Irradiation in Early-Stage Breast Cancer

Posted by Carla Rothaus • July 24th, 2015

Irradiation in Early-Stage Breast Cancer  PIT 7-24-15Women with breast cancer who are undergoing breast-conserving surgery were assigned to receive whole-breast irradiation with or without regional nodal irradiation. At 10 years, disease-free survival in the nodal-irradiation group was improved but overall survival was not.

Many women with early-stage breast cancer undergo breast-conserving surgery followed by whole breast irradiation, which reduces the rate of local recurrence. Radiotherapy to the chest wall and regional lymph nodes, termed regional nodal irradiation, which is commonly used after mastectomy in women with node-positive breast cancer who are treated with adjuvant systemic therapy, reduces locoregional and distant recurrence and improves overall survival. An unanswered question is whether the addition of regional nodal irradiation to whole-breast irradiation after breast-conserving surgery has the same effect.

Clinical Pearls

Does the addition of regional nodal irradiation to whole-breast irradiation after breast-conserving surgery prolong survival in early-stage breast cancer?

In the study by Whelan et al., eligible patients were women with invasive carcinoma of the breast who were treated with breast-conserving surgery and sentinel-lymph-node biopsy or axillary-node dissection and who had positive axillary lymph nodes or negative axillary nodes with high-risk features. The study randomly assigned women to undergo either whole-breast irradiation plus regional nodal irradiation (including internal mammary, supraclavicular, and axillary lymph nodes) (nodal-irradiation group) or whole-breast irradiation alone (control group). There was no significant between-group difference in overall survival, with 10-year rates of survival of 82.8% in the nodal-irradiation group and 81.8% in the control group (hazard ratio, 0.91; 95% confidence interval [CI], 0.72 to 1.13; P=0.38). Moreover, no significant difference was detected in breast-cancer mortality, with 10-year rates of 10.3% in the nodal-irradiation group and 12.3% in the control group (hazard ratio, 0.80; 95% CI, 0.61 to 1.05; P=0.11).

Table 1. Characteristics of the Patients at Baseline.

Figure 1. 10-Year Kaplan-Meier Estimates of Survival.

Does the addition of regional nodal irradiation to whole-breast irradiation after breast-conserving surgery prolong disease-free survival in early-stage breast cancer?

In the Whelan study, the rate of disease-free survival was higher in the nodal-irradiation group than in the control group, with 10-year rates of 82.0% and 77.0%, respectively (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). The 10-year rates of isolated locoregional disease-free survival were 95.2% in the nodal-irradiation group and 92.2% in the control group (hazard ratio, 0.59; 95% CI, 0.39 to 0.88; P=0.009). The rates of distant disease-free survival at 10 years were 86.3% in the nodal-irradiation group and 82.4% in the control group (hazard ratio, 0.76; 95% CI, 0.60 to 0.97; P=0.03).

Figure 2. Disease-free Survival at 10 Years, According to Subgroup.

Table 2. Disease Recurrence or Death.

Morning Report Questions

Q: Are there increases in the rates of adverse events with the addition of regional nodal irradiation in early-stage breast cancer?

A: For acute events (those occurring 3 months or less after the completion of radiation), significant increases in the rates of radiation dermatitis and pneumonitis were reported in the nodal-irradiation group. For delayed events (those occurring 3 months or less after the completion of radiation), there were significant increases in the rates of lymphedema, telangiectasia of the skin, and subcutaneous fibrosis in the nodal-irradiation group. No increases in rates of brachial neuropathy, cardiac disease, or second cancers were observed in the nodal-irradiation group, but the period of follow-up was not sufficiently long to rule out a difference in the rate of secondary cancers.

Table 3. Adverse Events of Grade 2 or Higher.

Q: Were there any subgroups in the Whelan study that appeared to particularly benefit from the addition of regional nodal irradiation?

A: Although subgroup analyses were prespecified, they were generally not adequately powered to assess the benefit of treatment in different subgroups. Furthermore, the P values of the subgroup analyses were not adjusted for multiple testing. Patients with ER-negative or PR-negative tumors appeared to benefit more from regional nodal irradiation than those with ER-positive or PR-positive tumors. Although this effect was not observed in previous trials of postmastectomy radiation therapy, it supports the hypothesis that further research on the molecular characterization of the primary tumor may identify patients who are more likely to benefit from regional nodal irradiation. Since the number of node-negative patients in this trial was relatively small, the application of the study results to node-negative patients is unclear.

Gallbladder Disease

Posted by Carla Rothaus • July 24th, 2015

Peroral Endoscopic 7-25-15A new review summarizes recent innovations in the approaches to gallbladder disease, including laparoscopic cholecystectomy, cholecystectomy with natural orifice transluminal endoscopic surgery, percutaneous cholecystostomy, and peroral endoscopic gallbladder drainage.

Cholecystectomy is a well-established and frequently performed procedure. The demand for safer and less-invasive interventions continues to promote innovations in the management of gallbladder disease.

Clinical Pearls

•Describe laparoscopic approaches that are less invasive then standard laparoscopic cholecystectomy.

In single-incision laparoscopic cholecystectomy, one large, transumbilical, multi-instrument port is used instead of four incisions, leaving only a periumbilical scar. Theoretical but unproven advantages include improved cosmesis and reductions in postoperative pain, recovery time, and wound-related adverse events. Another less invasive technique, mini-laparoscopy, involves the use of access ports and instruments with a small diameter (2 to 5 mm). The cosmetic results are better than with standard laparoscopic cholecystectomy, but randomized trials have not shown other advantages. Single-incision laparoscopic and mini-laparoscopic cholecystectomy have failed to gain widespread acceptance because the techniques are more challenging to learn, and the procedures prolong operative time and increase costs.

Figure 1. Comparison of Access-Port Locations and Diameters for Conventional Laparoscopic Cholecystectomy, Mini-Laparoscopic Cholecystectomy, and Single-Incision Laparoscopic Cholecystectomy.

•What is the advantage of natural orifice transluminal endoscopic surgery (NOTES) cholecystectomy as compared to the laparoscopic approach?

NOTES is a technique in which surgery is performed through a naturally existing orifice and does not leave a cutaneous scar. It is typically performed by means of transgastric or transvaginal access with the use of flexible or rigid endoscopes, alone or in combination with limited laparoscopic access (which is known as hybrid NOTES). A major advantage of NOTES over laparoscopic approaches is the fact that removal of the resected gallbladder does not require an incision in the abdominal wall, which can be a source of postoperative pain and complications in wound healing. The procedure has been performed only a few thousand times, most often through the transvaginal route in patients without acute cholecystitis. Outcomes have been similar to those achieved with laparoscopic cholecystectomy, although it is associated with a better aesthetic outcome, a shorter recovery time, and less pain. NOTES requires special equipment and is technically very difficult. Consequently, adoption of this technique has been limited to a few select medical centers.

Figure 2. Sites of Entry for Cholecystectomy with Natural Orifice Transluminal Endoscopic Surgery (NOTES).

Morning Report Questions

Q: Is there an alternative to percutaneous drainage of the gallbladder for patients who are not surgical candidates?

A: Transpapillary drainage of the gallbladder, which was first reported more than 25 years ago, follows the standard procedure for cannulation of the bile duct with the use of endoscopic retrograde cholangiography. A guidewire is advanced through the cystic duct and into the gallbladder. One end of a pigtail stent is deployed within the gallbladder, and the other end is either brought out through a nasobiliary catheter that exits through the nose or left to drain internally within the duodenum (double pigtail stent). The procedure is helpful in patients with symptomatic cholelithiasis who are not good candidates for percutaneous therapy or surgery, particularly those with advanced liver disease, ascites, or coagulopathy. The use of transpapillary drainage of the gallbladder is limited by the technical difficulty of advancing a guidewire from a retrograde position through the cystic duct, which is often long, narrow, and tortuous and is sometimes occluded by an impacted gallstone. In addition, the cystic duct can accommodate only small-caliber plastic stents (5 to 7 French), which are prone to occlusion with biofilm.

Q: Is transpapillary drainage the only alternative to percutaneous cholecystectomy?

A: The most recent alternative to percutaneous cholecystostomy is transmural endoscopic ultrasound-guided gallbladder drainage, which was described in 2007. The gallbladder is usually closely apposed to the gastrointestinal tract and is conspicuous on endosonography. The use of Doppler imaging allows the endoscopist to avoid vessels while introducing the needle into the gallbladder. A guidewire is then positioned within the gallbladder, which allows for the deployment of transnasal drainage catheters or internal stents. Although assessments of endoscopic ultrasound-guided gallbladder drainage have been limited to small studies conducted at expert centers, the procedure has been effective in the treatment of more than 95% of high-risk surgical patients who have acute cholecystitis. The development of endoscopic transmural access to the gallbladder introduces new questions, such as whether the stent can be easily removed, as well as whether the stent should be removed and, if so, when it should be removed.

Figure 3. Peroral Endoscopic Approaches to Gallbladder Drainage.

Table 2. Advantages and Disadvantages of Interventional Approaches to Symptomatic Gallbladder Disease.

Figure 4. Procedures for the Treatment of Symptomatic Gallbladder Disease, Stratified According to Patient Operative Status and Disease Severity.


Take the Fluids and Electrolytes Challenge

Posted by Jennifer Zeis • July 22nd, 2015

diabetic ketoacidosis 7-23-15A 28-year-old man presents with diabetic ketoacidosis after an influenza-like illness. Lab values include: sodium 144 mmol/L, potassium 5.7 mmol /L, chloride 98 mmol /L, sodium bicarbonate 13 mmol/L, creatinine 1.5 mg/dL, BUN 30 mg/dL, glucose 702 mg/dL, and venous pH 7.2. What is the best strategy to support this patient?

Take the poll and comment now. On Twitter use #NEJMCases.

Find the answers in the review article, “Electrolyte and Acid-Base Disturbances in Patients with Diabetes Mellitus,” to be published on August 6. 

Now on the NEJM Group Open Forum

Posted by Jennifer Zeis • July 21st, 2015

Here’s an update with the latest on the NEJM Group Open Forum.

The NEJM CareerCenter, in conjunction with Medstro and the American Physician Scientist Association, today opens an exploration of topics related to physician-scientist careers. Take the opportunity to chat with an esteemed panel from the National Institutes of Health, Brigham and Women’s Hospital, and the Mayo Clinic, as well as innovators from the TEDMED community and biotechnology.

The discussion series will focus on the following topics.

July 21, 2015: Physician-Scientists Shaping American Healthcare

July 28, 2015: Physician-Scientist Training: Current Options and Future Changes

August 4, 2015: How funding may impact the future of the Physician-Scientist

August 11, 2015: Successful Physician-Scientists mentor-mentee relationships

August 18, 2015: Physician-Scientist Transitions: How to take those next steps.

August 25, 2015: Role of Scientific Organizations in Training and Career

Also opening today, we bring together experts to discuss and share how we are implementing high value care strategies in daily practice, whether that’s in the hospital, on rounds, during Grand Rounds, or in the clinic. We’ll also discuss the place high value care has in the future of American health care.

The NEJM Group Open Forum is a pilot project we are running in collaboration with Medstro, a social professional network for physicians. Free registration is required; social login is available through Facebook, Twitter, Google, and LinkedIn.

You’re welcome to join any (or all!) of these discussions. Read the questions and answers posted so far; and like, share, and comment to become a part of the conversation.

Heparin-Induced Thrombocytopenia

Posted by Carla Rothaus • July 17th, 2015

Heparin-Induced 7-17-15A new Clinical Practice article provides an overview of heparin induced thrombocytopenia. HIT is characterized by a platelet count fall of more than 50% at 5 to 10 days after the start of heparin and hypercoagulability. Platelet factor 4–heparin antibody testing has a high negative, but low positive, predictive value. Treatment involves therapeutic-dose anticoagulation.

In contrast to other conditions caused by enhanced consumption, impaired production, or destruction of platelets, which lead to bleeding complications, immune-mediated heparin-induced thrombocytopenia (HIT) does not induce bleeding but rather results in a paradoxical prothrombotic state. Thromboembolic complications develop in approximately 50% of patients with confirmed HIT. Venous thrombosis of the large vessels of the lower limbs and pulmonary embolism are the most frequent complications, followed by peripheral arterial thrombosis and then stroke; myocardial infarction is uncommon.

Clinical Pearls

Who is most at risk for HIT?

HIT occurs in approximately 1 in 5000 hospitalized patients. The risk of HIT depends on the type of heparin and the patient population. The incidence is up to 10 times as high among patients receiving unfractionated heparin as it is among those receiving low-molecular-weight heparin, and HIT occurs more frequently among patients who have had major surgery than among those who have had minor surgery or are receiving medical therapy. HIT is rare in obstetrical patients, although in contexts other than pregnancy, women are at slightly higher risk than men.

Figure 1. Pathogenesis of Heparin-Induced Thrombocytopenia.

What is the typical time course for the onset of HIT, and what is the magnitude of the decrease in platelet count?

The onset of HIT characteristically occurs between 5 and 10 days after heparin is started, both in patients who receive heparin for the first time and in patients with reexposure. However, there are exceptions. In persons who have received heparin within the previous 90 days (especially, less than or equal to 30 days), there may be persistent circulating anti-platelet factor 4 (PF4)-heparin antibodies, and HIT can start abruptly on reexposure to heparin (rapid-onset HIT); in this case, HIT is sometimes complicated by an anaphylactoid reaction within 30 minutes after a heparin bolus. The fall in platelet count in HIT occurs rapidly (over a period of 1 to 3 days) and is assessed relative to the highest platelet count after the start of heparin. The typical nadir is 40,000 to 80,000 platelets per cubic millimeter, but the count may remain in the normal range (e.g., a decline from 500,000 to 200,000 per cubic millimeter). In less than 10% of patients, the decrease in platelet count is less pronounced (30 to 50% of the highest preceding value). Rarely, the platelet count may fall below 20,000 per cubic millimeter, especially when HIT is associated with other causes of thrombocytopenia, such as consumptive coagulopathy.

Morning Report Questions

Q: How should a patient at risk for or with suspected HIT be evaluated?

A: Although monitoring of platelet counts facilitates the recognition of HIT, it is difficult to justify in many patients, especially outpatients. Monitoring should be considered when the risk of HIT is relatively high (>1%), such as among patients who have undergone cardiac surgery and those receiving unfractionated heparin after major surgery (other than heparin received for intraoperative flushes or catheter-related flushes). Scoring systems can be helpful in estimating the probability of HIT. A widely used scoring system is the 4T score, which evaluates four indicators: the relative platelet-count fall, the timing of the onset of the platelet-count fall, the presence or absence of thrombosis, and the likelihood of another cause, with scores on the individual components ranging from 0 to 2 and higher scores indicating a higher likelihood of HIT. For those whose score is intermediate or high, laboratory tests are needed to rule out HIT. Anti-PF4-heparin enzyme immunoassays have an excellent negative predictive value (98 to 99%) but a low positive predictive value, owing to the detection of clinically insignificant anti-PF4-heparin antibodies. Diagnostic accuracy for HIT is improved with the use of both an anti-PF4-heparin enzyme immunoassay and a functional test (e.g., a platelet-activation assay).

Figure 2. Timing of HIT and Rationale for Platelet Count Monitoring at Various Time Points.

Table 1. 4T Scoring System for Evaluating the Pretest Probability of Heparin-Induced Thrombocytopenia.

Figure 3. Diagnosis of HIT.

Q: What is the appropriate management for HIT?

A: Key interventions in patients with highly suspected or confirmed acute HIT are the prompt cessation of heparin (if still being administered) and the initiation of an alternative anticoagulant at a therapeutic dose. Prophylactic-dose anticoagulation is insufficient to compensate for massive thrombin generation, even if the patient has no apparent thrombosis. Vitamin K antagonists (e.g., warfarin and phenprocoumon) must not be given until HIT has abated (e.g., the platelet count has increased to >150,000 per cubic millimeter at a stable plateau for 2 consecutive days), because they increase the risk of venous limb gangrene and limb loss by decreasing the level of protein C. Two drugs are approved for the treatment of HIT — the direct thrombin inhibitor argatroban (in the United States, Canada, the European Union, and Australia) and the antithrombin-dependent factor Xa inhibitor danaparoid (in Canada, the European Union, and Australia). Argatroban is frequently used in critically ill patients. It has a relatively short half-life, which is independent of renal function, but it requires intravenous administration. Fondaparinux and bivalirudin are also used in this context, although they have not been approved by the Food and Drug Administration for this indication. Prophylactic platelet transfusions should be avoided in patients with HIT. The risk of bleeding is very low, and such transfusions can increase the risk of thrombosis.

A Man with Sore Throat and Myalgias

Posted by Carla Rothaus • July 17th, 2015

A Man with Sore Throat and Myalgias 7-17-15In the latest Case Record of the Massachusetts General Hospital, a 20-year-old man presented with fever and a pericardial effusion. Five weeks earlier, sore throat, fever, malaise, and myalgias had developed. Broad-spectrum antibiotic therapy was administered, without improvement. A diagnosis was made.

A number of case reports indicate an association between tamponade and adult-onset Still’s disease. One case report describes a patient with adult-onset Still’s disease and reversible constrictive pericarditis.

Clinical Pearls

What clinical and laboratory findings are associated with adult-onset Still’s disease?

Adult-onset Still’s disease is classically characterized by four cardinal symptoms: spiking fever, evanescent salmon-pink maculopapular rash, arthritis, and a white-cell count greater than 10,000 per cubic millimeter, with predominance of neutrophilic polymorphonuclear cells. The rash associated with adult-onset Still’s disease is nonpruritic; it occurs with fever and commonly involves the trunk, arms, and legs. Persistent, atypical rashes may also occur. The arthralgias and arthritis associated with adult-onset Still’s disease generally involve the larger joints (i.e., knees, wrists, elbows, ankles, and shoulders). In addition, many affected patients present with sore throat, lymphadenopathy, anemia, and abnormal results of liver-function tests, and approximately one quarter of patients have pleuritis or pericarditis. Most patients have markedly elevated ferritin levels. Pericardial effusion occurs in approximately 4% of patients with adult-onset Still’s disease, and pleural effusion occurs in approximately 18%.

Figure 1. Clinical Photograph.

Does adult-onset Still’s disease have more than one clinical phenotype?

Adult-onset Still’s disease has two clinical phenotypes — a systemic form, which is predominantly characterized by systemic symptoms (e.g., high fever and rash), and a chronic form, which is predominantly characterized by arthritis that may become deforming. The systemic form is associated with a better prognosis and may be monophasic.

Morning Report Questions

Q: Are there diagnostic laboratory tests or specific histologic findings for adult-onset Still’s disease?

A: In patients with adult-onset Still’s disease, synovial or pleuropericardial fluids are sterile, inflammatory exudates. In addition, skin-biopsy or lymph-node-biopsy specimens have no specific histologic appearance. A low fraction of glycosylated ferritin may have specificity for adult-onset Still’s disease, but a test for this is not widely available. No laboratory tests are specific for adult-onset Still’s disease, and therefore the diagnosis of this disorder relies on the presence of a constellation of clinical findings. Because adult-onset Still’s disease remains a diagnosis of exclusion, there is often a considerable delay in establishing the diagnosis. Differentiating between adult-onset Still’s disease and acute rheumatic fever has long been a clinical challenge because of their overlapping clinical features. Patients with adult-onset Still’s disease may have a higher maximum temperature and greater temperature swings than do patients with acute rheumatic fever. The Yamaguchi criteria are the most validated diagnostic criteria for adult-onset Still’s disease, although the Yamaguchi criteria are considered valid only in the absence of infection.

Table 3. Diagnostic Criteria for Adult-Onset Still’s Disease and Acute Rheumatic Fever.

Q: How is adult-onset Still’s disease treated?

A: Adult-onset Still’s disease is characterized by inflammation, and interleukin-1 appears to be the dominant mediator. Biologic agents that block interleukin-1 activity are highly effective in the treatment of persons with adult-onset Still’s disease. However, evidence for the treatment of adult-onset Still’s disease is based on small studies and case series. For mild disease, glucocorticoids and nonsteroidal antiinflammatory drugs may be effective. For moderate disease, glucocorticoids are typically combined with methotrexate for chronic forms or combined with biologically active agents for systemic forms. For severe disease, evidence is limited.

Take the New Case Challenge!

Posted by Karen Buckley • July 16th, 2015

pregnantA 28-year-old pregnant woman was admitted in the summer with fever, headache, and fatigue. She reported neck stiffness, earache, intermittent contractions, and a possible erythematous rash on her shin. What is the most likely diagnosis?

Vote and comment now on The answer will appear within the full text of the Case Record of the Massachusetts General Hospital published on July 30. 

On Twitter use #NEJMCases.

Mastocytosis and Related Disorders

Posted by Carla Rothaus • July 10th, 2015

Mast-Cells-PITA new review article provides an overview of recent developments concerning the physiology and pathobiology of mast cells and discusses current diagnostic and therapeutic approaches to mast-cell disorders, with an emphasis on mastocytosis.

Pathologic conditions involving mast cells appear to be more common than once thought. The diagnosis and treatment of such disorders are challenging, given protean symptoms and the presence of coexisting conditions. In patients with severe symptoms or those with allergies to hymenoptera venom, the investigation of mast-cell monoclonality may provide the diagnosis. Most symptoms can be managed with histamine-receptor antagonists or other drugs that interfere with mast-cell mediators, along with blockers of mast-cell activation.

Table 1. Conditions That Can Mimic Mast-Cell Disorders.

Figure 1. Clinically Relevant Mediators Released from Mast Cells and Putative Effects.

Clinical Pearls

Describe the variants of mastocytosis and the associated clinical features.

The most common form of mastocytosis in children, cutaneous mastocytosis, is diagnosed in the first years of life. It is commonly characterized by multiple hyperpigmented macular or maculopapular lesions that become urticarial when rubbed or scratched (Darier’s sign). In most children with cutaneous mastocytosis, the condition resolves or improves by puberty. The categories of systemic mastocytosis, which is characterized by mast-cell infiltration of various internal organs (most commonly bone marrow), are indolent mastocytosis, aggressive mastocytosis, mastocytosis associated with a hematologic non-mast-cell-lineage disease, and mast-cell leukemia. Among patients with indolent systemic mastocytosis, which is the most common variant, life expectancy is similar to that in the general population. Aggressive systemic mastocytosis, which is characterized by specific tissue damage associated with mast cells, is most commonly identified in the bone marrow, liver, gastrointestinal tract, and cortical bone. Portal hypertension and ascites, malabsorption, cytopenias, and large osteolytic lesions with pathologic fractures may ultimately develop in these patients. Patients with systemic mastocytosis and associated hematologic disease often have evidence of an additional myeloproliferative or myelodysplastic syndrome.

What mutation is seen in a majority of patients with mastocytosis?

Almost all patients with indolent systemic mastocytosis and approximately 80% of all patients with systemic mastocytosis have a somatic “gain-of-function” mutation in KIT, most commonly in codon 816 (D816V), where a valine is substituted for an aspartate.

Cutaneous mastocytosis is associated with gain-of-function KIT mutations in approximately 60 to 80% of cases.

Morning Report Questions

Q: What are the diagnostic criteria for mastocytosis?

A: The diagnosis of systemic mastocytosis is based on the presence of one major and one minor criterion or three minor criteria established by the World Health Organization. The major criterion is multifocal clustering of mast cells (>15 mast cells per cluster) identified by means of tryptase immunohistochemical analysis, KIT immunohistochemical analysis, or both in an extracutaneous organ, commonly the bone marrow. Minor criteria include abnormal morphologic features of mast cells (e.g., spindle shapes with cytoplasmic projections and sometimes bilobed and multilobed nuclei), the presence of the KIT D816V mutation, expression of CD2 or CD25 on mast cells, and an increased basal serum tryptase level (greater than or equal to 20 ng per milliliter).

Q: What laboratory findings suggest mast-cell activation in patients in whom mast-cell counts are normal?

A: Patients with increased numbers of mast cells, as is the case in systemic mastocytosis, may not always have symptoms of mast-cell activation. Conversely, mast-cell activation is often seen in patients in whom the mast-cell burden is normal, as in patients with allergic rhinitis or those presenting with anaphylaxis in whom serum tryptase levels reportedly increase during the attack but later return to normal values. However, mast-cell activation and severe anaphylactic reactions are more common in patients with systemic mastocytosis than in healthy controls. The symptoms may be subtle in a patient who has a less severe form of mast-cell activation. Serum tryptase levels that increase by 20% above the baseline level plus an additional 2 ng per milliliter if measured within 4 hours after the onset of the acute event suggest mast-cell involvement. In some patients with primary severe mast-cell activation, there is evidence of mast-cell clonality (a KIT mutation or CD25+ mast cells) that may fulfill the diagnostic criteria for systemic mastocytosis. In other patients, there is evidence of clonal mast-cell expansion, but the criteria for systemic mastocytosis are not met and these patients are known to have monoclonal mast-cell activation, which is increasingly recognized in patients with hymenoptera-induced or idiopathic anaphylaxis.

Figure 2. Algorithm for Evaluation of Possible Mastocytosis.


A Man with Fever and Bacteremia

Posted by Carla Rothaus • July 10th, 2015

Man-with-Fever-and-Bacteremia-PITIn the latest Case Record of the Massachusetts General Hospital, fever developed in a 37-year-old American man living in Vietnam. He was transferred from a local infirmary to an international hospital. A blood culture grew Streptococcus constellatus; fever resolved with antibiotics. The patient was transferred for further evaluation.

The finding of Streptococcus constellatus bacteremia mandates a search for an abscess.

Clinical Pearls

What is the most common type of visceral abscess?

Liver abscess is the most common type of visceral abscess, accounting for about 13% of intraabdominal abscesses. Risk factors include diabetes, hepatobiliary or pancreatic diseases, or Klebsiella pneumoniae infection due to host factors (e.g., glucocorticoid therapy, alcoholism, chronic disease, or neoplasia). The mortality rate associated with a liver abscess can be as high as 12%.

What is the distinguishing feature of S. constellatus?

S. constellatus is a member of the S. milleri group, which is a member of the viridans group of streptococci. S. milleri are commensal organisms; they are usually not pathogenic. S. constellatus is part of the normal flora of the human oral cavity. Despite the usual commensal status of S. constellatus, the bacteria is considered to be a true pathogen when it is found in the blood. It is a facultative anaerobe whose distinguishing feature is its ability to cause abscesses.

Morning Report Questions

Q: What anatomic sites may be infected by S. milleri?

A: S. milleri infections usually affect the mouth and throat, causing dental, peritonsillar, or sinus abscesses. Spread of abscesses to deep spaces can lead to septic thrombophlebitis of the jugular vein (Lemierre’s syndrome). Bacteremia can occur, leading to metastatic abscess formation in the lung, brain, liver, kidney, and other tissues. Endocarditis can also occur, usually in a patient with an abnormal heart valve.

Q: What are some of the reported sequelae of fish-bone ingestion?

A: There have been many case reports of fish-bone ingestion in the literature. Most of these cases occur in Southeast Asia, because some of the fish there have smaller bones, as compared with the fish in Western regions. A common complication is a liver abscess, but esophageal perforation with deep-neck infection, a thyroid abscess, and tongue and mediastinal abscesses have also been reported. A 1999 case report from Japan included a review of seven previously reported cases of fish-bone ingestion. Hepatic abscess had occurred in all cases; in four cases, the fish bones penetrated the stomach wall (three penetrated the left lobe of the liver and one penetrated the right lobe), and in three cases, the fish bones pierced the duodenum. The case report from Japan also noted that few patients were aware that they had ingested a fish bone.

Loss of FEV1 and the pathogenesis of COPD

Posted by Rachel Wolfson • July 8th, 2015

Insight-picture-7-8-15For years, the dominant model for the pathogenesis of chronic obstructive pulmonary disease (COPD) has been that exposure to particulate matter (usually tobacco smoke) leads to a rapid decline in lung function, i.e., more than 40ml of FEV1 per year. This paradigm has recently come into question, but a careful study to test this model has yet to be performed.

In this week’s issue of NEJM, Lange et al. report the results of an analysis of three longitudinal cohort studies in which there was an initial spirometry assessment performed at around age 40-the “baseline”- and at least one subsequent measurement. The authors stratified the patients into two groups: those with a FEV1 below 80% at baseline (657 individuals) and those with baseline FEV1 greater than or equal to 80% (2207). In the former group, 26% had COPD after 22 years, while in the latter group 7% had COPD (P<0.001). Of the 332 individuals with COPD at the end of observation, about half had a normal FEV1 at the beginning of the trial and subsequently experienced a rapid decline of FEV1 (mean loss of 53 ml/year), while the other half had a reduced FEV1 at the start of the trial and a reduced rate of lung function decline (mean loss of 27 ml/year), despite similar rates of smoking between these two groups.

These results suggest that our current understanding of COPD may be neglecting another subtype of the disease. While some patients do indeed experience a rapid decline in lung function, it appears that others may have lower lung function at baseline, and experience a slow decline in lung function resulting in slower onset of COPD. However, these results do not rule out the possibility that a rapid decline in FEV1 occurred in the individuals with low FEV1 at baseline before the commencement of the trial. Thus, as Frank Speizer, MD, and James Ware, PhD, point out in an accompanying editorial, the ideal trial design would involve tracking lung function measurements from soon after birth through old age.

Another interesting question that arises is, if indeed there are subtypes of COPD, does this distinction reflect differences in the underlying pathogenesis, and would these patients respond differently to treatment? Although further studies will be needed to answer these important questions it will be a long time before we can get data about the lifetime changes in FEV1. As always the message for patients is that they are better off not smoking- that we know now.