Functional Dyspepsia

Posted by Carla Rothaus • November 6th, 2015

Functional DyspepsiaFunctional dyspepsia includes pain or burning in the epigastrium, early satiety, and fullness during or after a meal, without an organic cause. It affects 5 to 11% of the population. Suitable workup and treatment are summarized in this new review article.

Dyspepsia is a constellation of symptoms referable to the gastroduodenal region of the upper gastrointestinal tract. Functional dyspepsia, a relapsing and remitting disorder, is the most common cause of these symptoms.

Clinical Pearls

• What are the diagnostic criteria for functional dyspepsia and how is it classified?

The Rome III criteria for functional dyspepsia consist of a sensation of pain or burning in the epigastrium, early satiety (inability to finish a normal-sized meal), fullness during or after a meal, or a combination of these symptoms. Symptoms must be chronic, occurring at least weekly and over a period of at least 6 months, in the absence of an organic explanation. In the past 10 years, the terminology used to describe functional dyspepsia has changed, moving away from grouping patients according to the predominant reported symptom as having ulcer-like, reflux-like, or dysmotility-like functional dyspepsia and instead describing them as having one of two newly defined syndromes, the epigastric pain syndrome and the postprandial distress syndrome. These two syndromes were proposed because as many as 80% of persons with dyspepsia report that their symptoms are aggravated by the ingestion of a meal.

Table 1. Possible Underlying Causes of Symptoms of Dyspepsia.

Figure 1. Overlap between Subcategories of Functional Dyspepsia in Community-Based and Referral Populations.

• What is the role of upper gastrointestinal endoscopy in patients with dyspepsia?

Symptoms do not reliably distinguish between organic and functional forms of the disease, so the challenge for the physician evaluating a patient with dyspepsia lies in discriminating between functional dyspepsia and organic conditions of the stomach or duodenum that may provoke similar symptoms. Given that upper gastrointestinal endoscopy is associated with a relatively low rate of identification of organic disease, it is neither desirable nor realistic to perform this test in all patients with dyspepsia. Guidelines recommend that patients with dyspepsia who report so-called alarm symptoms (see Table 2), which may indicate an underlying gastroesophageal cancer, be referred urgently for upper gastrointestinal endoscopy. For patients with simple dyspepsia who do not have alarm symptoms, in whom the likeliest diagnosis is functional dyspepsia, the requirement for any further diagnostic testing depends on the background prevalence of Helicobacter pylori infection. In populations in which the prevalence of infection is at least 10%, noninvasive testing for H. pylori, with either carbon-13-labeled urea breath testing or stool antigen testing, is recommended. In practice, however, because it is unlikely that the physician will be aware of the local prevalence of H. pylori, it is reasonable to use one of these tests as a first-line strategy, given that the testing is neither invasive nor prohibitively expensive.

Table 2. Alarm Symptoms of an Underlying Upper Gastrointestinal Cancer.

Morning Report Questions

Q: What mechanisms are thought to produce the symptoms of functional dyspepsia?

A: An overarching disease model postulates that, in genetically predisposed persons, an allergen or infection leads to antigen presentation, barrier disruption, immune activation, and a type 2 helper T-cell response in functional dyspepsia, in which eosinophils are recruited that degranulate in some patients. In some patients, this process can lead to tissue injury and symptoms, whereas in others eosinophils may be protective and promote healing. An inflamed duodenum may be sensitive to acid and induce reflex responses and cytokine release that alter gastroduodenal function and esult in meal-related symptoms.

Figure 2. An Overarching Disease Model of Functional Dyspepsia.

Q: Is there any novel therapy for the treatment of functional dyspepsia?

A: A substantial proportion of patients with functional dyspepsia have abnormalities in gastric motility and fundal accommodation. Partly as a result of the lack of efficacy of existing prokinetic drugs, new agents have been developed and tested in recent years. Acotiamide is an acetylcholinesterase inhibitor that accelerates gastric emptying and enhances gastric accommodation. In a double-blind, placebo-controlled trial involving 897 patients with functional dyspepsia in Japan, symptoms improved in 52% of those ssigned to active therapy, as compared with 35% of those assigned to placebo (P<0.001). When the effect of acotiamide on individual dyspeptic symptoms was studied, significant improvements were identified in postprandial fullness, upper abdominal bloating, and early satiety but not in upper abdominal pain or discomfort. The drug has now been approved for the treatment of the postprandial distress syndrome in Japan, and phase 3 trials are ongoing in Western populations.

Figure 3. Recommended Treatment Algorithm for Patients with a Provisional Diagnosis of Functional Dyspepsia.

Nivolumab in Renal-Cell Carcinoma

Posted by Carla Rothaus • November 6th, 2015

Kaplan-Meier CurveIn a randomized trial involving patients with advanced previously treated renal-cell carcinoma, nivolumab produced higher response rates than everolimus (25% vs. 5%) and median overall survival was longer (by 5.4 months), to more than 2 years. A new Original Article summarizes.

Each year, an estimated 338,000 new cases of renal-cell carcinoma are diagnosed worldwide, and approximately 30% of patients present with metastatic disease at the time of diagnosis. A number of targeted therapies have been approved for the treatment of advanced or metastatic renal-cell carcinoma. Although everolimus and other agents  have changed the therapeutic landscape for this disease, these treatments are associated with limited overall survival after a given agent is no longer effective. Motzer et al. conducted a randomized, open-label, phase 3 study that compared nivolumab with everolimus in patients with advanced renal-cell carcinoma, who had previously received one or two cycles of antiangiogenic therapy.

Clinical Pearls

• Does nivolumab as compared to everolimus prolong survival in patients with renal-cell carcinoma who have previously received one or two cycles of antiangiogenic therapy?

In the study by Motzer et al., patients with advanced renal-cell carcinoma who had received previous antiangiogenic treatment had longer survival with nivolumab treatment than with everolimus treatment. The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) in the nivolumab group and 19.6 months (95% CI, 17.6 to 23.1) in the everolimus group. Death occurred in 183 of the 410 patients (45%) randomly assigned to receive nivolumab and in 215 of the 411 patients (52%) randomly assigned to receive everolimus. The hazard ratio for death (from any cause) with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority.

Figure 1. Kaplan-Meier Curve for Overall Survival.

• Is nivolumab associated with a higher objective response rate than everolimus in previously treated patients?

In the study by Motzer et al., the objective response rate was higher with nivolumab than with everolimus (25% vs. 5%; odds ratio 5.98; 95% CI, 3.68 to 9.72; P<0.001). Partial responses were observed in 99 patients (24%) in the nivolumab group and in 20 patients (5%) in the everolimus group. Complete responses were observed in 4 patients (1%) in the nivolumab group and in 2 patients (<1%) in the everolimus group.

Morning Report Questions

Q: Is nivolumab associated with fewer treatment-related adverse events as compared to everolimus?

A: In the Motzer trial, treatment-related adverse events of any grade occurred in 319 of the 406 patients (79%) treated with nivolumab and in 349 of the 397 patients (88%) treated with everolimus. Grade 3 or 4 treatment-related adverse events occurred in 76 of the 406 patients (19%) treated with nivolumab and in 145 of the 397 patients (37%) treated with everolimus; the most common grade 3 or grade 4 event was fatigue (10 patients, 2%) with nivolumab and anemia (31 patients, 8%) with everolimus.

Table 2. Treatment-Related Adverse Events Reported in 10% or More of Treated Patients in Either Group.

Q: Was the benefit observed with nivolumab in the Motzer study linked to programmed death 1 ligand (PD-L1) expression in tumors?

A: A benefit was observed with nivolumab irrespective of PD-L1 expression. Nivolumab has been reported to be associated with pharmacodynamic changes in blood and tumor markers that are consistent with PD-1 inhibition. The study data corroborate previous studies that have indicated that higher levels of PD-L1 expression are associated with poorer survival in renal-cell carcinoma, but they do not support PD-L1 as a marker of treatment benefit in renal-cell carcinoma. The relationship between PD-L1 expression and outcomes after treatment with nivolumab appears to depend on tumor type and histologic class. An association between PD-L1 expression and improved outcomes with nivolumab treatment has been observed for metastatic melanoma and only some types of lung cancer.

Figure 3. Kaplan-Meier Curve for Overall Survival, According to Programmed Death 1 Ligand (PD-L1) Expression Level.

Advanced Renal Cancer: What is a Breakthrough Worth?

Posted by Rena Xu • November 4th, 2015

Kaplan-Meier CurveWhen I tell people that I am a resident in urology, they often ask me why I chose this field. There are many reasons, but one of my primary motivations was to treat renal cancer, a disease that has affected several people close to me. With early detection, surgery can be curative. Unfortunately, a third of patients have metastatic disease at the time of presentation. These patients rely on systemic therapy.

Treatment for advanced clear-cell carcinoma, the most common variant of renal cancer, starts with inhibitors of vascular endothelial growth factor receptor (VEGFR). These are the “-nibs”: sunitinib, sorafenib, pazopanib, and axitinib. If one agent fails, another can be tried. Almost all patients treated with these drugs will develop drug resistance and disease progression within a year. After that, the next line of therapy typically is an inhibitor of the mammalian target of rapamycin (mTOR) – everolimus or temsirolimus. Studies have linked everolimus to longer progression-free-survival compared to placebo.

Two trials, published recently in NEJM, suggest there may be more effective alternatives. One is nivolumab, a drug that works by a differerent mechanism. Nivolumab inhibits an immune checkpoint regulator called programmed death 1 (PD-1); by disrupting signaling between PD-1 and ligands expressed on tumor cells, which would otherwise result in immunosuppression, it restores anti-tumor immunity. The CheckMate trial randomized over 800 patients with advanced clear-cell carcinoma whose disease had progressed after one or two regimens of anti-angiogenic therapy to receive either nivolumab or everolimus. The primary endpoint was overall survival.

The study found much better results with nivolumab than everolimus. The median overall survival was 25 months with nivolumab, as compared to under 20 months with everolimus, translating to a hazard ratio for death of 0.73 (P=0.002). The objective response rate, defined as the number of patients with complete or partial response divided by the total number of randomized patients, was also higher: 25% with nivolumab versus 5% with everolimus, for an odds ratio of nearly six. Meanwhile, the rate of grade 3 or 4 adverse events was lower by almost half.

A second promising agent is cabozantinib, a multikinase inhibitor that, in addition to inhibiting VEGFR, hits other targets that have been implicated in advanced renal cell cancer. The METEOR trial randomized over 650 patients to receive either cabozantinib or everolimus. Inclusion criteria were similar to that of the CheckMate trial, except there was no limit to the number of previously attempted therapies. The primary endpoint was progression-free survival (overall survival was a secondary endpoint).

Cabozantinib was found to be associated with longer median progression-free survival than everolimus – greater than 7 months, as compared to less than 3 months. That translated to a 42% lower rate of progression or death (hazard ratio 0.58). The objective response rate was 21% with cabozantinib, versus 5% with everolimus. There was also a trend toward improved overall survival (hazard ratio for death of 0.67, P=0.005), although this did not meet the requirement for statistical significance at the pre-specified interim analysis.

But cabozantinib also had its problems. Adverse events necessitated a dose reduction in 60% of patients receiving cabozantinib, as compared to only 25% of patients receiving everolimus. The rate of grade 3 or 4 adverse events was higher — 68% with cabozantinib (the most common being hypertension and diarrhea), versus 58% with everolimus (the most common being anemia and fatigue). Approximately 10% of both treatment groups had to discontinue therapy because of adverse events.

In an accompanying editorial, Drs. David Quinn and Primo Lara of the University of Southern California and University of California Davis, respectively, write: “Given the overall survival advantage it confers and its relatively good side-effect profile, nivolumab is the choice for patients who have disease progression while they are receiving VEGF-targeted therapy.” They continue, “Cabozantinib is a salvage treatment for patients whose tumors progress during VEGF therapy; however, without a significant overall survival benefit and with significant side effects…it will not precede nivolumab in the therapeutic sequence.”  Both agents, they conclude, offer clinical benefit over everolimus that is “unequivocal.”

Clinical benefit and value aren’t necessarily the same.  Quinn and Lara raise concern about the price of these new treatment options, which may put them out of affordable range for many patients. And with increasing scrutiny over health care spending, it’s unclear to what extent we can, or should, expect insurance to subsidize expensive therapies that prolong survival for a few months. Calculating cost is one thing. Determining value – to patients and their loved ones, to the doctors who care for them, and to the communities that surround them – is something else entirely.

A Woman with a Lung Mass

Posted by Carla Rothaus • October 30th, 2015

Woman with a Lung Mass, Pleural Effusion, and Hip PainIn a new Case Record of the Massachusetts General Hospital, a 36-year-old woman presented with a mass in the middle lobe of the right lung. Lobectomy was performed, and examination of the specimens revealed evidence of lipoid pneumonia and fibrinous pleuritis. Six months later, pain in the right hip developed. A diagnosis was made.

IgG4-related disease is a systemic fibroinflammatory condition that has been described in virtually every organ. Multiple-organ involvement can be present at the initial presentation or may evolve over time. Many entities that have been previously described as idiopathic fibrosing conditions are now considered to be IgG4-related disease, which has a tendency to result in mass lesions and is often mistaken for cancer.

Clinical Pearls

• What are the most likely infectious causes of pneumonia and retroperitoneal inflammation?

Tuberculosis and actinomycosis are the most likely infectious causes of pneumonia and retroperitoneal inflammation. Mycobacterium tuberculosis is a rare cause of retroperitoneal disease that can be manifested by tubercular pseudotumors, retroperitoneal lymphadenopathy, and abscesses. Rare cases have been described of retroperitoneal fibrosis with ureteral obstruction and chronic periaortitis that is associated with spinal, peritoneal, or hematogenous spread of distant M. tuberculosis infection. Actinomycosis is a bacterial infection that may cause chronic infection of the lung and retroperitoneum, often resulting in abscess formation, dense fibrosis, and draining sinus tracts. Pelvic actinomycosis preferentially involves the ileocecal region, ovary, and fallopian tubes in the retroperitoneal area.

• How often does IgG4-related disease affect the lung and pleura?

Lung and pleural involvement is reported in 15 to 54% of patients with IgG4-related disease. In affected patients, the lung parenchyma, airways, pleura, and lymph nodes can be involved. Patients can present with abnormal imaging findings and either no symptoms or respiratory symptoms, including cough, dyspnea, and chest pain. Constitutional symptoms of fever, weight loss, and fatigue are uncommon but have been reported. Pleural involvement of IgG4-related disease may be manifested by a broad range of clinical features, including a massive pleural effusion and extensive adhesive fibrinous pleural thickening.

Morning Report Questions

Q: What characterizes IgG4-related disease involving the retroperitoneum?

A: Retroperitoneal involvement of IgG4-related disease occurs in 20% of patients and is usually manifested by back and flank pain, leg swelling, or obstructive uropathy. Such involvement is usually characterized as a retroperitoneal mass, lymphadenopathy, or a strand of inflammation around the blood vessels that is defined as periaortitis or periarteritis. Furthermore, approximately 55 to 57% of patients with idiopathic retroperitoneal fibrosis have IgG4-related disease. In patients with IgG4-related retroperitoneal fibrosis, retroperitoneal involvement is mostly located in the periaortic and peri-iliac arterial regions and is followed by ureteral involvement. Growing evidence suggests that IgG4-related disease is an important cause of noninfectious aortitis and can also affect small-caliber arteries, including the iliac and mesenteric arteries.

Q: How is IgG4-related disease diagnosed?

A: The diagnosis of IgG4-related disease is often made by reviewing archived tissue samples and carefully correlating the clinical data and pathological findings. The diagnosis of IgG4-related disease requires the presence of characteristic histologic features, an elevated level of IgG4-positive plasma cells (>50 per high-power field in the lung), and an IgG4:IgG ratio of >0.40 (>0.30 on in situ hybridization staining). Histologic features of IgG4-related disease include a dense lymphoplasmacytic infiltrate, storiform fibrosis (i.e., fibrosis with an irregularly whorled pattern), and obliterative phlebitis.

Figure 3. Resection Specimens.

Cryopreservation of Oocytes

Posted by Carla Rothaus • October 30th, 2015

Cryopreservation of OocytesCryopreservation of oocytes, which is commonly performed for egg donation or because of gonadotoxic therapy or surgery threatening the ovaries, is an option for women who elect to delay childbearing. Factors affecting live-birth rates and uncertainties are reviewed in this new Clinical Practice article.

In the United States, more than 100,000 women of reproductive age receive a diagnosis of cancer each year, and they are at risk for diminished reproductive potential or infertility as a result of treatment. The freezing of oocytes has become a clinically viable option for women who wish to have a child in the future but are facing either an age-related or iatrogenic decrease in the quality and quantity of oocytes.

Clinical Pearls

• What is currently the preferred method for cryopreservation of oocytes?

The large size and high water content of oocytes make the formation of ice crystals and subsequent cell injury or death difficult to avoid during the cooling process. Vitrification has replaced the slow-freeze method as the method of choice for cryopreserving oocytes, since it minimizes ice-crystal formation and results in higher rates of cell survival, fertilization, embryo development, and pregnancy. As compared with the slow-freeze method, vitrification involves exposure of oocytes to relatively higher concentrations of cryoprotectants for a shorter duration, followed by ultrarapid cooling either through direct immersion into liquid nitrogen (in so-called open systems) or with the use of small, volume-sealed straws (in closed systems). Once vitrified, the cells can be stored indefinitely in liquid nitrogen.

• Is there an association between cryopreservation of oocytes and subsequent congenital abnormalities?

Oocyte cryopreservation by means of slow freezing or vitrification has not been shown to increase the incidence of aneuploidy or congenital abnormalities in children, although long-term studies involving large numbers of births resulting from thawed oocytes are still lacking. Collection of data on long-term outcomes by the Society for Assisted Reproductive Technology is under way.

Morning Report Questions

Q: What factors are central to the likelihood of achieving a live birth using cryopreserved oocytes?

A: In determining the probability of achieving a live birth with the use of cryopreserved oocytes, the two most critical factors are the woman’s age at oocyte collection and the total number of oocytes available. Rates of embryo implantation decline as women age, owing to increased embryo aneuploidy; this risk applies also to cryopreserved oocytes obtained from older women. Whether cryopreservation further damages the oocyte beyond the normal age-related decrease in oocyte quality is unknown. In a prospective study evaluating the efficiency of oocyte vitrification, the proportion of vitrified oocytes that resulted in a live birth was 8.2% (12.1 oocytes per live birth) in women 30 to 36 years of age and 3.3% (29.6 oocytes per live birth) in women 36 to 39 years of age. In a multicenter observational study that assessed predictors of outcome when oocytes were vitrified, the live-birth rate decreased by 7% for every year of increase in the age of the woman. For every additional mature oocyte, the delivery rate increased by 8%.

Q: What are the guidelines of the relevant professional societies concerning oocyte cryopreservation?

A: The American Society for Reproductive Medicine suggests that oocyte vitrification and warming should be recommended to women facing infertility due to chemotherapy or other gonadotoxic therapies. The American Society of Clinical Oncology recommends that “even if women are ambivalent” about having children, they should be referred to a reproductive endocrinologist. However, the guidelines of the American Society for Reproductive Medicine also recommend caution regarding the use of oocyte vitrification to circumvent the effects of age on the reproductive potential of healthy women. These guidelines specifically state that ” . . . there are no data to support the safety, efficacy, ethics, emotional risks and cost-effectiveness of oocyte cryopreservation for this indication.”

Table 1. Reasons to Consider Cryopreservation of Oocytes.

A Woman with a Deepening Voice

Posted by Carla Rothaus • October 23rd, 2015

Woman with Hair Loss and Deepening VoiceIn a new Case Record of the Massachusetts General Hospital, a 57-year-old woman presented with hirsutism, hair loss on the scalp, and deepening of her voice. Previous testing had revealed elevated total and free testosterone levels and a normal dehydroepiandrosterone sulfate level. A diagnostic procedure was performed.

Hyperandrogenism causes several phenotypic changes, the most notable of which is change in body hair. Laboratory testing for a patient with suspected hyperandrogenism should begin with measurement of the serum total testosterone level. Assays for total testosterone measure the levels of free testosterone, albumin-bound testosterone, and sex hormone-binding globulin (SHBG)-bound testosterone. Measurement of the dehydroepiandrosterone sulfate (DHEAS) level can help to identify women with an adrenal source of androgen production, although the test lacks sensitivity and specificity.

Clinical Pearls

• What signs and symptoms suggest a diagnosis of hyperandrogenism?

Signs and symptoms suggestive of hyperandrogenism and virilization include hair loss on the scalp, hirsutism, a deepening voice, an increased libido, and postmenopausal bleeding. Circulating androgens can induce the growth of body hair but also suppress hair growth on the scalp, thus accounting for the development of male-pattern baldness (androgenetic alopecia) in women with hyperandrogenism. In many cases, postmenopausal hyperandrogenism is associated with abnormal uterine bleeding, because the peripheral conversion of excess androgens to estrogens results in endometrial hyperplasia and breakthrough bleeding. The elevated hematocrit is also consistent with hyperandrogenism, because excess testosterone can suppress the iron-regulatory hormone hepcidin. The most common cause of hyperandrogenism in premenopausal women is the polycystic ovary syndrome.

Table 2. Selected Causes of Postmenopausal Hyperandrogenism.

 Describe features of androgen-secreting ovarian tumors.

Androgen-secreting ovarian tumors account for a small minority of all ovarian tumors but are much more common than androgen-secreting adrenal tumors and constitute a range of histologic types that typically originate from the sex-cord cells. These include tumors of Sertoli and Leydig cells, lipid-cell tumors, hilar-cell tumors, and rare androgen-producing theca-cell and Brenner tumors; virtually all are associated with very high testosterone levels. Tumors of Sertoli and Leydig cells account for less than 0.4% of all ovarian tumors and usually occur in women between 20 and 40 years of age; the tumor is most often unilateral and may measure 7 to 10 cm in diameter. Pure Leydig-cell tumors are usually smaller than tumors of Sertoli and Leydig cells; they are less than 5 cm in diameter, just slightly bigger than a normal ovary. Androgen-secreting ovarian tumors are rarely malignant but can recur. Laboratory tests of patients with androgen-secreting ovarian tumors typically reveal suppressed follicle-stimulating and luteinizing hormone levels, a low plasma androstenedione level, and a markedly elevated testosterone level.

Morning Report Questions

Q: What are some of the clinical features associated with ovarian hyperthecosis?

A: Ovarian hyperthecosis is a rare, noncancerous functional disorder that results from abnormal regulation of ovarian steroidogenesis. This disorder is characterized by features similar to those of the polycystic ovary syndrome that develop over months to years, high androgen levels, and, typically, bilateral ovarian enlargement. Severe insulin resistance occurs, leading to skin tags and acanthosis nigricans; diabetes mellitus develops in many affected patients.

Q: How is ovarian hyperthecosis managed?

A: The management of ovarian hyperthecosis is largely surgical. Bilateral salpingo-oophorectomy is both diagnostic and therapeutic. Before the surgical intervention, it is crucial to perform an endometrial biopsy to evaluate for endometrial hyperplasia or carcinoma; if there is evidence of either condition, a total hysterectomy should be performed. In women who have increased risks related to the surgery or are unwilling to undergo the surgery (including premenopausal women), gonadotropin-releasing hormone (GnRH)-agonist therapy is a treatment option. Administration of GnRH agonists in a continuous rather than a pulsatile fashion has a negative-feedback effect on the pituitary, decreasing the secretion of luteinizing and follicle-stimulating hormones and thereby decreasing ovarian steroidogenesis. The length of time to testosterone suppression is usually 1 to 3 months but can vary. In premenopausal women undergoing GnRH-agonist therapy, it is important to consider estrogen- and progesterone-replacement therapies in order to avoid inducing functional menopause. The long-term effectiveness of GnRH-agonist treatment is largely unknown, but treatment discontinuation can be considered after normal testosterone levels have been sustained. Because patients who are treated with GnRH-agonist therapy have no histologic diagnosis, close monitoring with biochemical and radiologic testing is required.

Eosinophilic Esophagitis

Posted by Carla Rothaus • October 23rd, 2015

Eosinophilic Esophagitis 1Eosinophilic esophagitis is an increasingly common diagnosis among children evaluated for feeding problems and among adults with dysphagia and food impaction. A new review article covers the diagnostic criteria, pathophysiology, clinical features, and treatment of this disease.

Once considered a rare condition, eosinophilic esophagitis is now one of the most common conditions diagnosed during the assessment of feeding problems in children and during the evaluation of dysphagia and food impaction in adults. The entity exists worldwide but has been most extensively studied in Western countries, where its prevalence has been estimated to be 0.4% among all children and adults.

Clinical Pearls

• Describe some of the characteristic features of eosinophilic esophagitis.

Eosinophilic esophagitis is currently defined as a chronic, immune-mediated or antigen-mediated esophageal disease characterized by symptoms related to esophageal dysfunction and eosinophil-predominant inflammation. The dominant antigens that mediate this disease appear to be food-based. Eosinophilic esophagitis has been described in all age groups, but it predominantly affects white men, with an onset from school age to midlife. A personal or family history of atopic disorders, such as asthma, eczema, rhinitis, and anaphylactic food allergy, is common. An increased number of eosinophils in the esophageal epithelium, which is a mucosa that is typically devoid of eosinophils, is the histologic hallmark of eosinophilic esophagitis. The evidence to date indicates that eosinophilic esophagitis is a not a premalignant disease and does not diminish life span.

• What are some of the factors associated with the pathogenesis of eosinophilic esophagitis?

The male predominance of eosinophilic esophagitis, as well as studies of family history and twin concordance and genomewide association studies, suggest that there is a genetic component to eosinophilic esophagitis. Assessment of esophageal tissues from patients with eosinophilic esophagitis has revealed a striking pattern of dilated interepithelial spaces, altered epithelial barrier function, and down-regulation of proteins associated with barrier function (filaggrin and zonulin-1) and adhesion molecules (desmoglein-1). Interleukin-13 has been shown to down-regulate desmoglein-1 and filaggrin in vitro. This altered permeability can lead to a permissive environment that enhances antigen presentation, which in turn leads to recruitment of eosinophils. Several lines of evidence support the concept that eosinophilic esophagitis is an entity mediated by type 2 helper T (Th2) cell activity and induced primarily by food antigens. Studies of case series have repeatedly reported that patients with eosinophilic esophagitis have environmental and food hypersensitivity, have a response to dietary elimination of food antigens, and have a relapse with reintroduction of similar food antigens. The predominant mechanism of food allergy in eosinophilic esophagitis appears to be a non-IgE-mediated process, because omalizumab, an anti-IgE biologic treatment, is not effective, esophageal eosinophilia can develop in IgE-null and B-cell-null mice, and IgE-based skin testing does not consistently identify food-antigen triggers.

Figure 1. Pathophysiological Mechanisms of Eosinophilic Esophagitis.

Figure 2. Histologic Characteristics of Eosinophilic Esophagitis.

Morning Report Questions

Q: What clinical and endoscopic findings are associated with eosinophilic esophagitis?

A: Children may have a wide variety of nonspecific symptoms, including feeding difficulty, nausea and vomiting, heartburn, and failure to thrive. In contrast, teenagers and adults are more likely to present with dysphagia and episodes of food impaction. In rare cases, eosinophilic esophagitis may manifest with spontaneous rupture of the esophagus from forceful retching (Boerhaave’s syndrome) after a food impaction. Heartburn, especially with the ingestion of alcohol, occurs in 30% of adult patients. The most common endoscopic findings are white specks (representative of eosinophilic exudates), mucosal edema, linear furrows, esophageal rings, and strictures. Chronic remodeling is represented by strictures; a so-called “crepe-paper esophagus,” in which linear tears occur in response to minimal trauma, such as passage of the endoscope; and the “tug sign,” a firm feeling sensed by the endoscopist when performing an esophageal biopsy. In contrast to the focal distal esophageal strictures found in patients with gastroesophageal reflux disease, strictures in patients with eosinophilic esophagitis may be lengthy and tapered and commonly escape detection during endoscopy but are evident in contrast esophagrams.

Q: Is there effective treatment for eosinophilic esophagitis?

A: The use of skin-prick, atopy-patch, or specific serum IgE testing performed by an allergist to determine targeted diets has been shown to have a high degree of success in children; however, more recent work indicates that this approach may not be as effective as initially thought, with only 45% of patients having a sustained response. Nevertheless, elimination diets and the avoidance of food anaphylaxis as directed by an allergist are reasonable treatment options. An alternative diet treatment does not rely on food-allergy testing but rather eliminates the six most commonly identified types of allergenic food (wheat, milk, soy, nuts, eggs, and seafood). This so-called six-food elimination diet was found to improve symptoms and histologic abnormalities in up to 26 of 35 children and 32 of 50 adults within 6 weeks. Glucocorticoids target key mechanisms in eosinophilic esophagitis. For example, glucocorticoids decrease fibrosis through the reduction of inflammatory cells. Furthermore, increased levels of interleukin-13 (a central regulator of allergic diseases) messenger RNA and the eosinophilic esophagitis transcriptome are largely reversible with glucocorticoid treatment in vivo. Although it has not been approved by the Food and Drug Administration, fluticasone administered orally as a spray from a metered-dose inhaler or a viscous preparation of liquid budesonide are the mainstays of pharmacologic therapy for eosinophilic esophagitis. The efficacy of these topical medications in improving symptoms and histologic abnormalities after 2 to 12 weeks of use ranges from 53% to 95%. Esophageal dilation to alleviate esophageal narrowing is a commonly accepted therapy for eosinophilic esophagitis, particularly in older teenagers and adults. One of the controversial questions in the management of eosinophilic esophagitis is the role of long-term maintenance therapy. In most patients, eosinophilic esophagitis is a chronic disease, and if treatment is stopped, inflammation ensues and symptoms recur.

Table 1. Medical Treatment of Active Eosinophilic Esophagitis.

A Randomized Controlled Trial of Total Knee Replacement

Posted by Andrea Merrill • October 21st, 2015

Insight post 10-21-15Ms. Smith, as we’ll call her, was a 60-something year old woman I met on my medicine rotation during my third year of medical school. She had presented to the emergency room with fevers, chills, and pain and redness around her knee- a knee that contained hardware from her total knee replacement (TKR) three years prior. Unfortunately, workup revealed septic arthritis of her knee plus bacteremia necessitating surgery and removal of that hardware. And thus began her long road of multiple operations, prolonged antibiotic therapy, and grueling rehabilitation. As Ms. Smith reflected on her situation prior to surgery, she wondered if she had made the right decision three years ago. Maybe she should have tried a course of physical therapy first instead of choosing surgery? If she had, she certainly wouldn’t be facing this situation today, but would she still be in constant daily pain from her osteoarthritis (OA)?

These questions posed by Ms. Smith are common and valid, but until recently, there was no randomized clinical trial addressing them. This week’s issue of NEJM fills this void with a new randomized controlled trial by Skou et al. comparing TKR to non-surgical treatment for the management of moderate to severe knee OA. They randomized 100 total eligible patients from Aalborg University Hospital in Denmark — 50 to non-surgical treatment (12 weeks of individualized exercise, education, dietary advice, insoles and pain medication) and 50 to TKR followed by non-surgical treatment. The primary outcome was the between-group difference in change from baseline to 12 month KOOS4 score — a mean of scores for pain, symptoms, activities of daily living (ADL) and quality of life (QOL); there was a battery of secondary outcomes that measured additional aspects of knee function. Adverse outcomes were also recorded for each group.

Nearly 100% of the non-surgical group and about 90% of the TKR group completed the 12 month follow-up. 13 patients (26%) from the non-surgical group underwent TKR during the 12 month follow-up period, while 1 patient in the TKR group opted for non-surgical treatment only. All patients were analyzed via an intention-to-treat analysis while about 50% of each group were included in the per protocol analysis. Baseline characteristics were similar between the two groups.

For the TKR group, KOOS4 scores (on a scale from 0-100) improved by 32 units as compared to 16 in the non-surgical group, a statistically significant difference. The TKR group also had greater improvements in their scores in the subscales of the KOOS score (pain, symptoms, ADL and QOL), the Timed Get Up and Go Test, and the EQ-5D index, compared to the non-surgical group. However, serious adverse events were more common for the TKR group including 3 DVTs, 1 deep infection, and 1 supracondylar femur fracture in the TKR group.

The takeaway message from this trial is that while both TKR and a regimented non-surgical program (which includes physical therapy) resulted in clinically relevant improvements in pain and function, TKR resulted in significantly greater improvements in these outcomes but at the price of more serious advents.

So with these results in mind, what do we tell our Ms. Smiths of the world when they ask about treatment options for knee OA? The accompanying editorial by Dr. Jeffrey Katz sheds some light on this issue which he says ultimately comes down to informed patient choice. Dr. Katz comments, “For most patients, the dramatic pain relief associated with TKR provides a compelling rationale to elect surgery. Others, particularly those more risk-averse, may prefer nonoperative care. As patients vary considerably in their preferences, physicians should present the relevant data to their patients and then listen carefully.”

The authors of the first study and the editorialist are available through October 30th to answer your questions on the NEJM Group Open Forum. There is also an NEJM Quick Take video summary available.

A Man with Respiratory Failure

Posted by Carla Rothaus • October 16th, 2015

man with feverIn a new Case Record of the Massachusetts General Hospital, a 57-year-old man was admitted to the ICU with fever and respiratory failure despite treatment for pneumonia. There was rapid-onset, right upper lobe consolidation with purulent secretions on bronchoscopy. What is the most likely diagnosis?

A positive urine test for histoplasma antigen is compatible with a diagnosis of blastomycosis, because there is extensive cross-reactivity with blastomyces antigen on the urine test for histoplasma antigen. For example, one study showed that such cross-reactivity occurred in 90% of patients with blastomycosis.

Clinical Pearls

• What congenital immunodeficiency syndromes can manifest in adulthood?

Several adult-onset congenital immunodeficiency syndromes are recognized, including adult-onset chronic granulomatous diseases, the hyper-IgE syndrome, GATA2 deficiency, and common variable immunodeficiency.

• What are two clinical findings that often accompany the hantavirus pulmonary syndrome?

In Maine and Vermont, exposure to excrement of the white-footed mouse can result in the hantavirus pulmonary syndrome. This hemorrhagic syndrome is characterized by rapid respiratory failure, often accompanied by profound thrombocytopenia and cardiomyopathy.

Morning Report Questions

Q: What pathogens should be included in the differential diagnosis of pulmonary infection acquired in Southeast Asia?

A: One pathogen of pulmonary infection that can be acquired in Indonesia is Yersinia pestis, the agent of bubonic plague. The clinical manifestations of Y. pestis infection, like those of tularemia, are related to inoculation route; pneumonic forms are related to inhalation of material from a contaminated rodent. Pneumonic plague is highly infectious and has a short incubation period. Another pathogen that is endemic to Southeast Asia is Burkholderia pseudomallei, the agent of melioidosis. The incidence of melioidosis rises after heavy rainfall, and the disease is clinically manifested by an indolent nodular pneumonia with features that often mimic those of tuberculosis. Moreover, infected persons often have advanced diabetes, alcoholism, or chronic lung disease. Paragonimus westermani, a lung fluke that is endemic to Southeast Asia, can be found in undercooked shellfish such as crayfish. After the metacercariae are ingested, they migrate through the bowel wall, penetrate the diaphragm, encyst in the lungs, and eventually cavitate. Penicillium marneffei is a dimorphic fungal pathogen that is endemic to Indonesia and Japan. Patients with penicilliosis can present with overt pulmonary infection and respiratory failure; most patients with penicilliosis have impaired immunity.

Q: What features are common to both Blastomyces dermatitidis and Histoplasma capsulatum infection, and what features help distinguish between them?

A: Two dimorphic fungal agents that are specifically endemic to the St. Lawrence River basin are Blastomyces dermatitidis and Histoplasma capsulatum. Respiratory involvement is the dominant manifestation of infection with either agent. Unlike histoplasmosis, blastomycosis progresses to acute respiratory distress syndrome (ARDS) with rapid pulmonary failure in up to 10% of cases. Of the patients in whom ARDS develops, a large number were previously immunocompetent; in such patients, ARDS is associated with a mortality rate of 60 to 80%. On examination of wet-mount preparation of tracheal secretions, blastomyces is found in a high concentration; in contrast, histoplasma can often be seen only on examination of tissue-biopsy specimens. Both agents can disseminate to multiple organ systems. Histoplasma can exist intracellularly in macrophages and is often found in histiocytes of draining lymph nodes. For this reason, radiographs of patients with pulmonary histoplasmosis often show massive mediastinal lymphadenopathy, a feature that is not typically seen in patients with blastomycosis.

Figure 2. Specimens from the Lower Respiratory Tract.

Figure 3. Autopsy Specimens.

Acute Lymphoblastic Leukemia

Posted by Carla Rothaus • October 16th, 2015

leukemiaThe most common cancer in childhood is now curable in 90% of patients. Current efforts are focused on devising molecular-based therapy for the subsets of acute lymphoblastic leukemia that are most resistant to current therapy. A new review article summarizes.

Approximately 6000 cases of acute lymphoblastic leukemia (ALL) are diagnosed in the United States annually; half of the cases occur in children and teenagers. Since the first description in 1948 of temporary remission of leukemia induced by chemotherapy, pediatric ALL has provided a model for improvement of survival among patients with cancer by progressive improvements in the efficacy of multiagent chemotherapy regimens and by stratification of treatment intensity according to the clinical features of the patient, the biologic features of the leukemia cells, and the early response to treatment, all of which are predictive of the risk of relapse. Collectively, these advances have increased the survival rate from less than 10% in the 1960s to 90% today.

Figure 1. Overall Survival among Children with Acute Lymphoblastic Leukemia (ALL) Who Were Enrolled in Children’s Cancer Group and Children’s Oncology Group Clinical Trials, 1968-2009.  

Clinical Pearls

• Describe some of the epidemiological factors associated with ALL.

In the United States, the incidence of ALL is about 30 cases per million persons younger than 20 years of age, with the peak incidence occurring at 3 to 5 years of age. The incidence varies significantly according to race and ethnic group: 14.8 cases per million blacks, 35.6 cases per million whites, and 40.9 cases per million Hispanics. Childhood ALL develops more frequently in boys than in girls (male:female ratio, 55% to 45%). Several genetic factors (most prominently Down’s syndrome) are associated with an increased risk of ALL, but most patients have no recognized inherited factors. Few environmental risk factors are associated with ALL in children.

• What are the major prognostic factors for ALL?

Major prognostic factors include the clinical features that are present at diagnosis, biologic and genetic features of leukemia cells, and early response to treatment. The patient’s age and initial white-cell count are predictive of outcome, with older age or a higher white-cell count portending a worse prognosis. A consensus conference defined “standard risk” (age 1 to 9.99 years and initial white-cell count of <50,000 per cubic millimeter) and “high risk (age greater than or equal to 10 years, initial white-cell count greater than or equal to 50,000 per cubic millimeter, or both) ALL subgroups comprising, respectively, about two thirds and one third of children with B-cell lineage ALL. Age and initial white-cell count have limited prognostic importance in T-cell ALL. Infants younger than 1 year are a special subgroup of patients with worse outcomes. The time required to eliminate the bulk leukemic-cell population to undetectable levels is the single most powerful prognostic factor in ALL in children. The risk of treatment failure and death is 3 to 5 times as high among children with levels of minimal residual disease that are 0.01% or higher at the end of induction therapy and at later time points than among those with levels that are lower than 0.01%.

Table 1. Important Prognostic Factors in Acute Lymphoblastic Leukemia (ALL) in Children.

Morning Report Questions

Q: What types of somatic genetic alterations characterize ALL?

A: ALL comprises multiple entities with distinct constellations of somatic genetic alterations. These genetic alterations include aneuploidy (changes in chromosome number), chromosomal rearrangements that deregulate gene expression or result in expression of chimeric fusion proteins, deletions and gains of DNA, and DNA sequence mutations. Chromosomal translocations and intrachromosomal rearrangements are early, possibly initiating events in leukemogenesis. These translocations and rearrangements are usually present in all leukemic cells, are retained at relapse, and with additional genetic alterations, induce leukemia in experimental model systems. There are two functional classes of translocations. The first class relocates oncogenes into regulatory regions of actively transcribed genes, causing dysregulated expression of an intact protein. The second major class of translocations juxtaposes two genes to encode a chimeric protein that has distinct functions from the proteins from which it is derived. In several subtypes of ALL, there is no single defining chromosomal alteration, but these subtypes are defined by other pathological or genomic features. With the exception of MLL (mixed-lineage leukemia)-rearranged leukemia in infants, each of these subtypes typically has multiple additional genetic alterations. These alterations commonly target genes encoding proteins involved in cell signaling, tumor-suppressor functions, and lymphoid differentiation.

Figure 2. Proposed Sequential Acquisition of Genetic Alterations Contributing to the Pathogenesis and Relapse of ALL.

Q: What are some of the newer targeted therapies that are being used or evaluated for the treatment of ALL?

A: The dramatic improvements in survival among children with ALL over the past 50 years are due almost exclusively to identification of the most effective doses and schedules of chemotherapeutic agents that have been widely available for decades rather than to the development of new therapies. Recent discoveries regarding the genetic basis of ALL and the development of therapies that target molecular lesions that drive survival of ALL cells have paved the way for the expanding use of precision-medicine approaches to cancer. One notable example is the use of tyrosine kinase inhibitors in patients with chronic myeloid leukemia, a cancer that is driven by the BCR-ABL1 fusion oncoprotein. The BCR-ABL1 fusion protein also occurs in 25% of adults and in 3 to 5% of children with ALL (Philadelphia chromosome-positive translocation [Ph-positive] ALL), and in ALL, as compared with chronic myeloid leukemia, it is associated with secondary genetic alterations, particularly alterations of IKZF1. Before the use of tyrosine kinase inhibitors, less than half the children with Ph-positive ALL survived. Combining imatinib with cytotoxic chemotherapy has proved to be highly effective in children with Ph-positive ALL and has minimized the need for hematopoietic-cell transplantation in the first remission. CD19 is a cell-surface antigen that is present at high density on most B-cell ALL cells. Several groups have developed strategies to transduce autologous T-cells with an anti-CD19 antibody fragment coupled to intracellular signaling domains of the T-cell receptor, thereby redirecting cytotoxic T lymphocytes to recognize and kill B-cell ALL cells. These chimeric antigen receptor-modified T cells provide a major new treatment option. A different strategy to harness the T-cell immune response against ALL cells is provided by blinatumomab, a genetically modified antibody that contains fragments that recognize both CD19 and CD3 (which is present on all T cells) and therefore brings T cells into direct contact with B-cell ALL cells, allowing the cytotoxic T cells to kill them. Blinatumomab is now being tested in children with a first relapse of B-cell ALL.