New Interactive Medical Case: “Dissecting a Case of Abdominal Pain”

Posted by • October 31st, 2016

interactive-medical-case-blog-post-picA 43-year-old man with no notable medical history presented to the emergency department within 1 hour after the abrupt onset of abdominal pain. The patient stated that he had been dressing for work when severe, “crampy” abdominal pain occurred in the left upper quadrant. On a scale of 0 to 10, with 0 indicating no pain and 10 the worst imaginable pain, the patient rated the pain at 10. After the onset of pain, the patient had nausea, several episodes of nonbilious, nonbloody emesis, and flatus.

Test your diagnostic and therapeutic skills with this free Interactive Medical Case! Video, animation, and interactive content allow you to receive feedback on your choices made based on a series of questions and exercises, review the condition and optimal treatment steps involved in a complex evolving patient history, and earn CME credit or MOC points.

You can also browse through a list of 42 previous Interactive Medical Cases and polish your skills in a wide range of medical scenarios.

Long-Term Oxygen for COPD

Posted by • October 27th, 2016


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Two trials that were conducted in the 1970s showed that long-term treatment with supplemental oxygen reduced mortality among patients with chronic obstructive pulmonary disease (COPD) and severe resting hypoxemia. In the 1990s, two trials evaluated long-term treatment with supplemental oxygen in patients with COPD who had mild-to-moderate daytime hypoxemia; neither trial showed a mortality benefit, but both were underpowered to assess mortality. The effects of oxygen treatment on hospitalization, exercise performance, and quality of life are unclear. The Long-Term Oxygen Treatment Trial assessed the potential benefits of supplemental oxygen among patients with COPD and moderate resting desaturation or exercise-induced desaturation. In this trial, long-term supplemental oxygen treatment did not result in longer survival than no use of supplemental oxygen among patients with stable COPD and moderate resting desaturation (Spo2, 89 to 93%) or moderate exercise-induced desaturation. A new Original Article explains.

Clinical Pearl

What are the estimated oxygen-related costs for patients with COPD in the United States?

Medicare reimbursements for oxygen-related costs for patients with COPD exceeded $2 billion in 2011. If long-term treatment with supplemental oxygen reduces the incidence of COPD-related hospitalizations, increased use could be cost-effective. Reliable estimates of the number of prescriptions for supplemental oxygen that are written for the indication of exercise-induced desaturation are unavailable. Data suggest that many patients with advanced emphysema who are prescribed oxygen may not have severe resting hypoxemia.

Clinical Pearl

What Spo2 values (oxyhemoglobin saturation), as measured by pulse oximetry, are consistent with moderate resting desaturation and moderate exercise-induced desaturation?

In the Long-Term Oxygen Treatment Trial, a total of 14 regional clinical centers and their associated sites (a total of 47 centers) screened patients who had stable COPD and moderate resting desaturation (Spo2, 89 to 93%) or moderate exercise-induced desaturation (during the 6-minute walk test, Spo2 ≥80% for ≥5 minutes and <90% for ≥10 seconds).

Morning Report Questions

Q: Are there benefits to long-term supplemental oxygen for patients with COPD who have moderate resting or exercise-induced hypoxemia?

A: The authors of the Long-Term Oxygen Treatment Trial found that the prescription of supplemental oxygen for patients with stable COPD and resting or exercise-induced moderate desaturation did not affect the time to death or first hospitalization, time to death, time to first hospitalization, time to first COPD exacerbation, time to first hospitalization for a COPD exacerbation, the rate of all hospitalizations, the rate of all COPD exacerbations, or changes in measures of quality of life, depression, anxiety, or functional status. The authors found no effect on the primary outcome in subgroups of patients defined according to desaturation type, prescription type, or adherence to the regimen. The consistency of the null findings strengthens the overall conclusion that long-term supplemental oxygen in patients with stable COPD and resting or exercise-induced moderate desaturation has no benefit with regard to the multiple outcomes measured.


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Q: How do the results of the Long-Term Oxygen Treatment Trial compare with some of the earlier studies of supplemental oxygen in patients with COPD?

A: The data from the Long-Term Oxygen Treatment Trial support the conclusions of earlier studies that among patients with COPD who have a resting Spo2 of more than 88%, long-term treatment with supplemental oxygen does not result in longer survival than no long-term supplemental oxygen therapy, regardless of whether the patients have exercise-induced desaturation. The findings contrast with the prolonged survival that was observed among patients with COPD and severe desaturation who were treated with supplemental oxygen.

A Woman with Lower Abdominal Pain

Posted by • October 27th, 2016


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Most ovarian abscesses that occur in patients in the Western world are associated with pelvic inflammatory disease and are preceded by involvement of the fallopian tube as part of an ascending bacterial infection. Direct extension from nongynecologic infections or hematogenous or lymphatic spread may occur less commonly. The absence of marked tubal involvement is uncommon. A 30-year-old woman presented to the hospital with abdominal pain, nausea, and chills. Evaluation showed tachycardia, bilateral lower-quadrant abdominal tenderness, leukocytosis, and an elevated CA-125 level. Imaging studies showed adnexal cysts. A diagnosis was made in a new Case Record article.

Clinical Pearl

Is abscess formation a common complication of endometriotic cysts?

Endometriosis and endometriotic cysts are commonly associated with a low-grade inflammatory response that is generally chronic. Acute inflammation with abscess formation is rare.

Clinical Pearl

What are some of the patient factors associated with an elevated CA-125 level?

As a large transmembrane glycoprotein derived from coelomic mesothelial cells (i.e., cells originating in the pericardium, pleura, or peritoneum) and müllerian epithelium (i.e., epithelium that lines the endometrium, endocervix, and fallopian tubes), CA-125 is a nonspecific marker for peritoneal inflammation. Many factors make an elevated CA-125 level unreliable for the screening and diagnosis of ovarian cancer, because many conditions can elevate the CA-125 level, and specific patient characteristics can raise and lower the level. For example, CA-125 levels are higher in premenopausal women and in women of African or Asian descent and lower in postmenopausal women, in women who smoke, and in women who have had a hysterectomy.


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Morning Report Questions

Q: How do isolated ovarian abscesses without tubal involvement differ from tubo-ovarian abscesses?

A: As compared with tubo-ovarian abscesses, ovarian abscesses without tubal involvement are frequently unilateral, with bilateral involvement present in only 20% of cases. In contrast to tubo-ovarian abscesses, which frequently involve the surface of the ovary, isolated ovarian abscesses are often unremarkable on the surface, and the abscess becomes apparent only on sectioning.

Q: What is known about the source of infection in cases of isolated ovarian abscesses?

A: An extensive body of literature exists regarding the types of infectious organisms associated with tubo-ovarian abscesses, with such abscesses attributed to Neisseria gonorrhoeae, Chlamydia trachomatis, mixed aerobic and anaerobic organisms that are reflective of normal vaginal or cervical flora, and, infrequently, mycobacteria. A less extensive body of literature exists regarding the causative agents in cases of isolated ovarian abscesses. Such cases have revealed a variety of causative organisms, including those found in the urinary, respiratory, or oropharyngeal and gastrointestinal tracts. A number of theories have been postulated with respect to the route of infection, including direct extension of a nongynecologic infection such as diverticulitis, appendicitis, or inflammatory bowel disease; hematogenous or lymphatic spread from a distant infection; and direct inoculation caused by procedural or operative manipulation of the ovary. Historically, the literature has focused on direct inoculation, with procedural and surgical manipulation being an obvious risk factor. Occasionally infection of a preexisting cyst may occur.

Public-Access Defibrillation and Out-of-Hospital Cardiac Arrest in Japan

Posted by • October 26th, 2016


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You are walking in a mall when you notice a crowd of people around a man lying unconscious on the ground. You run to him. No pulse. You start CPR (counting aloud, “1, 2, 3…”). You look around for an automated external defibrillator (AED) and see a bystander bringing it over. You pull off the man’s shirt, put the pads in place, and hear, “analyzing rhythm…shock advised.” You press the button. His body jumps and before restarting CPR, he begins to wake up. This is the ideal situation for public-access AEDs, but how many patients benefit from this intervention?

Early defibrillation with an AED is now a crucial part of prehospital care. Japan has been a leader in this movement. Since allowing citizens to use public-access AEDs in 2004, Japan has greatly increased the availability of these life-saving machines. In this week’s NEJM, Kitamura and colleagues expand on their previous assessment of the effect of widespread dissemination of public-access AEDs in Japan. Using nation-wide registry data, the investigators evaluated outcomes of out-of-hospital ventricular fibrillation cardiac arrest between 2005 and 2013 in patients who suffered a ventricular fibrillation arrest witnessed by bystanders, were treated by bystanders or emergency medical service (EMS), and were transferred to a medical institution. The primary outcome was one-month survival with favorable neurological outcome.

From 2005 to 2013, the number of public-access AEDs increased 40-fold from 10,961 to 428,821. Of the 43,762 patients with bystander-witnessed ventricular fibrillation arrest, 4499 (10.3%) received public-access defibrillation and 39,263 (89.7%) did not. The percentage of patients who received shocks from public-access AEDs for bystander-witnessed ventricular fibrillation arrest increased from 1.1% in 2005 to 16.5% in 2013 (P<0.001 for trend).

One-month survival in patients who received public-access defibrillation was 44.7%, versus 27.9% in those who did not receive public-access defibrillation (adjusted odds ratio, 1.66; 95% CI, 1.54-1.79). After controlling for confounding factors with propensity-score matching, a higher proportion of patients who received public-access defibrillation had favorable neurological outcomes than patients who did not (38.5% vs. 26.1%; adjusted OR, 1.99; 95% CI, 1.80-2.19). The absolute number of survivors with favorable neurological outcomes attributed to public-access defibrillation increased from 6 per year in 2005 to 201 per year in 2013 (P<0.001 for trend).

Studies based on registry data have several limitations. In this study, patients who received AED shocks had different baseline characteristics than patients who did not; they were less likely to be witnessed by a family member and more likely to receive bystander CPR. Additionally, the registry did not have data on failed AED attempts, AED location, and AED accessibility.

Overall, this study may inform public health policy. The results suggest that early public-access defibrillation, in addition to early CPR, can lead to better survival rates and neurological outcomes in out-of-hospital ventricular fibrillation cardiac arrests. However, a relatively small number of patients in the registry with ventricular fibrillation arrest benefited from the public-access AEDs. The authors argue that many factors could account for this finding, including the location and accessibility of AEDs, lack of CPR training, and inability of EMS dispatchers to inform bystanders of AED locations. Further cost-effectiveness analysis is needed to help guide public-access AED strategies and policies. John Jarcho, deputy editor at NEJM, adds, “This study demonstrates that increasing the number of public-access AEDs is not the only important step in improving the care of patients with out-of-hospital cardiac arrest.”

flanagan-ryanRyan Flanagan is an MD/MPH Candidate, Class of 2017, Tufts University School of Medicine

NEJM Hosts SPRINT Data Analysis Challenge

Posted by • October 24th, 2016

challengeClinical trials are paramount to the advancement of medical knowledge and directly impact patients’ lives. Sharing pivotal data from these trials across the medical profession in a fundamentally transparent way allows for the further advancement of science and maximization of clinical trial participants’ contributions.

In order to demonstrate the potential benefits of clinical trial data sharing, the New England Journal of Medicine is sponsoring the SPRINT Data Analysis Challenge. The SPRINT Challenge tasks you with analyzing the dataset underlying the SPRINT article, A Randomized Trial of Intensive versus Standard Blood-Pressure Control along with any other publicly available dataset, and identifying a novel scientific or clinical result.

The SPRINT Challenge is an opportunity for health care professionals, researchers, and scientists from around the world to shape the future of clinical trial data sharing. Additionally, participants with the best entries may win a prize and present their findings at the Aligning Incentives for Sharing Clinical Trial Data summit and web event on April 3-4, 2017 in Boston, MA.

Visit the SPRINT Challenge website at for more information and official rules.

Chronic Cough

Posted by • October 20th, 2016


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Cough is the most common symptom for which patients seek medical attention. Chronic cough is more common among women than among men, most commonly occurs in the fifth and sixth decades of life, and can persist for years, with substantial physical, social, and psychological effects. Professional guidelines describe systematic approaches to the evaluation and management of chronic cough; these guidelines are based largely on consensus opinion and observational data from the medical literature. The evaluation of chronic cough should address the possibilities of asthma, gastroesophageal reflux disease, and postnasal drip and may require more specialized investigations. For patients with refractory chronic cough, other treatment approaches may be necessary. A new Clinical Practice article explains.

Clinical Pearl

How is chronic cough defined?

Estimates of the prevalence of cough vary, but as much as 12% of the general population report chronic coughing, defined as a cough lasting for more than 8 weeks.

Clinical Pearl

Of the many drugs that may produce cough as a side effect, which drug class is most commonly associated with cough?

Cough is listed as a side effect of many drug treatments but is most commonly associated with the use of angiotensin-converting–enzyme (ACE) inhibitors; cough occurs in approximately 20% of patients treated with ACE inhibitors.

Morning Report Questions

Q: What tests or empiric treatment would be appropriate for a patient with a chronic cough, given the most common etiologies? 

A: In the context of normal results of chest radiography and spirometry, the most common conditions associated with chronic cough are asthma, gastroesophageal reflux disease, and rhinosinusitis, although the prevalence of each of these varies substantially among cough clinics. Although most cases of asthma are associated with abnormalities on routine spirometry, methacholine challenge to assess for bronchial hyperreactivity is indicated for patients who have normal results and no other obvious cause of cough; levels of exhaled nitric oxide may also be elevated. Although data from randomized trials to guide the management of cough-variant asthma are lacking, clinical experience suggests that this condition usually responds to treatment with inhaled glucocorticoids. The relationship between cough and esophageal reflux is complex but is becoming clearer. Guidelines suggest a trial of treatment with acid-suppression therapy — for example, twice-daily treatment with proton-pump inhibitors (PPIs) for up to 3 months — in patients with chronic cough. However, many patients with cough do not have symptomatic gastroesophageal reflux disease, and most randomized, controlled trials of reflux treatment for cough have not shown a significant improvement in association with this type of treatment. Patients with chronic cough often report a sensation of postnasal drip. Guidelines recommend nasal glucocorticoids and antihistamines for patients with allergic rhinitis and chronic cough, but randomized, controlled trials to support this approach are lacking, and clinical experience indicates that the responses to this treatment are often disappointing.

Q: What is the recommended management of patients in whom asthma, rhinosinusitis, and reflux have been ruled out as a cause of cough?


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A: In patients in whom asthma, nasal disease, and reflux have been ruled out (on the basis of diagnostic investigations or trials of treatment), other conditions that may manifest with chronic coughing and could respond to treatment should be considered, and referral should be made to a specialty cough clinic, if one is available. Conditions associated with chronic cough include obstructive sleep apnea, eosinophilic bronchitis, tonsillar enlargement and recurrent tonsillitis, and external ear disease mediated through the auricular branch of the vagus nerve. In cases in which cough remains refractory, high-resolution computed tomographic (CT) scanning of the thorax is recommended to rule out parenchymal lung disease that is not visible on plain chest radiographs (e.g., pulmonary fibrosis, bronchiectasis, or sarcoidosis). Bronchoscopy may be used to identify conditions such as tracheobronchomalacia, chronic bronchitis, and tracheopathia osteochondroplastica, which may be missed on CT scanning.

Graves’ Disease

Posted by • October 20th, 2016


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Graves’ disease is an autoimmune disorder in which the thyroid is activated by antibodies to the thyrotropin receptor. The hyperthyroidism that develops is one of many somatic and psychiatric manifestations of the disease that can affect the quality and length of life. The disease is the most common cause of hyperthyroidism, with an annual incidence of 20 to 50 cases per 100,000 persons. The incidence peaks between 30 and 50 years of age, but people can be affected at any age. The lifetime risk is 3% for women and 0.5% for men. A new Review Article summarizes.

Clinical Pearl

• How common is Graves’ ophthalmopathy?

Orbital imaging reveals subtle abnormalities in 70% of patients with Graves’ disease. In specialized centers, clinically consequential ophthalmopathy is detected in up to 50% of patients with Graves’ disease, and it threatens sight as a consequence of corneal breakdown or optic neuropathy in 3 to 5% of such patients.

Clinical Pearl

• How does patient age influence the clinical manifestations of Graves’ disease?

The manifestations of Graves’ disease depend on the age of the patient at the onset of hyperthyroidism, as well as the severity and the duration of hyperthyroidism. Weight loss, decreased appetite, and cardiac manifestations are more common in elderly persons with hyperthyroidism than in those who are younger. Atrial fibrillation due to hyperthyroidism is rare in patients who are younger than 60 years of age but occurs in more than 10% of patients who are 60 years or older. Palpable goiter develops in most patients with hyperthyroidism who are younger than 60 years of age, as compared with less than 50% of older patients. Severe ophthalmopathy is more likely to develop in older men than in younger persons.

Morning Report Questions

Q: What percentage of patients with Graves’ disease who are treated with methimazole and propylthiouracil have a durable remission? 

A: Methimazole, carbimazole (which is converted to methimazole and is not available in the United States), and propylthiouracil inhibit thyroid peroxidase and thus block thyroid hormone synthesis. Propylthiouracil also blocks extrathyroidal deiodination of thyroxine to triiodothyronine. Both methimazole and propylthiouracil are associated with a high risk of recurrence after treatment has been withdrawn. Durable remission occurs in 40 to 50% of patients. Repeated therapy carries an even lower likelihood of success.

Q: How does thyroid-associated ophthalmopathy present, and how is it treated?

A: Hyperthyroidism and ophthalmopathy typically occur within 1 year of each other but can be separated by decades. Disease development is heralded by an active phase lasting up to 3 years and dominated by evolving symptoms and signs of inflammation and congestion. Proptosis, eyelid swelling, and diplopia may prompt initial medical attention. Some patients have dry eye, increased tearing, and ocular discomfort early in the active phase. This is followed by an inactive phase in which the ocular manifestations become stable. In a cohort of consecutively assessed patients with Graves’ disease, the prevalence of distinct abnormalities was as follows: eyelid retraction, 92%; exophthalmos, 62%; extraocular muscle dysfunction, 43%; ocular pain, 30%; increased lacrimation, 23%; and optic neuropathy, 6%. Treatment for ophthalmopathy depends on the phase and severity of the disease. The majority of patients require only conservative measures. These include enhancement of tear-film quality and maintenance of ocular surface moisture. Patients with disease that is severely symptomatic and sight-threatening may benefit from intravenously administered pulse glucocorticoid therapy, which appears to have a more favorable side-effect profile than glucocorticoids administered orally, although pulse therapy is not without risks. Glucocorticoids are frequently effective in reducing inflammatory symptoms, but most experts do not believe that they modify the course of the disease. Orbital decompression surgery during active disease is usually reserved for patients in whom compressive optic neuropathy has developed or is imminent.


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Romosozumab Treatment in Postmenopausal Women with Osteoporosis

Posted by • October 19th, 2016


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You are seeing one of your patients, a vivacious and active 60-year-old woman who works full time. She underwent bone densitometry testing, and the results show a T score of -2.7 at the femoral neck. Further, a short sentence on the report confirms a diagnosis of osteoporosis. Knowing that osteoporosis can lead to both vertebral and nonvertebral fractures that can affect quality of life and increase mortality risk, you must decide what to recommend.

Treatment of osteoporosis prevents further deterioration of bone mineral density. Although effective options are available, patients and physicians are often concerned about the side effects of bisphosphonates, which are antiresorptive agents, and have been approved for treatment of osteoporosis for more than a decade. Another type of medication, denosumab, a monoclonal antibody that inhibits osteoclast activation, has been shown to reduce vertebral, nonvertebral, and hip fractures in postmenopausal women with osteoporosis. Denosumab was the first biologic therapy approved for osteoporosis treatment, but reservations exist about its widespread use because, as with bisphosphonates, osteonecrosis of the jaw and atypical femoral fractures have been reported. Yet another type of agent is now available, a monoclonal antibody developed to target and inhibit sclerostin, a protein synthesized by osteoclasts that negatively affects bone formation.

In this week’s issue of NEJM, Cosman and colleagues report the results of a phase 3, international, randomized, placebo-controlled trial that examined the effect of romosozumab on fracture risk. The investigators randomized 7180 ambulatory post-menopausal women, aged 55–90 years with T-scores of -2.5 to -3.5 at the total hip or femoral neck, to receive subcutaneous injections of romosozumab or placebo once monthly for 12 months. Most participants were recruited from Central and Latin America. Patients, investigators, and sponsors were blinded during the initial 12-month phase of the trial; during a follow-on phase, all participants received open-label subcutaneous injections of denosumab every 6 months for an additional 12 months. Thoracic and lumbar spine radiographs were obtained every 6 months during both phases of the study. The coprimary endpoints were the incidences of new vertebral fracture at 12 and 24 months.

During the first 12 months, the incidence of new vertebral fractures among the 3589 romosozumab recipients was 0.5%, compared to 1.8% among the 3591 placebo recipients, representing a relative decrease of 73% with romosozumab (risk ratio, 0.27; 95% CI, 0.16 to 0.47; P<0.001). During the same period, the relative decrease in the number of clinical fractures in the romosozumab group compared to placebo was 36% (P=0.008); however, a 25% relative decrease in nonvertebral fractures between groups was not significant (P=0.096). At 24 months, after the two groups transitioned to denosumab, the relative decrease in vertebral fractures among those treated with romosozumab remained significant at 75% (risk ratio, 0.25; 95% CI 0.16 – 0.40; P<0.001).

Rates of adverse events, such as arthralgia and cardiovascular events, were similar in the two groups; however, in the romosozumab group, seven cases of hypersensitivity were reported in the first year, as well as one atypical femoral fracture and two cases of osteonecrosis of the jaw (one during the first year and the other after one dose of denosumab).

Although romosozumab was associated with a reported relative decrease in the incidence of vertebral fractures, it is unclear whether bone biologists and clinicians will be satisfied with these outcomes. The editorialists, Dr. Clifford Rosen and Dr. Julie Ingelfinger, noted the “relatively rapid progress from discovery of sclerostin (1999) to the completion of a phase 3 trial (2016) with a sclerostin antibody” but raised concerns about romosozumab’s potentially limiting adverse events. Other factors to consider when considering biologic therapy for osteoporosis and other conditions include cost, access, and efficacy.

A Man with Diplopia and Polyuria

Posted by • October 13th, 2016


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The histologic diagnosis of IgG4-related disease is predicated on the presence of characteristic histologic features, which include the presence of a dense lymphoplasmacytic infiltrate accompanied by storiform fibrosis (fibrosis with a whorled or starlike pattern that resembles a woven mat), obliterative phlebitis, or both. Another essential component of the diagnostic algorithm is the presence of increased numbers of IgG4-positive plasma cells, as well as an elevated IgG4:IgG ratio. A 53-year-old man was seen in outpatient clinics of a hospital because of a 1-year history of diplopia, polydipsia, and polyuria. Imaging studies showed mucosal thickening of the sphenoid sinus and enlargement of the pituitary gland. A diagnostic procedure was performed in a new Case Record.

Clinical Pearl

Are serum IgG4 concentrations always elevated in IgG4-related disease?

Although many patients with IgG4-related disease have a substantially elevated serum IgG4 concentration, a 2015 study of histopathologically confirmed cases of IgG4-related disease showed that 45% of the patients had normal serum IgG4 concentrations before they received treatment.

Clinical Pearl

What are some of the findings in peripheral blood and tissues in patients with active IgG4-related disease?

Patients with active IgG4-related disease typically have large clonal expansions of CD4+ cytotoxic T lymphocytes in the peripheral blood that express perforin and granzymes and that secrete profibrotic cytokines. These clonally expanded CD4+ cytotoxic T lymphocytes are the dominant T cells in the immune infiltrate in affected tissues. Activated CD19+CD20−CD38highCD27high B cells (called plasmablasts) are also a dominant feature in the blood and tissues of patients with active IgG4-related disease.


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Morning Report Questions

Q: Compare and contrast IgG4-related disease with granulomatosis with polyangiitis.

A: Differentiating between these two conditions is exceptionally difficult in some cases. High concentrations of IgG4-positive plasma cells have been reported in patients with granulomatosis with polyangiitis, as well as in patients with other conditions, a finding that precludes reliance on immunostaining for IgG4 to diagnose IgG4-related disease. Fibrosis, which may occasionally be storiform, is not uncommon in patients with granulomatosis with polyangiitis. In fact, there is substantial overlap between the histologic and immunohistochemical features of the two diseases, and it is conceivable that before IgG4-related disease was recognized as a discrete disease, cases of IgG4-related disease may have been misclassified as granulomatosis with polyangiitis. IgG4-related disease is less likely than granulomatosis with polyangiitis to lead to erosive sinonasal disease, but cases of IgG4-related disease that led to facial-bone erosion have been described.

Q: What is the treatment for IgG4-related disease?

A: Treatment with glucocorticoids is an effective initial therapy for most patients with IgG4-related disease. Unfortunately, many patients require a prolonged course of glucocorticoids to maintain remission, and a substantial number of patients have disease flares despite ongoing therapy. Because IgG4-related disease is characterized not only by elevated serum IgG4 concentrations in many patients but also by increased numbers of circulating cells that are characterized as plasmablasts (i.e., IgG4+ and total plasmablasts), treatment strategies that target cells of the B-lymphocyte lineage are being investigated. Preliminary evidence indicates that B-cell depletion therapy is an effective treatment strategy in patients with IgG4-related disease.

Ten-Year Follow-up in the ProtecT Trial

Posted by • October 13th, 2016


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The management of clinically localized prostate cancer that is detected on the basis of prostate-specific antigen (PSA) levels remains controversial. The National Institute for Health Research–supported Prostate Testing for Cancer and Treatment (ProtecT) trial was designed to evaluate the effectiveness of the three major contemporary treatment approaches to reducing prostate-cancer mortality and improving clinical outcomes in men with PSA-detected clinically localized disease. Hamdy et al. reported the effectiveness of each intervention in relation to prostate-cancer–specific mortality and all-cause mortality and the incidence of metastases and disease progression at a median of 10 years of follow-up in the randomized trial. In the ProtecT trial, over 1600 men with PSA-detected localized prostate cancer were assigned to active monitoring, prostatectomy, or radiotherapy. Although more patients assigned to active monitoring had disease progression, overall survival was similar in the three groups in a new Original Article.

Clinical Pearl

• Why is the management of clinically localized prostate cancer that has been detected with PSA testing controversial?

In the United States alone, an estimated 180,890 cases will be diagnosed in 2016, and 26,120 men will die from the disease. The widespread use of PSA testing has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer, but many men do not benefit from intervention because the disease is either indolent or disseminated at diagnosis. Prostate cancer often progresses slowly, and many men die of competing causes. In addition, interventions for prostate cancer can have adverse effects on sexual, urinary, or bowel function.

Clinical Pearl

Are there prostate-cancer mortality differences between prostatectomy, radiotherapy, and active monitoring in men with PSA-detected clinically localized disease?

At a median follow-up of 10 years, the ProtecT trial showed that mortality from prostate cancer was low, irrespective of treatment assignment. Prostate-cancer–specific survival was at least 98.8% in all groups, and there was no significant difference among the three randomized groups (P=0.48 by log-rank test). There was no evidence that between-group differences in prostate-cancer mortality varied according to age, PSA level, Gleason score, or clinical stage.

Morning Report Questions

Q: How do prostatectomy, radiotherapy, and active monitoring compare regarding disease progression and all-cause mortality in men with PSA-detected clinically localized disease?

A: In the trial by Hamdy et al., the incidence of disease progression was higher in the active-monitoring group than in the surgery and radiotherapy groups (112 men in the active-monitoring group, 46 in the surgery group, and 46 in the radiotherapy group; P<0.001 for the overall comparison). Deaths from any cause were evenly distributed across the treatment groups (P=0.87 by likelihood-ratio test), although the confidence intervals for the hazard ratios were wide and so did not provide strong evidence of equivalence across the groups.

Q: What are some of the limitations of the ProtecT trial?

A: There are several limitations of the ProtecT trial. First, the protocol was developed almost two decades ago; since then, treatments and diagnostic techniques for prostate cancer have evolved. The ProtecT trial did not use multiparametric magnetic resonance imaging to evaluate patients at diagnosis or during monitoring. Surgical techniques have changed with robot-assisted laparoscopic prostatectomy, and although all patients in the radiotherapy group received neoadjuvant androgen-deprivation therapy with three-dimensional conformal irradiation, new techniques such as intensity-modulated radiotherapy have been introduced, and brachytherapy was not included. Second, less than 1% of the participants enrolled in this trial were of African–Caribbean ancestry, but this percentage reflected the population in the recruiting centers who were in the trial age range.