Definitive Evidence Of Benefit Research Articles

45-Year-Old Woman With Fever and Malaise

45-Year-Old Woman With Fever and Malaise

Targeted and immunotherapies in BRAF mutant melanoma: where we stand and what to expect.

The therapeutic landscape for melanoma has evolved drastically in the past decade. Currently, immune checkpoint inhibitors and small-molecule inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway are the two mainstay therapies for BRAFV600 mutant advanced melanoma. Although MAPK dependence has been variably demonstrated in melanomas lacking BRAFV600 mutations, definitive evidence of benefit with MAPK inhibitors has not been demonstrated. Thus, in the BRAFV600 'wild-type' setting, immune checkpoint inhibitors are the standalone option(s). In the BRAFV600 mutant setting, there is no definitive evidence prioritizing one therapeutic modality over another. Herein, we review the updated data of the pivotal phase III randomized controlled trials that established the standard-of-care first-line treatment for advanced melanoma, as it provides insights into long-term benefit, which is a major factor in therapy selection. We discuss the clinical considerations for choosing between these therapies in the front-line setting and beyond, specifically for patients with BRAFV600 mutant melanoma based on currently available evidence. We have previously proposed a time-dependent resistance paradigm in which future therapeutic development strategies can be rooted. We also discuss how these Food and Drug Administration (FDA)-approved therapeutic modalities are being pursued earlier in the course of disease management, namely in adjuvant and neoadjuvant settings. FDA-approved interlesional oncolytic virotherapy in the modern era is also briefly discussed.

Survival in homozygous familial hypercholesterolaemia is determined by the on-treatment level of serum cholesterol.

Homozygous familial hypercholesterolaemia (FH) is a rare inherited disorder characterized by extreme hypercholesterolaemia from birth, accelerated atherosclerosis, and premature death. Many forms of lipid-lowering therapies have been used in the past, but definitive evidence of benefit has been lacking. We therefore undertook a retrospective survey of lipid levels and clinical outcomes of FH homozygotes treated with a combination of lipid-lowering measures between 1990 and 2014 in South Africa and the UK. We divided 133 previously statin-naive homozygotes into quartiles according to their on-treatment levels of serum cholesterol and compared the occurrence of any death, cardiovascular death, and major adverse cardiovascular events (MACE) between the quartiles during 25 years of follow-up, using Cox and competing risks regression analysis. Patients in Quartile 4, with an on-treatment serum cholesterol >15.1 mmol/L, had a hazard ratio of 11.5 for any death compared with those in Quartile 1, with an on-treatment cholesterol of < 8.1 mmol/L. Those in Quartiles 2 and 3 combined, with on-treatment cholesterol of 8.1-15.1 mmol/L had a hazard ratio of 3.6 compared with Quartile 1. These differences were statistically significant (P < 0.001) and remained so after adjustments for confounding factors (P = 0.04). Significant differences between quartiles were also evident for cardiovascular deaths and MACE. These findings provide unequivocal evidence that the extent of reduction of serum cholesterol achieved by a combination of therapeutic measures, including statins, ezetimibe, lipoprotein apheresis, and evolocumab, is a major determinant of survival in homozygous FH.

Abstract ES9-3: Targeted interventions: Metformin and lifestyle change

Abstract Obesity is associated with increased risk of premenopausal (triple negative) and postmenopausal [primarily estrogen receptor (ER) positive] breast cancer (BC). Higher Body Mass Index [BMI = weight (kg)/height (m)2] and lower physical activity have been associated with increased risk of distant recurrence and death in both pre- and postmenopausal BC, regardless of ER status; some recent studies nested in clinical trials have found an association only in ER+ BC. There is growing evidence that obese women may have less benefit from aromatase inhibitors (AIs) other than letrozole. Translational and preclinical research suggests that obesity associated alterations in systemic physiology (higher estrogens, insulin resistance leading to higher insulin and glucose, altered adipokines and inflammation) or changes in the tumor microenvironment (localized inflammation) may mediate effects of obesity on BC outcomes. The presence of an association of obesity with breast cancer outcomes is not necessarily causal (non-causal associations may reflect healthy person bias, under-treatment of obese patients, or presentation of BC at more advanced stage in obese women). Even if the association is causal it may not be reversible (ie: adverse effects may be reflected in the biology of the BC that develops and may not be amenable to change). Evidence that an association is both causal and reversible can be obtained from any intervention research. Potential interventions include weight loss and targeted drugs such as metformin. Metformin, a biguanide commonly used to treat type 2 diabetes, may act (i) indirectly to improve obesity associated systemic physiology (e.g. by lowering circulating insulin leading to reduced insulin receptor mediated activation of PI3K and ras pathways), (ii) directly via an effect on the mitochondrium leading to an LKBI mediated AMPK activation and downstream mTOR inhibition or (iii) directly via other non-AMPK mediated direct effects. Metformin has been associated with lower BC risk and improved BC outcomes in observational studies that may be susceptible to survival biases. It has led to reduced proliferation and increased apoptosis in some neoadjuvant studies (similar to effects seen in preclinical studies). Despite this epidemiologic, clinical, translational and preclinical research, definitive evidence of benefits from Phase III trials is needed. A Phase III adjuvant trial (NCIC MA.32) testing metformin (vs placebo) in the adjuvant BC setting has completed accrual and is anticipated to report BC outcome data in 2017. Lifestyle based weight loss interventions (involving calorie restriction and enhanced physical activity) have been shown to lead to 5-7% weight loss in BC populations (and to improvement in potential systemic mediators noted above). Most ongoing or completed studies of weight loss in have been underpowered for BC outcomes and have focused primarily on weight loss. An adequately powered US Intergroup study (led by the Alliance) using a telephone based intervention involving over 3000 subjects is in advanced stages of planning. Results of this trial, anticipated 6-8 years after initiation, should provide rigorous evidence regarding possible benefits of the degree of weight loss that can be achieved through lifestyle change on BC outcomes. Citation Format: Goodwin PJ. Targeted interventions: Metformin and lifestyle change. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES9-3.

The American College of Obstetricians and Gynecologists Committee Opinion no. 630. Screening for perinatal depression.

Perinatal depression, which includes major and minor depressive episodes that occur during pregnancy or in the first 12 months after delivery, is one of the most common medical complications during pregnancy and the postpartum period, affecting one in seven women. It is important to identify pregnant and postpartum women with depression because untreated perinatal depression and other mood disorders can have devastating effects on women, infants, and families. Several screening instruments have been validated for use during pregnancy and the postpartum period. Although definitive evidence of benefit is limited, the American College of Obstetricians and Gynecologists recommends that clinicians screen patients at least once during the perinatal period for depression and anxiety symptoms using a standardized, validated tool. Although screening is important for detecting perinatal depression, screening by itself is insufficient to improve clinical outcomes and must be coupled with appropriate follow-up and treatment when indicated; clinical staff in obstetrics and gynecology practices should be prepared to initiate medical therapy, refer patients to appropriate behavioral health resources when indicated, or both.

EURECCA consensus conference highlights about rectal cancer clinical management: The radiation oncologist’s expert review

Background and PurposeAlthough rectal and colon cancer management has progressed greatly in the last few decades clinical outcomes still need to be optimized. Furthermore, consensus is required on several issues as some of the main international guidelines provide different recommendations. The European Registration of Cancer Care (EURECCA) drew up documents to standardize management and care in Europe and aid in decision-making. Material and MethodsIn the present section the panel of experts reviews and discusses data from the literature on rectal cancer, focusing on recommendations for selecting between short-course radiotherapy (SCRT) and long-course radio-chemotherapy (LCRTCT) as preoperative treatment as well as on the controversies about adjuvant treatment in patients who had received a pre-operative treatment. ResultsThe starting-point of the present EURECCA document is that adding SCRT or LCRTCT to TME improved loco-regional control but did not increase overall survival in any single trial which, in any case, had improved with the introduction of total mesorectal excision (TME) into clinical practice. Moderate consensus was achieved for cT3 anyNM0 disease. In this frame, agreement was reached on either SCRT followed by immediate surgery or LCRTCT with delayed surgery for mesorectal fascia (MRF) negative tumors at presentation. LCRTCT was recommended for tumor shrinkage in MRF+ at presentations but if patients were not candidates for chemotherapy, SCRT with delayed surgery is an option/alternative. LCRTCT was recommended for cT4 anycNM0. SCRT offers the advantages of less acute toxicity and lower costs, and LCRTCT tumor shrinkage and down-staging, with 13–36% pathological complete response (pCR) rates.To improve the efficacy of preoperative treatment both SCRT and LCRTCT have been, or are being, associated with diverse schedules of chemotherapy and even new targeted therapies but without any definitive evidence of benefit. Nowadays, standard treatment is fluoropyrimidine alone since alternative agents and regimens have not been shown to be more active, only more toxic. ConclusionsThe EURECCA panel summarized available evidence in an attempt to reduce variance in rectal cancer management. This is expected to benefit patients. Results from ongoing randomized trials will help clarify some of the issues that are still under debate.

Current state of penile rehabilitation after radical prostatectomy

Erectile dysfunction is a major source of morbidity for many men who undergo radical prostatectomy for localized prostate cancer annually. Few areas of urology remain as controversial as penile rehabilitation postprostatectomy, an ill defined treatment strategy designed to minimize the incidence and severity of erectile dysfunction. Contemporary approaches to penile rehabilitation include oral phosphodiesterase type-5 inhibitors, vacuum constriction devices, intracavernous vasoactive injections and attempts at frequent sexual encounters. The intent of penile rehabilitation strategies is to facilitate the recovery of erectile function through preservation of cavernous smooth muscle, though none has definitive evidence of benefit. This review will evaluate the current theories of the cause of postprostatectomy erectile dysfunction, alterations in surgical technique to minimize it, and the application of erectogenic pharmaceuticals to improve recovery of erectile function, or maximize its preservation. A discussion of basic science evidence and clinical trials will be reviewed.

New treatment options for bronchiectasis

Therapies shown to be effective in cystic fibrosis are often provided to patients with bronchiectasis, without definitive evidence of benefit. In recent years, there has been increased interest in validating and developing new therapies for patients with noncystic fibrosis bronchiectasis. While inhaled tobramycin improves microbiologic parameters, improvements in outcomes have been more difficult to demonstrate, in part due to the occurrence of bronchospasm in a significant minority of treated patients. Outcome data from studies of inhaled aztreonam and ciprofloxacin have not yet been reported, although the microbiologic data appear to be promising. Preliminary data regarding inhaled hyperosmolar agents such as hypertonic saline and mannitol are also promising, but these therapies cannot yet be recommended for routine therapy of patients with bronchiectasis. Macrolide antibiotics have anti-inflammatory properties in patients with chronic suppurative lung disease, through a variety of mechanisms. They have been proven to be beneficial in diffuse panbronchiolitis and are commonly being used in patients with bronchiectasis. Many small studies support their use in this population, although several had methodologic flaws. Thus, although chronic low-dose macrolide therapy is often used in these patients, more conclusive evidence is awaited.

Rare tumours of the chest

Malignant thoracic tumours include non-small cell lung cancer (NSCLC) – adenocarcinoma, squamous cell carcinoma, large cell carcinoma, undifferentiated carcinoma – and small cell lung cancer (SCLC) which account for more than 95% of all primary neoplasms. However, a variety of non-bronchiogenic malignant tumours may occasionally affect the lung and represent 3−5% of all primary chest tumours. The most frequently encountered malignant primary thoracic tumours are thymoma, sarcomas, malignant melanoma and carcinoid tumours [1–3]. Thymomas and thymic carcinomas constitute 30% of anterior mediastinal masses in adults and arise from thymic epithelial cells [4]. Thymomas commonly affect people aged between 40 and 60 years. Nearly one half are asymptomatic but when patients do have symptoms, they are due to local invasion in 65% of cases (chest pain, dyspnea, haemoptysis, stridor, cardiac arrythmias and Horner’s syndrome) and paraneoplasic syndromes. They rarely metastasise outside of the thorax. Surgery with complete resection is the mainstay of therapy for patients with completely encapsulated tumours and it plays a key role in locally invasive disease with increase in survival even if invasion is found to be present [5]. The role of subtotal resection in advanced disease remains controversial. Adjuvant radiotherapy can decrease recurrences in invasive disease but its benefit in encapsulated tumours has not been proved. In subtotal resections, radiotherapy maximises the chance of local control. Retrospective reviews show that 20−30% of patients may be candidates for systemic therapy including corticosteroid, single-agent or combination chemotherapy (platinum, doxorubicin, cyclophosphamide, taxanes), chemoradiotherapy or cytokine therapy, although the optimal regimen has not yet been determined [2,3,6]. Primary pulmonary sarcomas (PPS) account for less than 0.2% of all malignant pulmonary tumours. These tumours may occur at any age and there is no evidence of a gender predisposition. Leiomyosarcoma represents the most frequent subgroup followed by fibrosarcoma and haemangiopericytoma. Other types of PPS include solitary fibrous tumour, synovial sarcoma, malignant fibrous histiocytoma, rhabdomyosarcoma and angiosarcoma. PPS arise from the stromal elements of the bronchial tree, sanguineous vessel and lung parenchyma. Diagnosis frequently reveals local invasion, patients presenting with dyspnea, a cough, chest pain or haemoptysis. Pulmonary thromboembolism, pulmonary hypertension or right heart failure occasionally occur in angiosarcomas, and paraneoplasic syndromes may occur in patients with haemangiopericytoma. Occasionally, PPS metastasises to distant organs including contralateral lung, liver, brain, bone or soft tissues. Surgical treatment with complete resection (lobectomy or neumonectomy) is the mainstay treatment and the most important prognostic factor. Other prognostic factors are histologic grade and tumour size (poor prognosis tumours >5 cm) [3]. The addition of chemotherapy and radiotherapy to surgical treatment (neoor adjuvant) can increase the results but no definitive evidence of benefit has been shown. Chemotherapy, either as a single agent or in combination regimens, may have palliative benefit in unresectable disease. Experience for PPS with chemotherapy is predominantly gathered from patients with traditional soft tissue sarcomas and is extrapolated to pulmonary sarcomas. The most commonly used agents include doxorubicin (20% response rate), ifosfamide and dacarbazine [2]. Although malignant melanomas principally affect the skin and ocular area, there is well documented information about primary melanomas in the lungs [2, 3,7]. Primary lung melanomas are defined by minimal criteria including no history of a previous melanoma (cutaneous or ocular), no demonstrable melanoma in any other organ at the time of surgery, a solitary tumour in the surgical specimen from the lung, tumour morphology compatible with a primary tumour, and no evidence at autopsy of a primary melanoma elsewhere. Lung melanomas are unifocal and are commonly presented as a polypoid obstruction lesion within the tracheobronchial tree or as a mass in the lung parenchyma. Similar to NSCLC, lung melanomas metastasise to regional lymph nodes in hilar and

Intravenous antiarrhythmic drug therapy in the resuscitation from refractory ventricular arrhythmias

Prompt cardiopulmonary resuscitation (CPR) and early defibrillation significantly improve the likelihood of successful resuscitation from cardiac arrest and are the key components in the American Heart Association’s “chain of survival.” Although representing current clinical practice in the United States, there is limited evidence supporting the benefit of acute administration of such antiarrhythmic medications as lidocaine, bretylium, magnesium, and procainamide to a victim of cardiac arrest. There has been only 1 published case-controlled clinical trial in which shock-refractory victims of out-of-hospital ventricular fibrillation were stratified into those who received lidocaine and those who did not. In this trial, no significant differences were observed between treatment groups in the return of an organized rhythm, admission to the hospital, or survival to hospital discharge. In the recently published ARREST trial, a significant improvement in admission alive to the hospital was observed in recipients of intravenous amiodarone, compared with placebo (44% vs 34%, respectively, p = 0.03). With the possible exception of intravenous amiodarone, available evidence of definitive benefit from antiarrhythmic drugs in cardiac arrest is inconclusive. Due to regulatory issues, clinical trials in cardiac arrest are extremely difficult to design and perform.

Constraints on antidepressant prescribing and principles of cost-effective antidepressant use. Part 1: Depression and its treatment.

Depression is a common, recurrent, disabling and potentially fatal disorder. Its effect on quality of life is more severe than that of some other chronic medical conditions. Its cost burden (direct and indirect) has been estimated at $US26 billion to $US43.7 billion in the US (in 1990), and 3.4 billion pounds sterling in the UK (in 1992). With contemporary levels of diagnosis and treatment, and of treatment failure, the indirect economic losses to society from depression-associated morbidity and mortality may be up to 7 times the direct costs, with 69 to 98% of these costs related to morbidity. Impaired capacity while at work may equal absenteeism in terms of costs. Depression carries an increased risk of suicide and suicide attempts, both of which are costly. It is ironic, then, that the drugs used to treat depression account for 9% of poisoning deaths in England and Wales. The newer antidepressants are less toxic than the tricyclic antidepressants (TCAs). The physician's choice of antidepressant should be motivated primarily by clinical considerations, but cost implications are of increasing importance. In some healthcare systems, the expenditure associated with prescribing by doctors has been successfully modified, at least temporarily, by drug formularies, audit and feedback. This may be to the disadvantage of the selective serotonin (5-hydroxytryptamine: 5-HT) reuptake inhibitors; they have higher acquisition costs than the TCAs, since they are newer and lack cheaper generic forms, and definitive evidence of benefits may be inadequate or equivocal. However, market price is only one of many factors that should affect the prescriber, and the increasing trend towards cost containment policies is liable to lead to false economies.