCT. (See "Treatment of aplastic anemia in adults", section on 'Evidence for efficacy'.)
NEUROLOGY (April 2017)
Ocrelizumab for primary progressive multiple sclerosis
Ocrelizumab is the first drug to reduce the risk of disability progression among patients with primary progressive multiple sclerosis (PPMS), as shown by the multicenter ORATORIO randomized trial . Compared with placebo, ocrelizumab modestly reduced the proportion of patients with disability progression at 24 weeks (30 versus 36 percent). In addition, ocrelizumab slowed deterioration from baseline to week 120 on the timed 25-foot walk and led to improvements on other endpoints. While the long-term risks of infection and neoplasm with ocrelizumab are uncertain, there are no other disease-modifying therapies for PPMS. Therefore, we suggest treatment with ocrelizumab for most patients with PPMS. Ocrelizumab has also been approved by the US Food and Drug Administration for use in relapsing-remitting MS (RRMS), although its role in the early treatment of this form of the disease remains to be determined. (See "Treatment of progressive multiple sclerosis in adults", section on 'Ocrelizumab'.)
ONCOLOGY (March 2017)
Scalp hypothermia to prevent chemotherapy-induced alopecia
●For women with breast cancer who are receiving chemotherapy that is expected to result in significant alopecia, and who place a high value on avoiding chemotherapy-induced alopecia, we suggest the use of a scalp cooling device (Grade 2A). Scalp hypothermia could also be discussed as a potential option for patients with other solid tumors who are receiving chemotherapy that is expected to result in significant alopecia, although the evidence base is less robust,.
Two prospective studies have evaluated the efficacy of two different automated scalp cooling devices in women with early stage breast cancer [4,5]:
●In an interim analysis of a randomized trial comparing the Paxman Scalp Cooling device and no scalp hypothermia for women with breast cancer receiving adjuvant chemotherapy (one-third anthracycline-based, the remainder taxane-based), one-half of the hypothermia group had limited hair loss (to less than 50 percent, not requiring a wig) compared with none in the control group . Adverse events were all grade 1 and 2, including primarily headache and feeling cold. The success rate was higher with taxane-containing regimens.
●In a multicenter prospective cohort study, 101 patients receiving non-anthracycline taxane-based chemotherapy and who used the DigniCap Scalp Cooling device were compared with 16 concurrently treated controls who did not use the device . Two-thirds of the intervention group, compared with none of the control group, had limited hair loss (to less than 50 percent) one month after the end of chemotherapy. At a median follow-up of 2.5 years, no patient developed scalp metastases.
These results confirm prior studies on the efficacy and safety of scalp hypothermia to reduce chemotherapy-induced alopecia. One of these devices (DigniCap) is FDA-cleared for this use in the United States. (See "Chemotherapy-induced alopecia", section on 'Efficacy and safety'.)
ALLERGY AND IMMUNOLOGY (February 2017)
Immunotherapy for stinging insect hypersensitivity in adults
●We suggest not giving venom immunotherapy (VIT) to patients with reactions to stinging insects limited to cutaneous systemic symptoms and not involving other organ systems (Grade 2C). However, VIT is effective in reducing the severity of future reactions and may still be offered in selected situations.
Venom immunotherapy (VIT) for the treatment of patients with anaphylactic reactions to stings of Hymenoptera insects (eg, bees, yellow jackets, wasps, hornets, and fire ants) is highly effective in preventing future anaphylactic reactions. However, in an updated practice parameter from the American Joint Task Force, VIT is no longer suggested for adults with systemic reactions limited to the skin (ie, generalized erythema, pruritus, urticaria, or angioedema) as studies suggest these patients are at low risk for serious future systemic reactions . This change brings the American approach into closer alignment with guidelines of other countries and is similar to the existing recommendation for children. Despite this revision, VIT may be appropriate for certain adults with cutaneous systemic reactions (eg, those with underlying medical conditions or medications that could affect the outcome of a systemic reaction, frequent unavoidable exposure to Hymenoptera, or impaired quality of life due to fear of future stings). (See "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action", section on 'Patients with past cutaneous systemic reactions'.)
ONCOLOGY, ADULT PRIMARY CARE (July 2016, Modified February 2017)
Duration of adjuvant endocrine therapy for breast cancer
●For postmenopausal women with nonmetastatic hormone receptor-positive breast cancer who have completed a five-year course of an aromatase inhibitor (AI) and who have higher-risk disease (eg, node-positive or ≥T3 disease), we suggest continuing the AI for an additional five years (Grade 2B).
For postmenopausal women receiving adjuvant treatment with an aromatase inhibitor (AI) for hormone-positive breast cancer, the minimum duration of treatment is five years. While data from the MA17R trial demonstrated that extending the duration from 5 to 10 years improved recurrence-free survival , preliminary results from the NSABP-B42, DATA, and IDEAL trials, reported at the San Antonio Breast Cancer Symposium, have not confirmed this benefit [8-10]. No study has demonstrated a benefit in overall survival with extended adjuvant AI therapy, and bone-related toxic effects are more frequent among those receiving extended treatment. While variations in methodology likely account for the differences in recurrence-free survival between the studies, the magnitude of any potential benefit is likely to be greatest for those at highest risk for recurrence. While we previously had recommended an extended course of AI adjuvant therapy for most postmenopausal women with nonmetastatic hormone-positive disease, based on the new data, we now suggest offering extended adjuvant aromatase inhibitor therapy to those with high-risk disease (eg, node-positive or ≥T3 disease). (See "Adjuvant endocrine therapy for non-metastatic, hormone receptor-positive breast cancer", section on 'Duration of endocrine treatment'.)
INFECTIOUS DISEASES (December 2016)
Tenofovir alafenamide for the treatment of chronic hepatitis B virus infection
●For most patients with chronic HBV infection who initiate therapy with tenofovir, we recommend tenofovir alafenamide rather than tenofovir disoproxil fumarate (tenofovir DF) (Grade 1B). We also suggest that those initially started on tenofovir DF switch to tenofovir alafenamide (Grade 2B).
Tenofovir disoproxil fumarate is a first-line therapy for chronic hepatitis B virus (HBV) infection. A newer formulation of tenofovir, tenofovir alafenamide, was approved by the US Food and Drug Administration in November 2016 for the treatment of chronic HBV in patients with compensated liver disease . In two large randomized noninferiority trials among patients with chronic HBV infection (both treatment-naive and experienced, and including patients positive or negative for HBV e antigen), tenofovir alafenamide resulted in similar rates of HBV suppression and fewer adverse effects on renal function and bone density at 48 weeks compared with tenofovir disoproxil fumarate [12,13]. Given these findings, tenofovir alafenamide is our preferred formulation for patients with chronic HBV who initiate therapy with tenofovir. We also favor switching those initially started on tenofovir disoproxil fumarate to tenofovir alafenamide. Given limited available safety data, we do not currently use tenofovir alafenamide in pregnant women. (See "Hepatitis B virus: Overview of management", section on 'Nucleos(t)ide analogues'.)
INFECTIOUS DISEASES. PEDIATRICS, ADULT PRIMARY CARE, FAMILY MEDICINE (November 2016)
Meningococcal conjugate vaccination for HIV-infected patients
●For all HIV-infected individuals older than two months, we suggest meningococcal conjugate vaccination (Menactra or Menveo) (Grade 2C).
Growing evidence has suggested that HIV-infected individuals have a disproportionate incidence of invasive meningococcal disease, with an estimated risk 5 to 13 times that of the general population. Because of this, the Centers for Disease Control and Prevention in the United States now recommends meningococcal conjugate vaccination (with MenACWY-CRM [Menveo] or MenACWY-D [Menactra]) for all HIV-infected individuals older than two months . This includes a primary vaccine series for those who have not previously received it and interval booster doses every several years; the precise schedule depends on the age of the patient (table 1). Individuals may also have separate indications for serogroup B meningococcal vaccination. Evidence of vaccine efficacy in HIV-infected patients is limited to immunologic outcomes. (See "Immunizations in HIV-infected patients", section on 'Meningococcal vaccine' and "Meningococcal vaccines".)
INFECTIOUS DISEASES (November 2016)
HPV vaccine dosing for individuals younger than 15 years
●For individuals younger than 15 years, we advise administration of human papillomavirus (HPV) vaccine in two doses separated by six months. Those 15 years and older should continue to receive a three-dose vaccine series.
For individuals younger than 15 years receiving human papillomavirus (HPV) vaccination, two vaccine doses administered at least six months apart are now recommended by the Centers for Disease Control and Prevention in the United States . This new vaccine schedule is similar to schedules used in other countries and is supported by data demonstrating that two vaccine doses in young females have similar immunogenicity to three doses. However, the efficacy of fewer than three doses for prevention of cervical neoplastic disease has not been directly established. Three doses are still recommended for individuals older than 15 years because they have lower immunologic responses to HPV vaccination. (See "Recommendations for the use of human papillomavirus vaccines", section on 'Immunization schedule'.)
HEMATOLOGY (October 2016, Modified October 2016)
Daratumumab-based regimens in relapsed multiple myeloma
Two recent multicenter randomized trials including over 1000 patients have demonstrated large improvements in progression-free survival (PFS) when the anti-CD38 monoclonal antibody daratumumab is added to standard regimens in relapsed multiple myeloma. The addition of daratumumab to either lenalidomide plus dexamethasone (POLLUX trial) or to bortezomib plus dexamethasone (CASTOR trial) resulted in substantially improved response rates and PFS with a mild to moderate increase in toxicity [16,17]. Mostly mild infusion reactions were common with the first infusion, but rarely resulted in drug discontinuation. Overall survival data are not yet mature. Based on these results we now recommend a daratumumab-based regimen for the treatment of first relapse in myeloma. (See "Treatment of relapsed or refractory multiple myeloma", section on 'Daratumumab'.)
PULMONARY AND CRITICAL CARE MEDICINE (October 2016)
Mycophenolate mofetil for scleroderma lung disease
●For patients with systemic sclerosis who have respiratory symptoms, abnormal and/or declining pulmonary function, imaging evidence of interstitial lung disease, and no active infection, we suggest initiating treatment with mycophenolate mofetil (MMF) (Grade 2B).
Cyclophosphamide has been the suggested treatment for moderate-to-severe interstitial lung disease complicating systemic sclerosis (SSc-ILD) but has well-known toxicity. A recent randomized trial compared mycophenolate mofetil (MMF) with oral cyclophosphamide in 142 patients with SSc-ILD, exertional dyspnea, and features of progressive disease . Pulmonary function and dyspnea improved in both groups, without a significant difference between groups. MMF was better tolerated than cyclophosphamide based on a longer time to patient withdrawal and lower incidence of leukopenia and thrombocytopenia. We now suggest initiating treatment for symptomatic progressive SSc-ILD with mycophenolate, rather than cyclophosphamide, due to comparable efficacy, better safety profile, and the option for longer-term therapy. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Choice of an agent'.)
ONCOLOGY (October 2016)
Pembrolizumab in treatment-naïve advanced non-small cell lung cancer
●For patients with treatment-naïve advanced non-small cell lung cancer that lacks EGFR or ALK genetic aberrations and expresses PD-L1 in at least 50 percent of tumor cells, we recommend pembrolizumab for initial therapy (Grade 1B).
Immunotherapy for patients with advanced non-small cell lung cancer (NSCLC) that lacks a driver mutation has shown promising results in the frontline setting:
●In a phase III trial enrolling over 300 such patients whose tumors expressed programmed death ligand 1 (PD-L1) on at least 50 percent of tumor cells, pembrolizumab monotherapy improved progression-free survival, overall survival, and objective response rate compared with standard platinum-doublet chemotherapy . It was also associated with lower treatment-related adverse effects.
●In a randomized phase II trial of 123 patients with PD-L1 unselected advanced nonsquamous NSCLC, the addition of pembrolizumab to carboplatin and pemetrexed improved objective response rate (55 versus 29 percent, respectively) and progression-free survival (13 versus 6 months, respectively) relative to chemotherapy alone .
These data have led to approval by the US Food and Drug Administration (FDA) of pembrolizumab in the frontline setting for patients with advanced NSCLC lacking a driver mutation as monotherapy if PD-L1 is expressed on at least 50 percent of cells. More recently it has been approved in nonsquamous advanced NSCLC, in combination with carboplatin and pemetrexed, irrespective of PD-L1 levels. This regimen has not been compared, however, with platinum-based combinations incorporating concurrent and maintenance bevacizumab, which remains another option for such patients. (See "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'First-line setting'.)
ONCOLOGY, PALLIATIVE CARE (August 2016)
Olanzapine for prevention of nausea and vomiting induced by highly emetogenic chemotherapy regimens
●For patients receiving cisplatin and other highly emetogenic chemotherapy regimens, we suggest the addition of olanzapine on days 1 through 4 to standard antiemetic therapy (a combination of a 5-HT3 receptor antagonist, dexamethasone, and an NK1R antagonist) (Grade 2B).
The antipsychotic olanzapine may be a particularly useful agent for preventing delayed chemotherapy-induced nausea and vomiting, which is often poorly controlled with conventional antiemetics. The effectiveness of adding olanzapine to a standard antiemetic regimen was shown in a trial in which 380 patients receiving highly emetogenic chemotherapy (cisplatin or doxorubicin/cyclophosphamide for breast cancer) were randomly assigned to dexamethasone, an NK1R antagonist, and a 5-HT3 receptor antagonist plus either olanzapine (10 mg daily orally on days 1 through 4) or placebo . The proportion of patients with no chemotherapy-induced nausea (the primary endpoint) was higher with olanzapine both in the first 24 hours after chemotherapy and in the delayed period. Rates of complete response (no emesis and no use of rescue medication) were also higher with olanzapine over a five-day period. Patients receiving olanzapine had more sedation on day 2 (severe in 5 percent), which resolved despite continued olanzapine. On the basis of this trial, we now suggest the addition of olanzapine on days 1 through 4 to standard antiemetic therapy for patients receiving highly emetogenic chemotherapy. (See "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults", section on 'Olanzapine'.)
INFECTIOUS DISEASES, GASTROENTEROLOGY, PRIMARY CARE, FAMILY MEDICINE (July 2016)
Sofosbuvir-velpatasvir for all genotypes of chronic HCV infection
●For patients with chronic genotype 1 or 4 hepatitis C virus (HCV) infection, we suggest ledipasvir-sofosbuvir or sofosbuvir-velpatasvir (Grade 2B). For patients with chronic genotype 2 or 3 HCV infection, we suggest sofosbuvir-velpatasvir (Grade 2B). Depending on clinical factors, some patients with genotype 3 infection may also warrant the addition of ribavirin.
All-oral, direct-acting antiviral regimens for chronic hepatitis C virus (HCV) infection have proliferated over the past two years. Sofosbuvir-velpatasvir, a coformulated combination of an NS5B and an NS5A inhibitor, is the first such regimen that has high, well-established efficacy for all genotypes, even in patients with cirrhosis or prior treatment failure with interferon-based regimens [22-24]. This agent was approved by the US Food and Drug Administration in June 2016 and is now our preferred or one of our preferred regimens for adults with chronic HCV infection of any genotype because of its efficacy, simplicity of administration, and limited drug interactions (algorithm 1 and algorithm 2 and algorithm 3 and algorithm 4). Sofosbuvir-velpatasvir is given for 12 weeks for all genotypes. For genotype 3 infection, the addition of ribavirin may be warranted, depending on the presence of cirrhosis, the prior treatment history, and the presence of mutations associated with NS5A resistance. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Selection of treatment regimens' and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults", section on 'Selection of treatment regimen' and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults", section on 'Selection of treatment regimens'.)
ONCOLOGY (June 2016)
Choice of adjuvant chemotherapy for resected pancreatic cancer
●Following resection of pancreatic cancer, we suggest six months of combination chemotherapy with gemcitabine plus capecitabine rather than gemcitabine monotherapy for most patients (Grade 2B). However, therapy with gemcitabine alone (or, where available, S-1) is a reasonable option, particularly for patients with a borderline performance status or a comorbidity profile that precludes intensive therapy.
Adjuvant chemotherapy is recommended for all patients with resected pancreatic cancer. The standard approach has been gemcitabine monotherapy or, where available, S-1 alone. The benefit of a two-drug regimen was tested in the ESPAC-4 trial, which randomly assigned 730 patients with resected pancreatic adenocarcinoma to six months of gemcitabine with or without capecitabine . Combination therapy was associated with significantly longer median overall survival (28 versus 25.5 months) and twice as many patients remaining alive at five years (19 versus 9). Severe diarrhea, hand-foot syndrome, and neutropenia were all significantly more common with combined therapy.
For most patients we suggest six months of combination chemotherapy with gemcitabine plus capecitabine rather than gemcitabine monotherapy after resection of pancreatic cancer. However, therapy with gemcitabine or S-1 alone remains a reasonable option, particularly for patients with a borderline performance status or a comorbidity profile that precludes intensive therapy. (See "Treatment for potentially resectable exocrine pancreatic cancer", section on 'Gemcitabine plus capecitabine'.)
ONCOLOGY (May 2016)
No survival benefit from chemoradiotherapy after initial chemotherapy for locally advanced pancreatic cancer
●For most patients with locally advanced pancreatic cancer who are not considered candidates for surgical exploration after initial chemotherapy, we suggest continued chemotherapy rather than chemoradiotherapy (Grade 2B). However, for patients in whom resection is being considered, chemoradiotherapy is still advised in an attempt to increase the likelihood of a complete resection.
There is no consensus as to the best approach for patients with locally advanced pancreatic cancer. Given that initial chemoradiotherapy (CRT) has not demonstrated a consistent survival benefit, and that up to one-third of patients develop overt metastases during the initial phase of treatment, it had been hoped that reserving CRT for patients without metastases after initial chemotherapy would improve survival. However, data from the randomized LAP-07 trial suggest no survival benefit from CRT compared with continued systemic chemotherapy alone, at least for patients treated initially with gemcitabine monotherapy .
For patients who do not progress following initial chemotherapy, subsequent therapy depends on whether the patient is a candidate for resection. For patients in whom resection is being considered, we continue to suggest combined treatment with external beam radiotherapy plus concomitant low-dose fluorouracil (eg, 200 mg/m2 daily), in an attempt to increase the rate of complete (R0) resection. For most patients with truly unresectable tumors following initial chemotherapy, we now suggest continued chemotherapy rather than CRT. However, CRT may be appropriate for selected patients, such as those with localized disease and a good performance status who cannot tolerate further chemotherapy. (See "Initial chemotherapy and radiation for nonmetastatic, locally advanced, unresectable and borderline resectable, exocrine pancreatic cancer".)
INFECTIOUS DISEASES (May 2016)
Option for shortened MDR-TB regimen in updated WHO guidelines
●Consistent with WHO updated guidelines for patients with multidrug-resistant tuberculosis (MDR-TB), we suggest a shortened 9 to 12-month MDR-TB regimen for nonpregnant patients who have no extrapulmonary disease, an isolate known to be susceptible to fluoroquinolones and injectable antituberculous agents, and no prior exposure to second-line agents for more than one month (Grade 2C).
The conventional treatment regimen for multidrug-resistant tuberculosis (MDR-TB) consists of a fluoroquinolone, an injectable agent, and at least two other core second-line agents for a total duration of 20 to 26 months. Updated World Health Organization (WHO) guidelines present the option of a shortened regimen for nonpregnant patients with MDR-TB who have no extrapulmonary disease, an isolate known to be susceptible to fluoroquinolones and injectable antituberculous agents, and no prior exposure to second-line agents for more than one month . The shortened regimen consists of an intensive phase (four to six months of high-dose isoniazid, ethambutol, pyrazinamide, gatifloxacin [or moxifloxacin], kanamycin, prothionamide, and clofazimine) followed by a continuation phase (five months of ethambutol, pyrazinamide, gatifloxacin [or moxifloxacin], and clofazimine). Support for this regimen comes in part from a large study from Bangladesh that reported high rates of favorable bacteriologic outcomes with a similar 9 to 12-month regimen . The new WHO guidance also indicates that patients with rifampin monoresistance should be treated as for MDR-TB. Patients with known or suspected MDR-TB who do not meet criteria for the shortened MDR-TB regimen should be treated with the conventional regimen. (See "Treatment and prevention of drug-resistant tuberculosis", section on 'General principles'.)
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