Humans

Ovarian Cancer: A Review

Author/s: 
Giuseppe Caruso, MD, S. John Weroha, MD, PhD, William Cliby, MD

Importance: Ovarian cancer is the eighth most common cause of cancer and cancer death in women worldwide. In 2022, ovarian cancer was diagnosed in approximately 324 398 individuals, and 206 839 died of ovarian cancer worldwide. In 2025, it is estimated that 20 890 US women will be diagnosed with ovarian cancer and 12 730 patients will die of ovarian cancer.

Observations: Approximately 90% of ovarian cancers are epithelial malignancies, of which 70% to 80% are high-grade serous ovarian cancers. Less common epithelial subtypes include endometrioid, clear cell, low-grade serous, mucinous, and carcinosarcoma. The median age at diagnosis of ovarian cancer is 63 years. Risk factors include older age, family history of breast or ovarian cancer, endometriosis, and nulliparity. Hereditary factors are associated with 25% of cases, predominantly linked to BRCA1/2 gene variants. At diagnosis, approximately 95% of patients experience nonspecific symptoms, such as abdominal pain, bloating, and urinary urgency and frequency, and about 80% have advanced-stage disease (stage III-IV), including extrapelvic disease, ascites, and abdominal masses. Diagnostic and staging evaluation includes pelvic ultrasound; computed tomography of the chest, abdomen, and pelvis; and serum tumor markers such as carbohydrate antigen 125, carbohydrate antigen 19-9, and carcinoembryonic antigen. First-line treatment for early-stage ovarian cancer, defined as limited to the ovary or fallopian tube (stage I) or confined to the pelvis (stage II), is surgery (hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and lymphadenectomy), followed by adjuvant chemotherapy (carboplatin and paclitaxel). With treatment, early-stage ovarian cancer has a 5-year overall survival of 70% to 95%. Advanced-stage ovarian cancer may be treated with primary cytoreductive surgery (removal of all visible cancer in the abdominal cavity) and adjuvant chemotherapy (carboplatin and paclitaxel) or with neoadjuvant chemotherapy followed by cytoreductive surgery and adjuvant chemotherapy. Most patients with advanced-stage ovarian cancer receive maintenance therapy with bevacizumab (a monoclonal antibody that blocks angiogenesis) and/or poly–adenosine diphosphate ribose polymerase (PARP) inhibitors. With treatment, the 5-year overall survival rate for advanced-stage ovarian cancer is 10% to 40%. However, individuals with BRCA-related gene variants have a 5-year overall survival rate of approximately 70% with PARP inhibitor treatment. Despite an initial remission rate of 80%, approximately 75% of patients with advanced-stage disease have ovarian cancer relapse within 2 years.

Conclusions and Relevance: Approximately 21 000 women are diagnosed with ovarian cancer annually in the US, and approximately 80% have advanced-stage ovarian cancer at diagnosis. First-line treatment of early-stage ovarian cancer is surgery and adjuvant platinum-based chemotherapy. Treatment of advanced-stage ovarian cancer includes cytoreductive surgery, platinum-based chemotherapy, and targeted maintenance therapies such as bevacizumab and/or PARP inhibitors.

Canadian guideline for the clinical management of high-risk drinking and alcohol use disorder

Author/s: 
Evan Wood, Jessica Bright, Katrina Hsu, Nirupa Goel, Josey W G Ross

Background: In Canada, low awareness of evidence-based interventions for the clinical management of alcohol use disorder exists among health care providers and people who could benefit from care. To address this gap, the Canadian Research Initiative in Substance Misuse convened a national committee to develop a guideline for the clinical management of high-risk drinking and alcohol use disorder.

Methods: Development of this guideline followed the ADAPTE process, building upon the 2019 British Columbia provincial guideline for alcohol use disorder. A national guideline committee (consisting of 36 members with diverse expertise, including academics, clinicians, people with lived and living experiences of alcohol use, and people who self-identified as Indigenous or Métis) selected priority topics, reviewed evidence and reached consensus on the recommendations. We used the Appraisal of Guidelines for Research and Evaluation Instrument (AGREE II) and the Guidelines International Network’s Principles for Disclosure of Interests and Management of Conflicts to ensure the guideline met international standards for transparency, high quality and methodological rigour. We rated the final recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) tool; the recommendations underwent external review by 13 national and international experts and stakeholders.

Recommendations: The guideline includes 15 recommendations that cover screening, diagnosis, withdrawal management and ongoing treatment, including psychosocial treatment interventions, pharmacotherapies and community-based programs. The guideline committee identified a need to emphasize both underused interventions that may be beneficial and common prescribing and other practice patterns that are not evidence based and that may potentially worsen alcohol use outcomes.

Interpretation: The guideline is intended to be a resource for physicians, policymakers and other clinical and nonclinical personnel, as well as individuals, families and communities affected by alcohol use. The recommendations seek to provide a framework for addressing a large burden of unmet treatment and care needs for alcohol use disorder within Canada in an evidence-based manner.

Hidradenitis suppurativa

Author/s: 
Robert Sabat, Afsaneh Alavi, Kerstin Wolk, Ximena Wortsman, Barry McGrath, Amit Garg, Jacek C Szepietowski

Hidradenitis suppurativa is a chronic inflammatory disease characterised by painful, deep-seated nodules, abscesses, and draining tunnels in the skin of axillary, inguinal, genitoanal, or inframammary areas. In recent years, the body of knowledge in hidradenitis suppurativa has advanced greatly. This disorder typically starts in the second or third decade of life. The average worldwide prevalence is 1% but varies geographically. Hidradenitis suppurativa has a profound negative effect on patients' quality of life and on the gross value added to society. Comorbidities (eg, metabolic syndrome, inflammatory arthritis, and inflammatory bowel disease) frequently accompany skin alterations, because of systemic inflammation. Pathogenesis of hidradenitis suppurativa is complex and includes innate immune mechanisms (eg, macrophages, neutrophils, IL-1β, tumour necrosis factor [TNF], and granulocyte colony-stimulating factor), T-cell mechanisms (eg, IL-17 and IFN-γ), and B-cell mechanisms (eg, associated with dermal tertiary lymphatic structures and autoantibodies). Chronic inflammation leads to irreversible skin damage with tunnel formation and morbid scarring. Current treatment includes drug therapy (for the initial, purely inflammatory phase), combined drug and surgical therapy (for the destructive phase), or surgery alone (for the burnout phase). The first systemic therapies approved for hidradenitis suppurativa targeting TNF (adalimumab) and IL-17 (secukinumab and bimekizumab) have expanded drug therapy options for moderate-to-severe disease, which were previously mainly restricted to oral antibiotics. Moreover, there is a robust pipeline of immunomodulatory drugs in various stages of development for hidradenitis suppurativa. Aims of management should include early intervention to prevent irreversible skin damage, adequate control of symptoms including pain, and mitigation of extra-cutaneous comorbidities, all requiring early diagnosis and an interdisciplinary, holistic and personalised approach.

Long-Term Use of Muscle Relaxant Medications for Chronic Pain: A Systematic Review

Author/s: 
Benjamin J Oldfield, Brynna Gleeson, Kenneth L Morford, Zoe Adams, Melissa C Funaro, William C Becker, Jessica S Merlin

Importance: Stricter opioid prescribing guidelines have increased prescriptions of skeletal muscle relaxants (SMRs) for chronic pain, but the efficacy of long-term use of SMRs for chronic pain is unknown.

Objective: To systematically review the effectiveness or efficacy of long-term use of SMRs for chronic pain.

Evidence review: Two reviewers systematically searched Ovid MEDLINE, Embase (Ovid), Web of Science, CINAHL, and Cochrane through December 4, 2023. They included articles published in English, Spanish, or Italian. Only randomized clinical trials (RCTs) and cohort studies with comparator groups evaluating at least 1-month duration of SMRs for chronic pain were included. The reviewers dually reviewed data abstraction, risk-of-bias, and quality. They characterized studies by chronic pain syndrome: low back pain, fibromyalgia, headaches, painful cramps or spasticity, and other syndromes.

Findings: A total of 30 RCTs with 1314 participants and 14 cohort studies with 1168 participants assessed SMRs for chronic pain. Studies were primarily short-term (4-6 weeks). Nine unique SMRs were represented by the studies identified. Eleven studies (25%) examined baclofen, 8 (18%) examined tizanidine, and 7 (16%) examined cyclobenzaprine. Evidence for effectiveness was strongest for SMRs used for trigeminal neuralgia, neck pain, and painful cramps; evidence suggested SMRs for fibromyalgia, low back pain, and other syndromes were not more beneficial than placebo. The most common adverse effects were sedation and dry mouth. RCTs had a low to moderate risk of bias, and the quality of cohort studies was fair to good.

Conclusions and relevance: In this systematic review of long-term use of SMRs for chronic pain, findings suggest that their long-term use may benefit patients with painful spasms or cramps and neck pain; their long-term use for low back pain, fibromyalgia, and headaches did not appear to be beneficial. Clinicians should be vigilant for adverse effects and consider deprescribing if pain-related goals are not met.

Melanoma crash course

Author/s: 
Ashton, R., Wilkinson, A.N.

Cutaneous melanoma represents about 4% of skin cancers but is responsible for more than 75% of deaths from skin cancer. The incidence of cutaneous melanoma is reported as 25 per 100,000 people in North America and 60 per 100,000 people in Australia and New Zealand. Melanoma diagnoses are increasing worldwide, possibly owing to improved detection; in Canada the largest increase in age-standardized incidence of melanoma has occurred in males, with an increase of 2.2% per year between 1984 and 2019. Mortality rates for melanoma have declined since 2013 due to the use of immunotherapy; however, there has been no noted reduction in mortality among non-White patients or among populations with lower socioeconomic status, with a study demonstrating that these populations have higher incidences of thick melanoma with poorer prognoses.

There is insufficient evidence to support the effectiveness of skin cancer screening in reducing melanoma mortality, with an Australian study published in 2022 finding that skin screening increases the risks of biopsy and melanoma in situ without increasing the detection rate of invasive melanoma, compared with unscreened individuals. The United States Preventive Services Task Force also does not recommend regular skin checks in the average individual as part of age-appropriate screening guidelines. A guideline published by the Canadian Task Force on Preventive Health Care, based on reports from Australia and New Zealand, recommends regular skin examinations for those at high risk of melanoma (Table 1).

Keywords 

Assessment of urinary incontinence in older adults, part 1

Author/s: 
Gibson, W., Molnar, F., Frank, C.

Clinical question
How should I assess my older patient who has urinary incontinence (UI)?

Bottom line
Urinary incontinence, the involuntary loss of any urine, is a common problem among people older than 65 or those living with frailty but should not be considered part of “normal” aging. The cornerstones of assessment are comprehensive history, basic physical examination, and focused investigations. Urinary incontinence is a multifactorial geriatric syndrome, not necessarily a disorder of the lower urinary tract itself. A detailed review of this topic was published in 2015 in the Canadian Geriatrics Society Journal of CME.

Examining for a Dislocated Hip in Infants

In many countries clinical examination is the primary screening tool to identify dislocated hips in newborns, with a positive screening examination typically triggering an ultrasound assessment of the hips. However, the condition is rare and the examination can be difficult to perform. We explore the key components of the examination - symmetry of limb length, symmetry of abduction and consider the ’special tests’ of instability, known as the ‘Barlow’ and ‘Ortolani’ maneuvre. However, given the rarity of the disease, even in expert hands for every 1000 newborn hips screened with the clinical examination, relying on the Barlow and Ortolani maneuvres will identify 5 dislocations, result in 13 “unnecessary” ultrasound scans and 4 missed diagnoses. For every 1000 newborn hips screened with limited hip abduction, the system would identify 1 dislocation, result in 33 “unnecessary” ultrasound scans and 8 missed diagnoses per 1000 newborn hips.

Semaglutide vs Endoscopic Sleeve Gastroplasty for Weight Loss

Author/s: 
Haseeb, M., Chhatwal, J., Xiao, J., Jirapinyo, P., Thompson, C.C.

Importance: Obesity is a disease with a large socioeconomic burden. Endoscopic sleeve gastroplasty (ESG) is a minimally invasive endoscopic bariatric procedure with wide global adoption. More recently, new weight-loss medications, such as glucagon-like peptide-1 receptor agonists (eg, semaglutide), have attracted increased attention due to their efficacy. However, their cost-effectiveness over an extended period compared with ESG is a critical gap that needs to be better explored for informed health care decision-making.

Objective: To assess the cost-effectiveness of semaglutide compared with ESG over 5 years for individuals with class II obesity.

Design, setting, and participants: This economic evaluation study, conducted from September 1, 2022, to May 31, 2023, used a Markov cohort model to compare ESG and semaglutide, with a no-treatment baseline strategy. The study comprised adult patients in the US health care system with class II obesity (body mass index [BMI] of 35-39.9). The base case was a 45-year-old patient with class II obesity (BMI of 37). Patients undergoing ESG were subjected to risks of perioperative mortality and adverse events with resultant costs and decrement in quality of life.

Interventions: Strategies included treatment with semaglutide and ESG.

Main outcomes and measures: Costs (2022 US dollars), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) with a willingness-to-pay threshold of $100 000/QALY. A 5-year time horizon with a cycle length of 1 month with a 3% discount rate was used. Probabilities, costs, and quality-of-life estimates of the model were derived from published literature. One-way, 2-way, and probabilistic sensitivity analyses were also performed.

Results: The model found that ESG was more cost-effective than semaglutide over a 5-year time horizon, with an ICER of -$595 532/QALY. Endoscopic sleeve gastroplasty added 0.06 QALYs and reduced total cost by $33 583 relative to semaglutide. The results remained robust on 1-way and probabilistic sensitivity analyses. Endoscopic sleeve gastroplasty sustained greater weight loss over 5 years vs semaglutide (BMI of 31.7 vs 33.0). To achieve nondominance, the annual price of semaglutide, currently $13 618, would need to be $3591.

Conclusions and relevance: This study suggests that ESG is cost saving compared with semaglutide in the treatment of class II obesity. On price threshold analyses, a 3-fold decrease in the price of semaglutide is needed to achieve nondominance.

Uterine Fibroids

Author/s: 
Marsh, E.E., Wegienka, G., Williams, D.R.

Uterine fibroids are sex–steroid responsive benign tumors primarily composed of smooth muscle cells and extracellular matrix that develop in the wall of the uterus.1 They are one of the most common neoplasms in reproductive-aged women. Lifetime prevalence estimates in premenopausal women range from 40% to 89%, depending on the method of detection, the study population, and the ages of those studied. Fibroids can range in size from less than 1 cm to more than 20 cm. Although not all individuals with fibroids have symptoms, typical symptoms include abnormal uterine bleeding/heavy menstrual bleeding (AUB/HMB), pelvic bulk symptoms (protruding abdomen, pressure on bladder and bowels), pain, and reproductive morbidity (ie, infertility). Due to their high prevalence and associated symptoms, fibroids are the leading cause of hysterectomy in the US and account for up to $34 billion annually in direct and indirect costs.

Drug Efficacy in the Treatment of Antipsychotic-Induced Akathisia: A Systematic Review and Network Meta-Analysis

Author/s: 
Gerolymos, C, Barazer, R, Yon, D.K., Loundou, A, Boyer, L, Fond, G

Importance: Antipsychotic-induced akathisia (AIA) occurs in 14% to 35% of patients treated with antipsychotics and is associated with increased suicide and decreased adherence in patients with schizophrenia. However, no comprehensive review and network meta-analysis has been conducted to compare the efficacy of treatments for AIA.

Objective: To compare the efficacy associated with AIA treatments.

Data sources: Three databases (MEDLINE, Web of Science, and Google Scholar) were systematically searched by multiple researchers for double-blind randomized clinical trials (RCTs) comparing active drugs for the treatment of AIA with placebo or another treatment between May 30 and June 18, 2023.

Study selection: Selected studies were RCTs that compared adjunctive drugs for AIA vs placebo or adjunctive treatment in patients treated with antipsychotics fulfilling the criteria for akathisia, RCTs with sample size of 10 patients or more, only trials in which no additional drugs were administered during the study, and RCTs that used a validated akathisia score. Trials with missing data for the main outcome (akathisia score at the end points) were excluded.

Data extraction and synthesis: Data extraction and synthesis were performed, estimating standardized mean differences (SMDs) through pairwise and network meta-analysis with a random-effects model. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed.

Main outcomes and measures: The primary outcome was the severity of akathisia measured by a validated scale at the last available end point.

Results: Fifteen trials involving 492 participants compared 10 treatments with placebo. Mirtazapine (15 mg/d for ≥5 days; SMD, -1.20; 95% CI, -1.83 to -0.58), biperiden (6 mg/d for ≥14 days; SMD, -1.01; 95% CI, -1.69 to -0.34), vitamin B6 (600-1200 mg/d for ≥5 days; SMD, -0.92; 95% CI, -1.57 to -0.26), trazodone (50 mg/d for ≥5 days; SMD, -0.84; 95% CI, -1.54 to -0.14), mianserin (15 mg/d for ≥5 days; SMD, -0.81; 95% CI, -1.44 to -0.19), and propranolol (20 mg/d for ≥6 days; SMD, -0.78; 95% CI, -1.35 to -0.22) were associated with greater efficacy than placebo, with low to moderate heterogeneity (I2 = 34.6%; 95% CI, 0.0%-71.1%). Cyproheptadine, clonazepam, zolmitriptan, and valproate did not yield significant effects. Eight trials were rated as having low risk of bias; 2, moderate risk; and 5, high risk. Sensitivity analyses generally confirmed the results for all drugs except for cyproheptadine and propranolol. No association between effect sizes and psychotic severity was found.

Conclusions and relevance: In this systematic review and network meta-analysis, mirtazapine, biperiden, and vitamin B6 were associated with the greatest efficacy for AIA, with vitamin B6 having the best efficacy and tolerance profile. Trazodone, mianserin, and propranolol appeared as effective alternatives with slightly less favorable efficacy and tolerance profiles. These findings should assist prescribers in selecting an appropriate medication for treating AIA.

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