The Hematology and Oncology Department at the VA Central California Health Care System (VACCHCS) in Fresno, California, is developing multiple programs to increase access to clinical trials for veterans. The department secured funding for an investigator-initiated supportive care clinical trial, which looks at the feasibility of using olanzapine to replace dexamethasone in elderly patients with diabetes who are undergoing moderate-intensity chemotherapy for prevention of nausea and vomiting. The department received a grant from the Southwest Oncology Group (SWOG) HOPE Foundation to help its clinical trials research team become members of SWOG. Currently, VACCHCS Fresno has 4 active industry-sponsored clinical trials to offer to veterans with myelodysplastic syndrome/acute myeloid leukemia, lung, prostate, and bladder cancers. They are in the process of getting another 4 clinical trials in the next 6 months.

“Our primary responsibility is to provide timely and excellent care to our veterans,” said Sachdev P. Thomas, MD, Chief of Hematology/Oncology at Fresno VACCHCS. “Wait time for new patients in our Hematology/Oncology clinic is less than 7 business days. We also have a walk-in clinic. Before we initiated our Clinical Trial program, we ensured that this metric for timely care was in place.”

Through the Association of VA Hematology/Oncology (AVAHO), Fresno VACCHCS  oncologists and a team at the Richmond VAMC in, Virginia are currently working with the National Institutes of Health, to create a VA-specific cancer clinical trials’ filter at the website Clinicaltrials.gov. This VA-specific filter will enable, any VA physician, nationwide to easily search for available clinical trials for any cancer type, throughout the VHA.

The Hematology and Oncology Department at the VA Central California Health Care System (VACCHCS) in Fresno, California, is developing multiple programs to increase access to clinical trials for veterans. The department secured funding for an investigator-initiated supportive care clinical trial, which looks at the feasibility of using olanzapine to replace dexamethasone in elderly patients with diabetes who are undergoing moderate-intensity chemotherapy for prevention of nausea and vomiting. The department received a grant from the Southwest Oncology Group (SWOG) HOPE Foundation to help its clinical trials research team become members of SWOG. Currently, VACCHCS Fresno has 4 active industry-sponsored clinical trials to offer to veterans with myelodysplastic syndrome/acute myeloid leukemia, lung, prostate, and bladder cancers. They are in the process of getting another 4 clinical trials in the next 6 months.

“Our primary responsibility is to provide timely and excellent care to our veterans,” said Sachdev P. Thomas, MD, Chief of Hematology/Oncology at Fresno VACCHCS. “Wait time for new patients in our Hematology/Oncology clinic is less than 7 business days. We also have a walk-in clinic. Before we initiated our Clinical Trial program, we ensured that this metric for timely care was in place.”

Through the Association of VA Hematology/Oncology (AVAHO), Fresno VACCHCS  oncologists and a team at the Richmond VAMC in, Virginia are currently working with the National Institutes of Health, to create a VA-specific cancer clinical trials’ filter at the website Clinicaltrials.gov. This VA-specific filter will enable, any VA physician, nationwide to easily search for available clinical trials for any cancer type, throughout the VHA.

The Hematology and Oncology Department at the VA Central California Health Care System (VACCHCS) in Fresno, California, is developing multiple programs to increase access to clinical trials for veterans. The department secured funding for an investigator-initiated supportive care clinical trial, which looks at the feasibility of using olanzapine to replace dexamethasone in elderly patients with diabetes who are undergoing moderate-intensity chemotherapy for prevention of nausea and vomiting. The department received a grant from the Southwest Oncology Group (SWOG) HOPE Foundation to help its clinical trials research team become members of SWOG. Currently, VACCHCS Fresno has 4 active industry-sponsored clinical trials to offer to veterans with myelodysplastic syndrome/acute myeloid leukemia, lung, prostate, and bladder cancers. They are in the process of getting another 4 clinical trials in the next 6 months.

“Our primary responsibility is to provide timely and excellent care to our veterans,” said Sachdev P. Thomas, MD, Chief of Hematology/Oncology at Fresno VACCHCS. “Wait time for new patients in our Hematology/Oncology clinic is less than 7 business days. We also have a walk-in clinic. Before we initiated our Clinical Trial program, we ensured that this metric for timely care was in place.”

Through the Association of VA Hematology/Oncology (AVAHO), Fresno VACCHCS  oncologists and a team at the Richmond VAMC in, Virginia are currently working with the National Institutes of Health, to create a VA-specific cancer clinical trials’ filter at the website Clinicaltrials.gov. This VA-specific filter will enable, any VA physician, nationwide to easily search for available clinical trials for any cancer type, throughout the VHA.

Beginning in less than 90 days, new veterans will become eligible for VA mental health care as soon as they leave military service. More than 250,000 service members transition out of the military each year. On Tuesday, the President signed an executive order that gives the DoD, Department of Homeland Security, and VA just 60 days to develop a plan for handling the influx of new patients into the system.

“As service members transition to veteran status, they face higher risk of suicide and mental health difficulties,” said VA Secretary David Shulkin, MD. “During this critical phase, many transitioning service members may not qualify for enrollment in health care. The focus of this executive order is to coordinate federal assets to close that gap.”

How the VA will meet the increased demand remains to be seen. As an executive order, the mandate does not come with additional funds. And in October testimony, Secretary Shulkin admitted that the VA already was having difficulty hiring and training enough mental health care providers to meet existing demand.  

The executive order is focused on the 60% of new veterans who are not immediately eligible for VA health care benefits. According to Secretary Shulkin, in the first year postseparation, often before VA eligibility is determined, these new veterans are especially at risk for suicide. “That 12-month period after you leave service is the highest risk for suicide,” Secretary Shulkin noted. Veterans during that period face almost one and a half to 2 times the risk of suicide in that first 12 months when they leave the service.

The VA outlined 3 approaches that would be implemented to meet the mental health needs for transitioning veterans. Peer counseling will play a particularly important role in the new services. First, the VA will expand its peer community outreach and group session offers and the VA whole health patient-centered care initiative. Currently, the VA Whole Health program is in 18 facilities, but it will be expanded to all facilities. The program focuses on wellness and establishing individual health goals.

In addition, the DoD “Be There Peer Support Call and Outreach Center” services will be expanded. The program will begin to offer peer support for veterans in the year following separation from the uniformed service.

Most consequently, the executive order will expand the DoD Military OneSource, which currently provides free mental health care counseling to active-duty service members and their families. The program will be expanded to include recently transitioned veterans as well. And according to a report in Military Times, Military OneSource care also may be available to the families of new veterans.

Beginning in less than 90 days, new veterans will become eligible for VA mental health care as soon as they leave military service. More than 250,000 service members transition out of the military each year. On Tuesday, the President signed an executive order that gives the DoD, Department of Homeland Security, and VA just 60 days to develop a plan for handling the influx of new patients into the system.

“As service members transition to veteran status, they face higher risk of suicide and mental health difficulties,” said VA Secretary David Shulkin, MD. “During this critical phase, many transitioning service members may not qualify for enrollment in health care. The focus of this executive order is to coordinate federal assets to close that gap.”

How the VA will meet the increased demand remains to be seen. As an executive order, the mandate does not come with additional funds. And in October testimony, Secretary Shulkin admitted that the VA already was having difficulty hiring and training enough mental health care providers to meet existing demand.  

The executive order is focused on the 60% of new veterans who are not immediately eligible for VA health care benefits. According to Secretary Shulkin, in the first year postseparation, often before VA eligibility is determined, these new veterans are especially at risk for suicide. “That 12-month period after you leave service is the highest risk for suicide,” Secretary Shulkin noted. Veterans during that period face almost one and a half to 2 times the risk of suicide in that first 12 months when they leave the service.

The VA outlined 3 approaches that would be implemented to meet the mental health needs for transitioning veterans. Peer counseling will play a particularly important role in the new services. First, the VA will expand its peer community outreach and group session offers and the VA whole health patient-centered care initiative. Currently, the VA Whole Health program is in 18 facilities, but it will be expanded to all facilities. The program focuses on wellness and establishing individual health goals.

In addition, the DoD “Be There Peer Support Call and Outreach Center” services will be expanded. The program will begin to offer peer support for veterans in the year following separation from the uniformed service.

Most consequently, the executive order will expand the DoD Military OneSource, which currently provides free mental health care counseling to active-duty service members and their families. The program will be expanded to include recently transitioned veterans as well. And according to a report in Military Times, Military OneSource care also may be available to the families of new veterans.

Beginning in less than 90 days, new veterans will become eligible for VA mental health care as soon as they leave military service. More than 250,000 service members transition out of the military each year. On Tuesday, the President signed an executive order that gives the DoD, Department of Homeland Security, and VA just 60 days to develop a plan for handling the influx of new patients into the system.

“As service members transition to veteran status, they face higher risk of suicide and mental health difficulties,” said VA Secretary David Shulkin, MD. “During this critical phase, many transitioning service members may not qualify for enrollment in health care. The focus of this executive order is to coordinate federal assets to close that gap.”

How the VA will meet the increased demand remains to be seen. As an executive order, the mandate does not come with additional funds. And in October testimony, Secretary Shulkin admitted that the VA already was having difficulty hiring and training enough mental health care providers to meet existing demand.  

The executive order is focused on the 60% of new veterans who are not immediately eligible for VA health care benefits. According to Secretary Shulkin, in the first year postseparation, often before VA eligibility is determined, these new veterans are especially at risk for suicide. “That 12-month period after you leave service is the highest risk for suicide,” Secretary Shulkin noted. Veterans during that period face almost one and a half to 2 times the risk of suicide in that first 12 months when they leave the service.

The VA outlined 3 approaches that would be implemented to meet the mental health needs for transitioning veterans. Peer counseling will play a particularly important role in the new services. First, the VA will expand its peer community outreach and group session offers and the VA whole health patient-centered care initiative. Currently, the VA Whole Health program is in 18 facilities, but it will be expanded to all facilities. The program focuses on wellness and establishing individual health goals.

In addition, the DoD “Be There Peer Support Call and Outreach Center” services will be expanded. The program will begin to offer peer support for veterans in the year following separation from the uniformed service.

Most consequently, the executive order will expand the DoD Military OneSource, which currently provides free mental health care counseling to active-duty service members and their families. The program will be expanded to include recently transitioned veterans as well. And according to a report in Military Times, Military OneSource care also may be available to the families of new veterans.

African American women with alopecia have significantly higher odds of developing fibroids, based on data from more than 400,000 women.

In a study published in JAMA Dermatology, researchers reviewed data from 487,104 black women seen at a single center between Aug. 1, 2013, and Aug. 1, 2017. Overall, 14% of women with central centrifugal cicatricial alopecia (CCCA) also had a history of uterine fibroids, compared with 3% percent of black women without CCCA.

“Alopecia is more than just a cosmetic problem. … It could signal an increased risk of developing other conditions,” corresponding author Crystal Aguh, MD, of Johns Hopkins University in Baltimore said in an interview. “To our knowledge, this is the first time that an association has been noted between these two conditions. We believe that the fact that both are related to excess scarring and fibrous tissue deposition may reflect similarities in how both [conditions] develop, but this is still unknown.” 

[email protected]

SOURCE: Dina Y et al. JAMA Dermatol. 2017 Dec 27. doi: 10.1001/jamadermatol.2017.5163

African American women with alopecia have significantly higher odds of developing fibroids, based on data from more than 400,000 women.

In a study published in JAMA Dermatology, researchers reviewed data from 487,104 black women seen at a single center between Aug. 1, 2013, and Aug. 1, 2017. Overall, 14% of women with central centrifugal cicatricial alopecia (CCCA) also had a history of uterine fibroids, compared with 3% percent of black women without CCCA.

“Alopecia is more than just a cosmetic problem. … It could signal an increased risk of developing other conditions,” corresponding author Crystal Aguh, MD, of Johns Hopkins University in Baltimore said in an interview. “To our knowledge, this is the first time that an association has been noted between these two conditions. We believe that the fact that both are related to excess scarring and fibrous tissue deposition may reflect similarities in how both [conditions] develop, but this is still unknown.” 

[email protected]

SOURCE: Dina Y et al. JAMA Dermatol. 2017 Dec 27. doi: 10.1001/jamadermatol.2017.5163

African American women with alopecia have significantly higher odds of developing fibroids, based on data from more than 400,000 women.

In a study published in JAMA Dermatology, researchers reviewed data from 487,104 black women seen at a single center between Aug. 1, 2013, and Aug. 1, 2017. Overall, 14% of women with central centrifugal cicatricial alopecia (CCCA) also had a history of uterine fibroids, compared with 3% percent of black women without CCCA.

“Alopecia is more than just a cosmetic problem. … It could signal an increased risk of developing other conditions,” corresponding author Crystal Aguh, MD, of Johns Hopkins University in Baltimore said in an interview. “To our knowledge, this is the first time that an association has been noted between these two conditions. We believe that the fact that both are related to excess scarring and fibrous tissue deposition may reflect similarities in how both [conditions] develop, but this is still unknown.” 

[email protected]

SOURCE: Dina Y et al. JAMA Dermatol. 2017 Dec 27. doi: 10.1001/jamadermatol.2017.5163

More veterans are developing diabetes, say researchers from East Tennessee University in Johnson City, Tennessee. The rise is linked to a similar climb in obesity rates.

The researchers analyzed data from 5 cycles of the National Health and Nutrition Examination Survey (NHANES). The survey sample sizes ranged from 472 to 685.

Diabetes prevalence rose from 15.5% in 2005-2006 to 20.5% in 2013-2014, and rose significantly among men, from 16.5% in 2005-2006 to 22% in 2013-2014. Diabetes was most prevalent among veterans who were aged > 65 years, had more than 12 years of education, and had an income below the 100% federal poverty level. Those same subgroups had the highest prevalence of obesity except for the age subgroup. Obesity was more prevalent among veterans aged 45 to 64 years. Hispanic veterans had the highest prevalence of both obesity and diabetes. 

The researchers note that some factors limited the accuracy of the estimated prevalence of diabetes among U.S. veterans when using VA databases. One is that in fiscal year 2014, < 30% of the total veteran population sought VA health care, and > 70% sought care outside the VA system even though some were enrolled.

More veterans are developing diabetes, say researchers from East Tennessee University in Johnson City, Tennessee. The rise is linked to a similar climb in obesity rates.

The researchers analyzed data from 5 cycles of the National Health and Nutrition Examination Survey (NHANES). The survey sample sizes ranged from 472 to 685.

Diabetes prevalence rose from 15.5% in 2005-2006 to 20.5% in 2013-2014, and rose significantly among men, from 16.5% in 2005-2006 to 22% in 2013-2014. Diabetes was most prevalent among veterans who were aged > 65 years, had more than 12 years of education, and had an income below the 100% federal poverty level. Those same subgroups had the highest prevalence of obesity except for the age subgroup. Obesity was more prevalent among veterans aged 45 to 64 years. Hispanic veterans had the highest prevalence of both obesity and diabetes. 

The researchers note that some factors limited the accuracy of the estimated prevalence of diabetes among U.S. veterans when using VA databases. One is that in fiscal year 2014, < 30% of the total veteran population sought VA health care, and > 70% sought care outside the VA system even though some were enrolled.

More veterans are developing diabetes, say researchers from East Tennessee University in Johnson City, Tennessee. The rise is linked to a similar climb in obesity rates.

The researchers analyzed data from 5 cycles of the National Health and Nutrition Examination Survey (NHANES). The survey sample sizes ranged from 472 to 685.

Diabetes prevalence rose from 15.5% in 2005-2006 to 20.5% in 2013-2014, and rose significantly among men, from 16.5% in 2005-2006 to 22% in 2013-2014. Diabetes was most prevalent among veterans who were aged > 65 years, had more than 12 years of education, and had an income below the 100% federal poverty level. Those same subgroups had the highest prevalence of obesity except for the age subgroup. Obesity was more prevalent among veterans aged 45 to 64 years. Hispanic veterans had the highest prevalence of both obesity and diabetes. 

The researchers note that some factors limited the accuracy of the estimated prevalence of diabetes among U.S. veterans when using VA databases. One is that in fiscal year 2014, < 30% of the total veteran population sought VA health care, and > 70% sought care outside the VA system even though some were enrolled.

Carcinoid lung tumors represent the most indolent form of a spectrum of bronchopulmonary neuroendocrine tumors (NETs) that includes small-cell carcinoma as its most malignant member, as well as several other forms of intermediately aggressive tumors, such as atypical carcinoid.¹ Carcinoids represent 1.2% of all primary lung malignancies. Their incidence in the United States has increased rapidly over the last 30 years and is currently about 6% a year. Lung carcinoids are more prevalent in whites compared with blacks, and in Asians compared with non-Asians. They are less common in Hispanics compared with non-Hispanics.¹ Typical carcinoids represent 80%-90% of all lung carcinoids and occur more frequently in the fifth and sixth decades of life. They can, however, occur at any age, and are the most common lung tumor in childhood.¹

Etiology and risk factors

Unlike carcinoma of the lung, no external environmental toxin or other stimulus has been identified as a causative agent for the development of pulmonary carcinoid tumors. It is not clear if there is an association between bronchial NETs and smoking.¹ Nearly all bronchial NETs are sporadic; however, they can rarely occur in the setting of multiple endocrine neoplasia type 1.¹

Presentation

About 60% of the patients with bronchial carcinoids are symptomatic at presentation. The most common clinical findings are those associated with bronchial obstruction, such as persistent cough, hemoptysis, and recurrent or obstructive pneumonitis. Wheezing, chest pain, and dyspnea also may be noted.² Various endocrine or neuroendocrine syndromes can be initial clinical manifestations of either typical or atypical pulmonary carcinoid tumors, but that is not common Cushing syndrome (ectopic production and secretion of adrenocorticotropic hormone [ACTH]) may occur in about 2% of lung carcinoid.³ In cases of malignancy, the presence of metastatic disease can produce weight loss, weakness, and a general feeling of ill health.

Diagnostic work-up

Biochemical test

There is no biochemical study that can be used as a screening test to determine the presence of a carcinoid tumor or to diagnose a known pulmonary mass as a carcinoid tumor. Neuroendocrine cells produce biologically active amines and peptides that can be detected in serum and urine. Although the syndromes associated with lung carcinoids are seen in about 1%-2% of the patients, assays of specific hormones or other circulating neuroendocrine substances, such as ACTH, melanocyte-stimulating hormone, or growth hormone may establish the existence of a clinically suspected syndrome.

Chest radiography

An abnormal finding on chest radiography is present in about 75% of patients with a pulmonary carcinoid tumor.¹ Findings include either the presence of the tumor mass itself or indirect evidence of its presence observed as parenchymal changes associated with bronchial obstruction from the mass.

Computed-tomography imaging

High-resolution computed-tomography (CT) imaging is the one of the best types of CT examination for evaluation of a pulmonary carcinoid tumor.⁴ A CT scan provides excellent resolution of tumor extent, location, and the presence or absence of mediastinal adenopathy. It also aids in morphologic characterization of peripheral (Figure 1) and especially centrally located carcinoids, which may be purely intraluminal (polypoid configuration), exclusively extra luminal, or more frequently, a mixture of intraluminal and extraluminal components.

CT scans may also be helpful for differentiating tumor from postobstructive atelectasis or bronchial obstruction-related mucoid impaction. Intravenous contrast in CT imaging can be useful in differentiating malignant from benign lesions. Because carcinoid tumors are highly vascular, they show greater enhancement on contrast CT than do benign lesions. The sensitivity of CT for detecting metastatic hilar or mediastinal nodes is high, but specificity is as low as 45%.⁴

Typical carcinoid is rarely metastatic so most patients do not need CT or MRI imaging to evaluate for liver involvement. Liver imaging is appropriate in patients with evidence of mediastinal involvement, relatively high mitotic rate, or clinical evidence of the carcinoid syndrome.⁸ To evaluate for metastatic spread to the liver, multiphase contrast-enhanced liver CT scans should be performed with arterial and portal-venous phases because carcinoid liver metastases are often hypervascular and appear isodense relative to the liver parenchyma after contrast administration.⁴ An MRI is often preferred the modality to evaluate for metastatic spread to the liver because of its higher sensitivity.⁵

Positron-emission tomography

Although carcinoid tumors of the lung are highly vascular, they do not show increased metabolic activity on positron-emission tomography (PET) and would be incorrectly designated as benign lesions on the basis of findings from a PET scan. Fludeoxyglucose F-18 PET has shown utility as a radiologic marker for atypical carcinoids, particularly for those with a higher proliferation index with Ki-67 index of 10%-20%.⁶

Radionucleotide studies

Somatostatin receptors (SSRs) are present in many tumors of neuroendocrine origin, including carcinoid tumors. These receptors interact with each other and undergo dimerization and internalization. SSTR subtypes (SSTRs) overexpressed in NETs are related to the type, origin, and grade of differentiation of tumor. The overexpression of an SSTR is a characteristic feature of bronchial NETs, which can be used to localize the primary tumor and its metastases by imaging with the radiolabeled SST analogues. Radionucleotide imaging modalities commonly used include single-photon–emission tomography and positron-emission tomography.

With regard to SSR scintigraphy testing, PET using Ga–DOTATATE/TOC is preferable to Octreoscan if it is available, because offers better spatial resolution and has a shorter scanning time. It has sensitivity of 97% and specificity of 92% and hence is preferable over Octreoscan in highly aggressive, atypical bronchial NETs. It also provides an estimate of receptor density and evidence of the functionality of receptors, which helps with selection of suitable treatments that act on these receptors.⁷

Tumor markers

Serum levels of chromogranin A in bronchial NETs are expressed at a lower rate than are other sites of carcinoid tumors, so its measurement is of limited utility in following disease activity in bronchial NETs.^4,8

Bronchoscopy

About 75% of pulmonary carcinoids are visible on bronchoscopy. The bronchoscopic appearance may be characteristic but it is preferable that brushings or biopsy be performed to confirm the diagnosis. For central tumors endobronchial; and for peripheral tumors, CT-guided percutaneous biopsy is the accepted diagnostic approach. Cytologic study of bronchial brushings is more sensitive than sputum cytology, but the diagnostic yield of brushing is low overall (about 40%) and hence fine-needle biopsy is preferred. ⁸

A negative finding on biopsy should not produce a false sense of confidence. If a suspicion of malignancy exists despite a negative finding on transthoracic biopsy, surgical excision of the nodule and pathologic analysis should be undertaken.

Histological findings

In typical carcinoid tumors, cells tend to group in nests, cords, or broad sheets. Arrangement is orderly, with groups of cells separated by highly vascular septa of connective tissue.⁹Individual cell features include small and polygonal cells with finely granular eosinophilic cytoplasm (Figure 2). Nuclei are small and round. Mitoses are infrequent (Figure 3).

Typical vs atypical tumors

In all, 10% of the carcinoid tumors are atypical in nature. They are generally larger than typical carcinoids and are located in the periphery of the lung in about 50% of cases. They have more aggressive behavior and tend to metastasize more commonly.² Neither location nor size are distinguishing features. The distinction is based on histology and includes one or all of the following features:^8,9

n Increased mitotic activity in a tumor with an identifiable carcinoid cellular arrangement with 2-10 mitotic figures per high-power field.⁹

n Pleomorphism and irregular nuclei with hyperchromatism and prominent nucleoli.

n Areas of increased cellularity with loss of the regular, organized architecture observed in typical carcinoid.

n Areas of necrosis within the tumor.

Ki-67 cell proliferation labeling index can be used to distinguish between high-grade lung NETs (>40%) and carcinoids (<20%), particularly in crushed biopsy specimens in which carcinoids may be mistaken for small-cell lung cancers. However, given overlap in the distribution of Ki-67 labeling index between typical carcinoids (≤5%) and atypical carcinoids (≤20%), Ki-67 expression does not reliably distinguish between well-differentiated lung carcinoids. The utility of Ki-67 to differentiate between typical and atypical carcinoids has yet to be established, and it is not presently recommended.⁹ Hence, the number of mitotic figures per high-power field of viable tumor area and presence or absence of necrosis continue to be the salient features distinguishing typical and atypical bronchial NETs.

Staging¹⁰

Lung NETs are staged using the same tumor, node, metastasis (TNM) classification from the American Joint Committee on Cancer (AJCC) that is used for bronchogenic lung carcinomas (Table).

Treatment

Localized or nonmetastatic and rescetable disease

Surgical treatment. As with other non–small-cell lung cancers (NSCLCs), surgical resection is the treatment of choice for early-stage carcinoid. The long-term prognosis is typically excellent, with a 10-year disease-free survival of 77%-94%.^{11, 12} The extent of resection is determined by the tumor size, histology, and location. For NSCLC, the standard surgical approach is the minimal anatomic resection (lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy) needed to get microscopically negative margins, with an associated mediastinal and hilar lymph node dissection for staging.¹³

Given the indolent nature of typical carcinoids, there has been extensive research to evaluate whether a sublobar resection is oncologically appropriate for these tumors. Although there are no comprehensive randomized studies comparing sublobar resection with lobectomy for typical carcinoids, findings from numerous database reviews and single-center studies suggest that sublobar resections are noninferior.^14-17 Due to the higher nodal metastatic rate and the overall poorer prognosis associated with atypical carcinoids, formal anatomic resection is still recommended with atypical histology.¹⁸

An adaptive approach must be taken for patients who undergo wedge resection of pulmonary lesions without a known diagnosis. If intraoperative frozen section is consistent with carcinoid and the margins are negative, mediastinal lymph node dissection should be performed. If the patient is node negative, then completion lobectomy is not required. In node-positive patients with adequate pulmonary reserve, lobectomy should be performed regardless of histology. If atypical features are found during pathologic evaluation, then interval completion lobectomy may be patients with adequate pulmonary reserve.^19,20

As with other pulmonary malignancies, clinical or radiographic suspicion of mediastinal lymph node involvement requires invasive staging before pulmonary resection is considered. If the patient is proven to have mediastinal metastatic disease, then multimodality treatment should be considered.²⁰

Adjuvant therapy. Postoperative adjuvant therapy for most resected bronchial NETs, even in the setting of positive lymph nodes, is generally not recommended.⁷ In clinical practice, adjuvant platinum-based chemotherapy with or without radiation therapy (RT) is a reasonable option for patients with histologically aggressive-appearing or poorly differentiated stage III atypical bronchial NETs, although there is only limited evidence to support this. RT is a reasonable option for atypical bronchial NETs if gross residual disease remains after surgery, although it has not been proven that this improves outcomes.⁷

Nonmetastatic and unresectable disease

For inoperable patients and for those with surgically unresectable but nonmetastatic disease, options for local control of tumor growth include RT with or without concurrent chemotherapy and palliative endobronchial resection of obstructing tumor.²¹

Metastatic and unresectable disease

Everolimus. In February 2016, everolimus was approved by the US Food and Drug Administration (FDA) as first-line therapy for progressive, well-differentiated, nonfunctional NETs of lung origin that are unresectable, locally advanced, or metastatic. The aApproval was based on the RADIANT-4 trial, in which median progression-free survival was 11 months in the 205 patients allocated to receive everolimus (10 mg/day) and 3.9 months in the 97 patients who received placebo. Everolimus was associated with a 52% reduction in the estimated risk of progression or death.²²

Somastatin analogues (SSA). There is lack of comprehensive data on the role of SSA compared with everolimus in lung carcinoid. The National Comprehensive Cancer Network (NCCN) guidelines on NETs and SCLCs recommend the consideration of octreotide or lanreotide as first-line therapies for select patients with symptoms of carcinoid syndrome or octreotide-positive scans.²¹ Guidelines from the European Neuroendocrine Tumor Society (ENETS)¹⁹ also recommend the use of SSAs as a first-line option in patients with: lung carcinoids exhibiting hormone-related symptoms or slowly progressive typical or atypical carcinoid with a low proliferative index (preferably Ki-67 <10%), provided there is a strongly positive SSTR status.

In cases in which metastatic lung NETs are associated with the carcinoid syndrome, initiation of long-acting SSA therapy in combination with everolimus is recommended.

Cytotoxic chemotherapy. According to the NCCN guidelines, cisplatin-etoposide or other cytotoxic regimens (eg, those that are temozolomide based) are recommended for advanced typical and atypical carcinoids, with cisplatin-etoposide being the preferred first-line systemic regimen in stage IV atypical carcinoid.²² ENETS guidelines stipulate that systemic chemotherapy is generally restricted to atypical carcinoid after failure of first-line therapies and only under certain conditions (Ki-67 >15%, rapidly progressive disease, and SSTR-negative disease).¹⁹ Based on a summary of NCCN and ENET guidelines:

n For patients with highly aggressive atypical bronchial NETs, a combination of platinum- and etoposide-based regimens such as those used for small-cell lung cancer has shown better response rate and overall survival data.

n For patients with typical or atypical bronchial NETs, temozolomide can be used as monotherapy or combination with capecitabine, although there are no findings from large randomized controlled trials to support this. Capecitabine-temozolomide has recently shown moderate activity in a small, single-institution study of patients with advanced lung carcinoids (N = 19), with 11 of 17 assessable patients (65%) demonstrating stable disease or partial response.²³

n The following regimens can also be used for advanced disease after failure of somastatin analogues, although there are limited data for objective responses:^24,25fluorouracil plus dacarbazine; epirubicin, capecitabine plus oxaliplatin; and capecitabine plus liposomal doxorubicin.

Participation in a clinical trial should be encouraged for patients with progressive bronchial NETs during any line of therapy. For patients who have a limited, potentially resectable liver-isolated metastatic NET, surgical resection should be pursued. For more extensive unresectable liver-dominant metastatic disease, treatment options include embolization, radiofrequency ablation, and cryoablation.^20,22

Posttreatment surveillance

Posttreatment surveillance after resection of node-positive typical bronchial NETs and for all atypical tumors.²⁶ Patients with lymph-node–negative typical bronchial NETs are very unlikely to benefit from postoperative surveillance because of the very low risk of recurrence. CT imaging (including the thorax and abdomen) every 6 months for 2 years, followed by annual scans for a total of 5-10 years are a reasonable surveillance schedule.

Prognosis ^18,27

Typical bronchial NETs have an excellent prognosis after surgical resection. Reported 5-year survival rates are 87%-100%; the corresponding rates at 10 years are 82%-87%. Features associated with negative prognostic significance include lymph-node involvement and incomplete resection.

Atypical bronchial NETs have a worse prognosis than do typical tumors. Five-year survival rates range widely, from 30%-95%; the corresponding rates at 10 years are 35%-56%. Atypical tumors have a greater tendency to metastasize (16%-23%) and recur locally (3%-25%). Distant metastases to the liver or bone are more common than local recurrence. Adverse influence of nodal metastases on prognosis is more profound than for typical tumors. Survival rates by stage for patients who underwent surgical resection (including typical and atypical carcinoid²⁷) are: stage I, 93%; stage II, 85%; stage III, 75%; and stage IV, 57%.

Carcinoid lung tumors represent the most indolent form of a spectrum of bronchopulmonary neuroendocrine tumors (NETs) that includes small-cell carcinoma as its most malignant member, as well as several other forms of intermediately aggressive tumors, such as atypical carcinoid.¹ Carcinoids represent 1.2% of all primary lung malignancies. Their incidence in the United States has increased rapidly over the last 30 years and is currently about 6% a year. Lung carcinoids are more prevalent in whites compared with blacks, and in Asians compared with non-Asians. They are less common in Hispanics compared with non-Hispanics.¹ Typical carcinoids represent 80%-90% of all lung carcinoids and occur more frequently in the fifth and sixth decades of life. They can, however, occur at any age, and are the most common lung tumor in childhood.¹

Etiology and risk factors

Unlike carcinoma of the lung, no external environmental toxin or other stimulus has been identified as a causative agent for the development of pulmonary carcinoid tumors. It is not clear if there is an association between bronchial NETs and smoking.¹ Nearly all bronchial NETs are sporadic; however, they can rarely occur in the setting of multiple endocrine neoplasia type 1.¹

Presentation

About 60% of the patients with bronchial carcinoids are symptomatic at presentation. The most common clinical findings are those associated with bronchial obstruction, such as persistent cough, hemoptysis, and recurrent or obstructive pneumonitis. Wheezing, chest pain, and dyspnea also may be noted.² Various endocrine or neuroendocrine syndromes can be initial clinical manifestations of either typical or atypical pulmonary carcinoid tumors, but that is not common Cushing syndrome (ectopic production and secretion of adrenocorticotropic hormone [ACTH]) may occur in about 2% of lung carcinoid.³ In cases of malignancy, the presence of metastatic disease can produce weight loss, weakness, and a general feeling of ill health.

Diagnostic work-up

Biochemical test

There is no biochemical study that can be used as a screening test to determine the presence of a carcinoid tumor or to diagnose a known pulmonary mass as a carcinoid tumor. Neuroendocrine cells produce biologically active amines and peptides that can be detected in serum and urine. Although the syndromes associated with lung carcinoids are seen in about 1%-2% of the patients, assays of specific hormones or other circulating neuroendocrine substances, such as ACTH, melanocyte-stimulating hormone, or growth hormone may establish the existence of a clinically suspected syndrome.

Chest radiography

An abnormal finding on chest radiography is present in about 75% of patients with a pulmonary carcinoid tumor.¹ Findings include either the presence of the tumor mass itself or indirect evidence of its presence observed as parenchymal changes associated with bronchial obstruction from the mass.

Computed-tomography imaging

High-resolution computed-tomography (CT) imaging is the one of the best types of CT examination for evaluation of a pulmonary carcinoid tumor.⁴ A CT scan provides excellent resolution of tumor extent, location, and the presence or absence of mediastinal adenopathy. It also aids in morphologic characterization of peripheral (Figure 1) and especially centrally located carcinoids, which may be purely intraluminal (polypoid configuration), exclusively extra luminal, or more frequently, a mixture of intraluminal and extraluminal components.

CT scans may also be helpful for differentiating tumor from postobstructive atelectasis or bronchial obstruction-related mucoid impaction. Intravenous contrast in CT imaging can be useful in differentiating malignant from benign lesions. Because carcinoid tumors are highly vascular, they show greater enhancement on contrast CT than do benign lesions. The sensitivity of CT for detecting metastatic hilar or mediastinal nodes is high, but specificity is as low as 45%.⁴

Typical carcinoid is rarely metastatic so most patients do not need CT or MRI imaging to evaluate for liver involvement. Liver imaging is appropriate in patients with evidence of mediastinal involvement, relatively high mitotic rate, or clinical evidence of the carcinoid syndrome.⁸ To evaluate for metastatic spread to the liver, multiphase contrast-enhanced liver CT scans should be performed with arterial and portal-venous phases because carcinoid liver metastases are often hypervascular and appear isodense relative to the liver parenchyma after contrast administration.⁴ An MRI is often preferred the modality to evaluate for metastatic spread to the liver because of its higher sensitivity.⁵

Positron-emission tomography

Although carcinoid tumors of the lung are highly vascular, they do not show increased metabolic activity on positron-emission tomography (PET) and would be incorrectly designated as benign lesions on the basis of findings from a PET scan. Fludeoxyglucose F-18 PET has shown utility as a radiologic marker for atypical carcinoids, particularly for those with a higher proliferation index with Ki-67 index of 10%-20%.⁶

Radionucleotide studies

Somatostatin receptors (SSRs) are present in many tumors of neuroendocrine origin, including carcinoid tumors. These receptors interact with each other and undergo dimerization and internalization. SSTR subtypes (SSTRs) overexpressed in NETs are related to the type, origin, and grade of differentiation of tumor. The overexpression of an SSTR is a characteristic feature of bronchial NETs, which can be used to localize the primary tumor and its metastases by imaging with the radiolabeled SST analogues. Radionucleotide imaging modalities commonly used include single-photon–emission tomography and positron-emission tomography.

With regard to SSR scintigraphy testing, PET using Ga–DOTATATE/TOC is preferable to Octreoscan if it is available, because offers better spatial resolution and has a shorter scanning time. It has sensitivity of 97% and specificity of 92% and hence is preferable over Octreoscan in highly aggressive, atypical bronchial NETs. It also provides an estimate of receptor density and evidence of the functionality of receptors, which helps with selection of suitable treatments that act on these receptors.⁷

Tumor markers

Serum levels of chromogranin A in bronchial NETs are expressed at a lower rate than are other sites of carcinoid tumors, so its measurement is of limited utility in following disease activity in bronchial NETs.^4,8

Bronchoscopy

About 75% of pulmonary carcinoids are visible on bronchoscopy. The bronchoscopic appearance may be characteristic but it is preferable that brushings or biopsy be performed to confirm the diagnosis. For central tumors endobronchial; and for peripheral tumors, CT-guided percutaneous biopsy is the accepted diagnostic approach. Cytologic study of bronchial brushings is more sensitive than sputum cytology, but the diagnostic yield of brushing is low overall (about 40%) and hence fine-needle biopsy is preferred. ⁸

A negative finding on biopsy should not produce a false sense of confidence. If a suspicion of malignancy exists despite a negative finding on transthoracic biopsy, surgical excision of the nodule and pathologic analysis should be undertaken.

Histological findings

In typical carcinoid tumors, cells tend to group in nests, cords, or broad sheets. Arrangement is orderly, with groups of cells separated by highly vascular septa of connective tissue.⁹Individual cell features include small and polygonal cells with finely granular eosinophilic cytoplasm (Figure 2). Nuclei are small and round. Mitoses are infrequent (Figure 3).

Typical vs atypical tumors

In all, 10% of the carcinoid tumors are atypical in nature. They are generally larger than typical carcinoids and are located in the periphery of the lung in about 50% of cases. They have more aggressive behavior and tend to metastasize more commonly.² Neither location nor size are distinguishing features. The distinction is based on histology and includes one or all of the following features:^8,9

n Increased mitotic activity in a tumor with an identifiable carcinoid cellular arrangement with 2-10 mitotic figures per high-power field.⁹

n Pleomorphism and irregular nuclei with hyperchromatism and prominent nucleoli.

n Areas of increased cellularity with loss of the regular, organized architecture observed in typical carcinoid.

n Areas of necrosis within the tumor.

Ki-67 cell proliferation labeling index can be used to distinguish between high-grade lung NETs (>40%) and carcinoids (<20%), particularly in crushed biopsy specimens in which carcinoids may be mistaken for small-cell lung cancers. However, given overlap in the distribution of Ki-67 labeling index between typical carcinoids (≤5%) and atypical carcinoids (≤20%), Ki-67 expression does not reliably distinguish between well-differentiated lung carcinoids. The utility of Ki-67 to differentiate between typical and atypical carcinoids has yet to be established, and it is not presently recommended.⁹ Hence, the number of mitotic figures per high-power field of viable tumor area and presence or absence of necrosis continue to be the salient features distinguishing typical and atypical bronchial NETs.

Staging¹⁰

Lung NETs are staged using the same tumor, node, metastasis (TNM) classification from the American Joint Committee on Cancer (AJCC) that is used for bronchogenic lung carcinomas (Table).

Treatment

Localized or nonmetastatic and rescetable disease

Surgical treatment. As with other non–small-cell lung cancers (NSCLCs), surgical resection is the treatment of choice for early-stage carcinoid. The long-term prognosis is typically excellent, with a 10-year disease-free survival of 77%-94%.^{11, 12} The extent of resection is determined by the tumor size, histology, and location. For NSCLC, the standard surgical approach is the minimal anatomic resection (lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy) needed to get microscopically negative margins, with an associated mediastinal and hilar lymph node dissection for staging.¹³

Given the indolent nature of typical carcinoids, there has been extensive research to evaluate whether a sublobar resection is oncologically appropriate for these tumors. Although there are no comprehensive randomized studies comparing sublobar resection with lobectomy for typical carcinoids, findings from numerous database reviews and single-center studies suggest that sublobar resections are noninferior.^14-17 Due to the higher nodal metastatic rate and the overall poorer prognosis associated with atypical carcinoids, formal anatomic resection is still recommended with atypical histology.¹⁸

An adaptive approach must be taken for patients who undergo wedge resection of pulmonary lesions without a known diagnosis. If intraoperative frozen section is consistent with carcinoid and the margins are negative, mediastinal lymph node dissection should be performed. If the patient is node negative, then completion lobectomy is not required. In node-positive patients with adequate pulmonary reserve, lobectomy should be performed regardless of histology. If atypical features are found during pathologic evaluation, then interval completion lobectomy may be patients with adequate pulmonary reserve.^19,20

As with other pulmonary malignancies, clinical or radiographic suspicion of mediastinal lymph node involvement requires invasive staging before pulmonary resection is considered. If the patient is proven to have mediastinal metastatic disease, then multimodality treatment should be considered.²⁰

Adjuvant therapy. Postoperative adjuvant therapy for most resected bronchial NETs, even in the setting of positive lymph nodes, is generally not recommended.⁷ In clinical practice, adjuvant platinum-based chemotherapy with or without radiation therapy (RT) is a reasonable option for patients with histologically aggressive-appearing or poorly differentiated stage III atypical bronchial NETs, although there is only limited evidence to support this. RT is a reasonable option for atypical bronchial NETs if gross residual disease remains after surgery, although it has not been proven that this improves outcomes.⁷

Nonmetastatic and unresectable disease

For inoperable patients and for those with surgically unresectable but nonmetastatic disease, options for local control of tumor growth include RT with or without concurrent chemotherapy and palliative endobronchial resection of obstructing tumor.²¹

Metastatic and unresectable disease

Everolimus. In February 2016, everolimus was approved by the US Food and Drug Administration (FDA) as first-line therapy for progressive, well-differentiated, nonfunctional NETs of lung origin that are unresectable, locally advanced, or metastatic. The aApproval was based on the RADIANT-4 trial, in which median progression-free survival was 11 months in the 205 patients allocated to receive everolimus (10 mg/day) and 3.9 months in the 97 patients who received placebo. Everolimus was associated with a 52% reduction in the estimated risk of progression or death.²²

Somastatin analogues (SSA). There is lack of comprehensive data on the role of SSA compared with everolimus in lung carcinoid. The National Comprehensive Cancer Network (NCCN) guidelines on NETs and SCLCs recommend the consideration of octreotide or lanreotide as first-line therapies for select patients with symptoms of carcinoid syndrome or octreotide-positive scans.²¹ Guidelines from the European Neuroendocrine Tumor Society (ENETS)¹⁹ also recommend the use of SSAs as a first-line option in patients with: lung carcinoids exhibiting hormone-related symptoms or slowly progressive typical or atypical carcinoid with a low proliferative index (preferably Ki-67 <10%), provided there is a strongly positive SSTR status.

In cases in which metastatic lung NETs are associated with the carcinoid syndrome, initiation of long-acting SSA therapy in combination with everolimus is recommended.

Cytotoxic chemotherapy. According to the NCCN guidelines, cisplatin-etoposide or other cytotoxic regimens (eg, those that are temozolomide based) are recommended for advanced typical and atypical carcinoids, with cisplatin-etoposide being the preferred first-line systemic regimen in stage IV atypical carcinoid.²² ENETS guidelines stipulate that systemic chemotherapy is generally restricted to atypical carcinoid after failure of first-line therapies and only under certain conditions (Ki-67 >15%, rapidly progressive disease, and SSTR-negative disease).¹⁹ Based on a summary of NCCN and ENET guidelines:

n For patients with highly aggressive atypical bronchial NETs, a combination of platinum- and etoposide-based regimens such as those used for small-cell lung cancer has shown better response rate and overall survival data.

n For patients with typical or atypical bronchial NETs, temozolomide can be used as monotherapy or combination with capecitabine, although there are no findings from large randomized controlled trials to support this. Capecitabine-temozolomide has recently shown moderate activity in a small, single-institution study of patients with advanced lung carcinoids (N = 19), with 11 of 17 assessable patients (65%) demonstrating stable disease or partial response.²³

n The following regimens can also be used for advanced disease after failure of somastatin analogues, although there are limited data for objective responses:^24,25fluorouracil plus dacarbazine; epirubicin, capecitabine plus oxaliplatin; and capecitabine plus liposomal doxorubicin.

Participation in a clinical trial should be encouraged for patients with progressive bronchial NETs during any line of therapy. For patients who have a limited, potentially resectable liver-isolated metastatic NET, surgical resection should be pursued. For more extensive unresectable liver-dominant metastatic disease, treatment options include embolization, radiofrequency ablation, and cryoablation.^20,22

Posttreatment surveillance

Posttreatment surveillance after resection of node-positive typical bronchial NETs and for all atypical tumors.²⁶ Patients with lymph-node–negative typical bronchial NETs are very unlikely to benefit from postoperative surveillance because of the very low risk of recurrence. CT imaging (including the thorax and abdomen) every 6 months for 2 years, followed by annual scans for a total of 5-10 years are a reasonable surveillance schedule.

Prognosis ^18,27

Typical bronchial NETs have an excellent prognosis after surgical resection. Reported 5-year survival rates are 87%-100%; the corresponding rates at 10 years are 82%-87%. Features associated with negative prognostic significance include lymph-node involvement and incomplete resection.

Atypical bronchial NETs have a worse prognosis than do typical tumors. Five-year survival rates range widely, from 30%-95%; the corresponding rates at 10 years are 35%-56%. Atypical tumors have a greater tendency to metastasize (16%-23%) and recur locally (3%-25%). Distant metastases to the liver or bone are more common than local recurrence. Adverse influence of nodal metastases on prognosis is more profound than for typical tumors. Survival rates by stage for patients who underwent surgical resection (including typical and atypical carcinoid²⁷) are: stage I, 93%; stage II, 85%; stage III, 75%; and stage IV, 57%.

Carcinoid lung tumors represent the most indolent form of a spectrum of bronchopulmonary neuroendocrine tumors (NETs) that includes small-cell carcinoma as its most malignant member, as well as several other forms of intermediately aggressive tumors, such as atypical carcinoid.¹ Carcinoids represent 1.2% of all primary lung malignancies. Their incidence in the United States has increased rapidly over the last 30 years and is currently about 6% a year. Lung carcinoids are more prevalent in whites compared with blacks, and in Asians compared with non-Asians. They are less common in Hispanics compared with non-Hispanics.¹ Typical carcinoids represent 80%-90% of all lung carcinoids and occur more frequently in the fifth and sixth decades of life. They can, however, occur at any age, and are the most common lung tumor in childhood.¹

Etiology and risk factors

Unlike carcinoma of the lung, no external environmental toxin or other stimulus has been identified as a causative agent for the development of pulmonary carcinoid tumors. It is not clear if there is an association between bronchial NETs and smoking.¹ Nearly all bronchial NETs are sporadic; however, they can rarely occur in the setting of multiple endocrine neoplasia type 1.¹

Presentation

About 60% of the patients with bronchial carcinoids are symptomatic at presentation. The most common clinical findings are those associated with bronchial obstruction, such as persistent cough, hemoptysis, and recurrent or obstructive pneumonitis. Wheezing, chest pain, and dyspnea also may be noted.² Various endocrine or neuroendocrine syndromes can be initial clinical manifestations of either typical or atypical pulmonary carcinoid tumors, but that is not common Cushing syndrome (ectopic production and secretion of adrenocorticotropic hormone [ACTH]) may occur in about 2% of lung carcinoid.³ In cases of malignancy, the presence of metastatic disease can produce weight loss, weakness, and a general feeling of ill health.

Diagnostic work-up

Biochemical test

There is no biochemical study that can be used as a screening test to determine the presence of a carcinoid tumor or to diagnose a known pulmonary mass as a carcinoid tumor. Neuroendocrine cells produce biologically active amines and peptides that can be detected in serum and urine. Although the syndromes associated with lung carcinoids are seen in about 1%-2% of the patients, assays of specific hormones or other circulating neuroendocrine substances, such as ACTH, melanocyte-stimulating hormone, or growth hormone may establish the existence of a clinically suspected syndrome.

Chest radiography

An abnormal finding on chest radiography is present in about 75% of patients with a pulmonary carcinoid tumor.¹ Findings include either the presence of the tumor mass itself or indirect evidence of its presence observed as parenchymal changes associated with bronchial obstruction from the mass.

Computed-tomography imaging

High-resolution computed-tomography (CT) imaging is the one of the best types of CT examination for evaluation of a pulmonary carcinoid tumor.⁴ A CT scan provides excellent resolution of tumor extent, location, and the presence or absence of mediastinal adenopathy. It also aids in morphologic characterization of peripheral (Figure 1) and especially centrally located carcinoids, which may be purely intraluminal (polypoid configuration), exclusively extra luminal, or more frequently, a mixture of intraluminal and extraluminal components.

CT scans may also be helpful for differentiating tumor from postobstructive atelectasis or bronchial obstruction-related mucoid impaction. Intravenous contrast in CT imaging can be useful in differentiating malignant from benign lesions. Because carcinoid tumors are highly vascular, they show greater enhancement on contrast CT than do benign lesions. The sensitivity of CT for detecting metastatic hilar or mediastinal nodes is high, but specificity is as low as 45%.⁴

Typical carcinoid is rarely metastatic so most patients do not need CT or MRI imaging to evaluate for liver involvement. Liver imaging is appropriate in patients with evidence of mediastinal involvement, relatively high mitotic rate, or clinical evidence of the carcinoid syndrome.⁸ To evaluate for metastatic spread to the liver, multiphase contrast-enhanced liver CT scans should be performed with arterial and portal-venous phases because carcinoid liver metastases are often hypervascular and appear isodense relative to the liver parenchyma after contrast administration.⁴ An MRI is often preferred the modality to evaluate for metastatic spread to the liver because of its higher sensitivity.⁵

Positron-emission tomography

Although carcinoid tumors of the lung are highly vascular, they do not show increased metabolic activity on positron-emission tomography (PET) and would be incorrectly designated as benign lesions on the basis of findings from a PET scan. Fludeoxyglucose F-18 PET has shown utility as a radiologic marker for atypical carcinoids, particularly for those with a higher proliferation index with Ki-67 index of 10%-20%.⁶

Radionucleotide studies

Somatostatin receptors (SSRs) are present in many tumors of neuroendocrine origin, including carcinoid tumors. These receptors interact with each other and undergo dimerization and internalization. SSTR subtypes (SSTRs) overexpressed in NETs are related to the type, origin, and grade of differentiation of tumor. The overexpression of an SSTR is a characteristic feature of bronchial NETs, which can be used to localize the primary tumor and its metastases by imaging with the radiolabeled SST analogues. Radionucleotide imaging modalities commonly used include single-photon–emission tomography and positron-emission tomography.

With regard to SSR scintigraphy testing, PET using Ga–DOTATATE/TOC is preferable to Octreoscan if it is available, because offers better spatial resolution and has a shorter scanning time. It has sensitivity of 97% and specificity of 92% and hence is preferable over Octreoscan in highly aggressive, atypical bronchial NETs. It also provides an estimate of receptor density and evidence of the functionality of receptors, which helps with selection of suitable treatments that act on these receptors.⁷

Tumor markers

Serum levels of chromogranin A in bronchial NETs are expressed at a lower rate than are other sites of carcinoid tumors, so its measurement is of limited utility in following disease activity in bronchial NETs.^4,8

Bronchoscopy

About 75% of pulmonary carcinoids are visible on bronchoscopy. The bronchoscopic appearance may be characteristic but it is preferable that brushings or biopsy be performed to confirm the diagnosis. For central tumors endobronchial; and for peripheral tumors, CT-guided percutaneous biopsy is the accepted diagnostic approach. Cytologic study of bronchial brushings is more sensitive than sputum cytology, but the diagnostic yield of brushing is low overall (about 40%) and hence fine-needle biopsy is preferred. ⁸

A negative finding on biopsy should not produce a false sense of confidence. If a suspicion of malignancy exists despite a negative finding on transthoracic biopsy, surgical excision of the nodule and pathologic analysis should be undertaken.

Histological findings

In typical carcinoid tumors, cells tend to group in nests, cords, or broad sheets. Arrangement is orderly, with groups of cells separated by highly vascular septa of connective tissue.⁹Individual cell features include small and polygonal cells with finely granular eosinophilic cytoplasm (Figure 2). Nuclei are small and round. Mitoses are infrequent (Figure 3).

Typical vs atypical tumors

In all, 10% of the carcinoid tumors are atypical in nature. They are generally larger than typical carcinoids and are located in the periphery of the lung in about 50% of cases. They have more aggressive behavior and tend to metastasize more commonly.² Neither location nor size are distinguishing features. The distinction is based on histology and includes one or all of the following features:^8,9

n Increased mitotic activity in a tumor with an identifiable carcinoid cellular arrangement with 2-10 mitotic figures per high-power field.⁹

n Pleomorphism and irregular nuclei with hyperchromatism and prominent nucleoli.

n Areas of increased cellularity with loss of the regular, organized architecture observed in typical carcinoid.

n Areas of necrosis within the tumor.

Ki-67 cell proliferation labeling index can be used to distinguish between high-grade lung NETs (>40%) and carcinoids (<20%), particularly in crushed biopsy specimens in which carcinoids may be mistaken for small-cell lung cancers. However, given overlap in the distribution of Ki-67 labeling index between typical carcinoids (≤5%) and atypical carcinoids (≤20%), Ki-67 expression does not reliably distinguish between well-differentiated lung carcinoids. The utility of Ki-67 to differentiate between typical and atypical carcinoids has yet to be established, and it is not presently recommended.⁹ Hence, the number of mitotic figures per high-power field of viable tumor area and presence or absence of necrosis continue to be the salient features distinguishing typical and atypical bronchial NETs.

Staging¹⁰

Lung NETs are staged using the same tumor, node, metastasis (TNM) classification from the American Joint Committee on Cancer (AJCC) that is used for bronchogenic lung carcinomas (Table).

Treatment

Localized or nonmetastatic and rescetable disease

Surgical treatment. As with other non–small-cell lung cancers (NSCLCs), surgical resection is the treatment of choice for early-stage carcinoid. The long-term prognosis is typically excellent, with a 10-year disease-free survival of 77%-94%.^{11, 12} The extent of resection is determined by the tumor size, histology, and location. For NSCLC, the standard surgical approach is the minimal anatomic resection (lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy) needed to get microscopically negative margins, with an associated mediastinal and hilar lymph node dissection for staging.¹³

Given the indolent nature of typical carcinoids, there has been extensive research to evaluate whether a sublobar resection is oncologically appropriate for these tumors. Although there are no comprehensive randomized studies comparing sublobar resection with lobectomy for typical carcinoids, findings from numerous database reviews and single-center studies suggest that sublobar resections are noninferior.^14-17 Due to the higher nodal metastatic rate and the overall poorer prognosis associated with atypical carcinoids, formal anatomic resection is still recommended with atypical histology.¹⁸

An adaptive approach must be taken for patients who undergo wedge resection of pulmonary lesions without a known diagnosis. If intraoperative frozen section is consistent with carcinoid and the margins are negative, mediastinal lymph node dissection should be performed. If the patient is node negative, then completion lobectomy is not required. In node-positive patients with adequate pulmonary reserve, lobectomy should be performed regardless of histology. If atypical features are found during pathologic evaluation, then interval completion lobectomy may be patients with adequate pulmonary reserve.^19,20

As with other pulmonary malignancies, clinical or radiographic suspicion of mediastinal lymph node involvement requires invasive staging before pulmonary resection is considered. If the patient is proven to have mediastinal metastatic disease, then multimodality treatment should be considered.²⁰

Adjuvant therapy. Postoperative adjuvant therapy for most resected bronchial NETs, even in the setting of positive lymph nodes, is generally not recommended.⁷ In clinical practice, adjuvant platinum-based chemotherapy with or without radiation therapy (RT) is a reasonable option for patients with histologically aggressive-appearing or poorly differentiated stage III atypical bronchial NETs, although there is only limited evidence to support this. RT is a reasonable option for atypical bronchial NETs if gross residual disease remains after surgery, although it has not been proven that this improves outcomes.⁷

Nonmetastatic and unresectable disease

For inoperable patients and for those with surgically unresectable but nonmetastatic disease, options for local control of tumor growth include RT with or without concurrent chemotherapy and palliative endobronchial resection of obstructing tumor.²¹

Metastatic and unresectable disease

Everolimus. In February 2016, everolimus was approved by the US Food and Drug Administration (FDA) as first-line therapy for progressive, well-differentiated, nonfunctional NETs of lung origin that are unresectable, locally advanced, or metastatic. The aApproval was based on the RADIANT-4 trial, in which median progression-free survival was 11 months in the 205 patients allocated to receive everolimus (10 mg/day) and 3.9 months in the 97 patients who received placebo. Everolimus was associated with a 52% reduction in the estimated risk of progression or death.²²

Somastatin analogues (SSA). There is lack of comprehensive data on the role of SSA compared with everolimus in lung carcinoid. The National Comprehensive Cancer Network (NCCN) guidelines on NETs and SCLCs recommend the consideration of octreotide or lanreotide as first-line therapies for select patients with symptoms of carcinoid syndrome or octreotide-positive scans.²¹ Guidelines from the European Neuroendocrine Tumor Society (ENETS)¹⁹ also recommend the use of SSAs as a first-line option in patients with: lung carcinoids exhibiting hormone-related symptoms or slowly progressive typical or atypical carcinoid with a low proliferative index (preferably Ki-67 <10%), provided there is a strongly positive SSTR status.

In cases in which metastatic lung NETs are associated with the carcinoid syndrome, initiation of long-acting SSA therapy in combination with everolimus is recommended.

Cytotoxic chemotherapy. According to the NCCN guidelines, cisplatin-etoposide or other cytotoxic regimens (eg, those that are temozolomide based) are recommended for advanced typical and atypical carcinoids, with cisplatin-etoposide being the preferred first-line systemic regimen in stage IV atypical carcinoid.²² ENETS guidelines stipulate that systemic chemotherapy is generally restricted to atypical carcinoid after failure of first-line therapies and only under certain conditions (Ki-67 >15%, rapidly progressive disease, and SSTR-negative disease).¹⁹ Based on a summary of NCCN and ENET guidelines:

n For patients with highly aggressive atypical bronchial NETs, a combination of platinum- and etoposide-based regimens such as those used for small-cell lung cancer has shown better response rate and overall survival data.

n For patients with typical or atypical bronchial NETs, temozolomide can be used as monotherapy or combination with capecitabine, although there are no findings from large randomized controlled trials to support this. Capecitabine-temozolomide has recently shown moderate activity in a small, single-institution study of patients with advanced lung carcinoids (N = 19), with 11 of 17 assessable patients (65%) demonstrating stable disease or partial response.²³

n The following regimens can also be used for advanced disease after failure of somastatin analogues, although there are limited data for objective responses:^24,25fluorouracil plus dacarbazine; epirubicin, capecitabine plus oxaliplatin; and capecitabine plus liposomal doxorubicin.

Participation in a clinical trial should be encouraged for patients with progressive bronchial NETs during any line of therapy. For patients who have a limited, potentially resectable liver-isolated metastatic NET, surgical resection should be pursued. For more extensive unresectable liver-dominant metastatic disease, treatment options include embolization, radiofrequency ablation, and cryoablation.^20,22

Posttreatment surveillance

Posttreatment surveillance after resection of node-positive typical bronchial NETs and for all atypical tumors.²⁶ Patients with lymph-node–negative typical bronchial NETs are very unlikely to benefit from postoperative surveillance because of the very low risk of recurrence. CT imaging (including the thorax and abdomen) every 6 months for 2 years, followed by annual scans for a total of 5-10 years are a reasonable surveillance schedule.

Prognosis ^18,27

Typical bronchial NETs have an excellent prognosis after surgical resection. Reported 5-year survival rates are 87%-100%; the corresponding rates at 10 years are 82%-87%. Features associated with negative prognostic significance include lymph-node involvement and incomplete resection.

Atypical bronchial NETs have a worse prognosis than do typical tumors. Five-year survival rates range widely, from 30%-95%; the corresponding rates at 10 years are 35%-56%. Atypical tumors have a greater tendency to metastasize (16%-23%) and recur locally (3%-25%). Distant metastases to the liver or bone are more common than local recurrence. Adverse influence of nodal metastases on prognosis is more profound than for typical tumors. Survival rates by stage for patients who underwent surgical resection (including typical and atypical carcinoid²⁷) are: stage I, 93%; stage II, 85%; stage III, 75%; and stage IV, 57%.

Research Hospital

New research has revealed germline variations associated with high-risk acute lymphoblastic leukemia (ALL) in children.

Researchers sequenced the TP53 tumor suppressor gene in nearly 4000 children with ALL and identified 22 pathogenic germline variants.

These variants were associated with inferior survival and an increased risk of developing second malignancies.

Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in the Journal of Clinical Oncology.

The researchers performed targeted sequencing of TP53 coding regions in 3801 children with ALL who were enrolled in 2 Children’s Oncology Group trials (AALL0232 and P9900).

The sequencing revealed 49 unique TP53 coding variants, which were found in 77 children. Twenty-two of the variants were pathogenic, and they were found in 26 children.

The researchers also analyzed data from 60,706 control subjects without ALL and found the 22 pathogenic variants were more likely to be found in the ALL patients than controls. The odds ratio was 5.2 (P<0.001).

Among the ALL patients, those who had the pathogenic variants were significantly older at diagnosis than those without the variants, with median ages of 15.5 years and 7.3 years, respectively (P<0.001).

The pathogenic variants were most common in patients with hypodiploid ALL. About 65% of patients who carried the pathogenic variants had hypodiploid ALL, as did 1.2% of children with wild-type genotype (P<0.001).

The pathogenic variants were associated with inferior event-free survival and overall survival as well. The hazard ratios were 4.2 (P<0.001) and 3.9 (P=0.001), respectively.

And the pathogenic variants were associated with a higher risk of second cancers. The 5-year cumulative incidence of second malignancies was 25.1% among patients with the pathogenic variants and 0.7% among patients without the variants (P<0.001).

“These germline variations are a double whammy for carriers,” Dr Yang said. “Not only is their risk of developing leukemia very high, they are also more likely to relapse or develop a second cancer.”

The association between the pathogenic variants and second cancers has prompted Dr Yang and his colleagues to explore ways to help patients manage their risk.

“Maybe these patients should avoid certain ALL therapies in order to reduce their risk of developing another cancer,” Dr Yang said. “I believe this finding may change treatment and follow-up for these high-risk patients.”

Dr Yang and his colleagues also noted that inherited variations in TP53 are a hallmark of Li-Fraumeni syndrome. And the syndrome might partially explain the high rate of second cancers in ALL patients with the pathogenic TP53 variants.

“The ALL treatment might have added to that risk,” Dr Yang said, “but we do not know for sure.”

Research Hospital

New research has revealed germline variations associated with high-risk acute lymphoblastic leukemia (ALL) in children.

Researchers sequenced the TP53 tumor suppressor gene in nearly 4000 children with ALL and identified 22 pathogenic germline variants.

These variants were associated with inferior survival and an increased risk of developing second malignancies.

Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in the Journal of Clinical Oncology.

The researchers performed targeted sequencing of TP53 coding regions in 3801 children with ALL who were enrolled in 2 Children’s Oncology Group trials (AALL0232 and P9900).

The sequencing revealed 49 unique TP53 coding variants, which were found in 77 children. Twenty-two of the variants were pathogenic, and they were found in 26 children.

The researchers also analyzed data from 60,706 control subjects without ALL and found the 22 pathogenic variants were more likely to be found in the ALL patients than controls. The odds ratio was 5.2 (P<0.001).

Among the ALL patients, those who had the pathogenic variants were significantly older at diagnosis than those without the variants, with median ages of 15.5 years and 7.3 years, respectively (P<0.001).

The pathogenic variants were most common in patients with hypodiploid ALL. About 65% of patients who carried the pathogenic variants had hypodiploid ALL, as did 1.2% of children with wild-type genotype (P<0.001).

The pathogenic variants were associated with inferior event-free survival and overall survival as well. The hazard ratios were 4.2 (P<0.001) and 3.9 (P=0.001), respectively.

And the pathogenic variants were associated with a higher risk of second cancers. The 5-year cumulative incidence of second malignancies was 25.1% among patients with the pathogenic variants and 0.7% among patients without the variants (P<0.001).

“These germline variations are a double whammy for carriers,” Dr Yang said. “Not only is their risk of developing leukemia very high, they are also more likely to relapse or develop a second cancer.”

The association between the pathogenic variants and second cancers has prompted Dr Yang and his colleagues to explore ways to help patients manage their risk.

“Maybe these patients should avoid certain ALL therapies in order to reduce their risk of developing another cancer,” Dr Yang said. “I believe this finding may change treatment and follow-up for these high-risk patients.”

Dr Yang and his colleagues also noted that inherited variations in TP53 are a hallmark of Li-Fraumeni syndrome. And the syndrome might partially explain the high rate of second cancers in ALL patients with the pathogenic TP53 variants.

“The ALL treatment might have added to that risk,” Dr Yang said, “but we do not know for sure.”

Research Hospital

New research has revealed germline variations associated with high-risk acute lymphoblastic leukemia (ALL) in children.

Researchers sequenced the TP53 tumor suppressor gene in nearly 4000 children with ALL and identified 22 pathogenic germline variants.

These variants were associated with inferior survival and an increased risk of developing second malignancies.

Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in the Journal of Clinical Oncology.

The researchers performed targeted sequencing of TP53 coding regions in 3801 children with ALL who were enrolled in 2 Children’s Oncology Group trials (AALL0232 and P9900).

The sequencing revealed 49 unique TP53 coding variants, which were found in 77 children. Twenty-two of the variants were pathogenic, and they were found in 26 children.

The researchers also analyzed data from 60,706 control subjects without ALL and found the 22 pathogenic variants were more likely to be found in the ALL patients than controls. The odds ratio was 5.2 (P<0.001).

Among the ALL patients, those who had the pathogenic variants were significantly older at diagnosis than those without the variants, with median ages of 15.5 years and 7.3 years, respectively (P<0.001).

The pathogenic variants were most common in patients with hypodiploid ALL. About 65% of patients who carried the pathogenic variants had hypodiploid ALL, as did 1.2% of children with wild-type genotype (P<0.001).

The pathogenic variants were associated with inferior event-free survival and overall survival as well. The hazard ratios were 4.2 (P<0.001) and 3.9 (P=0.001), respectively.

And the pathogenic variants were associated with a higher risk of second cancers. The 5-year cumulative incidence of second malignancies was 25.1% among patients with the pathogenic variants and 0.7% among patients without the variants (P<0.001).

“These germline variations are a double whammy for carriers,” Dr Yang said. “Not only is their risk of developing leukemia very high, they are also more likely to relapse or develop a second cancer.”

The association between the pathogenic variants and second cancers has prompted Dr Yang and his colleagues to explore ways to help patients manage their risk.

“Maybe these patients should avoid certain ALL therapies in order to reduce their risk of developing another cancer,” Dr Yang said. “I believe this finding may change treatment and follow-up for these high-risk patients.”

Dr Yang and his colleagues also noted that inherited variations in TP53 are a hallmark of Li-Fraumeni syndrome. And the syndrome might partially explain the high rate of second cancers in ALL patients with the pathogenic TP53 variants.

“The ALL treatment might have added to that risk,” Dr Yang said, “but we do not know for sure.”

Photo by Graham Colm

A new blood stabilization method significantly prolongs the lifespan of blood samples for microfluidic sorting and transcriptome profiling of rare circulating tumor cells (CTCs), according to researchers.

The method involves reducing the storage temperature to 4° C to reversibly slow down cellular processes while also counteracting the platelet activation that can occur because of the low temperature.

The researchers said this work overcomes a significant barrier to the translation of liquid biopsy technologies for precision oncology and other applications.

Keith Wong, PhD, of the Massachusetts General Hospital Center for Engineering in Medicine (MGH-CEM), and his colleagues described this work in Nature Communications.

When isolating CTCs from fresh, unprocessed blood, timing is everything. Even minor changes in the quality of a blood sample—such as the breakdown of red cells, leukocyte activation, or clot formation— can greatly affect cell-sorting mechanisms and the quality of the biomolecules isolated for cancer detection.

According to published studies, factors such as the total number of CTCs in a sample and the number with high-quality RNA decrease by around 50% within the first 4 to 5 hours after the sample is collected.

“At Mass. General, we have the luxury of being so integrated with the clinical team that we can process blood specimens in the lab typically within an hour or 2 after they are drawn,” Dr Wong said.

“But to make these liquid biopsy technologies routine lab tests for the rest of the world, we need ways to keep blood alive for much longer than several hours, since these assays are best performed in central laboratories for reasons of cost-effectiveness and reproducibility.”

With this in mind, Dr Wong and his colleagues set out to preserve blood in its native state with minimal alterations.

“We wanted to slow down the biological clock as much as possible by using hypothermia, but that is not as simple as it sounds,” said study author Shannon Tessier, PhD, also of MGH-CEM.

“Low temperature is a powerful means to decrease metabolism, but a host of unwanted side effects occur at the same time. In some ways, these challenges are similar to those we face in organ preservation, where we have to optimize strategies for a very complex mix of cells.”

To achieve these goals, the researchers first analyzed the effects of hypothermic storage conditions.

The team found that hypothermic storage (4° C) of blood anticoagulated with acid citrate dextrose maintained “cellular morphology, integrity, and surface epitope stability of diverse hematologic cell types” over 72 hours.

However, the researchers also observed platelet activation.

“We are preserving the blood very well, including the coagulation function of platelets,” Dr Wong said. “But, unfortunately, cooling causes profound activation of platelets. Now, we need a targeted approach for platelets so they don’t form nasty clots in the microfluidic blood-sorting device.”

Fortunately, the researchers found that glycoprotein IIb/IIIa inhibitors were able to counter cooling-induced platelet aggregation. And ion chelation treatment with ethylenediaminetetraacetic acid removed activated platelets from leukocytes.

The team said these steps—hypothermic storage, treatment with glycoprotein IIb/IIIa inhibitors, and ion chelation—allowed whole blood preserved for 3 days to be processed as if it were freshly drawn, with very high purity and virtually no loss in CTC numbers.

“The critical achievement here is that the isolated tumor cells contain high-quality RNA that is suitable for demanding molecular assays, such as single-cell qPCR, droplet digital PCR, and RNA sequencing,” Dr Tessier said.

To test their blood preservation method, Dr Tessier and her colleagues used blood specimens from a group of 10 patients with metastatic prostate cancer.

The researchers compared CTC analysis in preserved blood samples and paired fresh samples from the same patients.

There was 92% agreement in the detection of 12 cancer-specific gene transcripts between the fresh and preserved blood samples.

In addition, there was 100% agreement in the detection of a transcript called AR-V7. Recently published studies showed that the presence of AR-V7 mRNA in prostate cancer CTCs predicts resistance to androgen receptor inhibitors, indicating that chemotherapy may be a better option for such patients.

“The ability to preserve the blood for several days and still be able to pick up this clinically relevant biomarker is remarkable,” said study author David Miyamoto, MD, PhD, of MGH Cancer Center.

“This is very exciting for clinicians because AR-V7 mRNA can only be detected using CTCs and not with circulating tumor DNA or other cell-free assays.”

The researchers highlighted the universal nature of their blood preservation approach by pointing to its compatibility with the microfluidic CTC-iChip device, which isolates tumor cells by rapid removal of blood cells. The team said this suggests the potential impact of this work extends beyond cancer detection.

“With exciting breakthroughs in immunotherapy, stem cell transplantation, and regenerative medicine—in which peripheral blood is often the source of cells for functional assays or ex vivo expansion—the ability to preserve live cells will greatly ease logistical timelines and reduce the cost of complex cell-based assays,” Dr Wong said.

Photo by Graham Colm

A new blood stabilization method significantly prolongs the lifespan of blood samples for microfluidic sorting and transcriptome profiling of rare circulating tumor cells (CTCs), according to researchers.

The method involves reducing the storage temperature to 4° C to reversibly slow down cellular processes while also counteracting the platelet activation that can occur because of the low temperature.

The researchers said this work overcomes a significant barrier to the translation of liquid biopsy technologies for precision oncology and other applications.

Keith Wong, PhD, of the Massachusetts General Hospital Center for Engineering in Medicine (MGH-CEM), and his colleagues described this work in Nature Communications.

When isolating CTCs from fresh, unprocessed blood, timing is everything. Even minor changes in the quality of a blood sample—such as the breakdown of red cells, leukocyte activation, or clot formation— can greatly affect cell-sorting mechanisms and the quality of the biomolecules isolated for cancer detection.

According to published studies, factors such as the total number of CTCs in a sample and the number with high-quality RNA decrease by around 50% within the first 4 to 5 hours after the sample is collected.

“At Mass. General, we have the luxury of being so integrated with the clinical team that we can process blood specimens in the lab typically within an hour or 2 after they are drawn,” Dr Wong said.

“But to make these liquid biopsy technologies routine lab tests for the rest of the world, we need ways to keep blood alive for much longer than several hours, since these assays are best performed in central laboratories for reasons of cost-effectiveness and reproducibility.”

With this in mind, Dr Wong and his colleagues set out to preserve blood in its native state with minimal alterations.

“We wanted to slow down the biological clock as much as possible by using hypothermia, but that is not as simple as it sounds,” said study author Shannon Tessier, PhD, also of MGH-CEM.

“Low temperature is a powerful means to decrease metabolism, but a host of unwanted side effects occur at the same time. In some ways, these challenges are similar to those we face in organ preservation, where we have to optimize strategies for a very complex mix of cells.”

To achieve these goals, the researchers first analyzed the effects of hypothermic storage conditions.

The team found that hypothermic storage (4° C) of blood anticoagulated with acid citrate dextrose maintained “cellular morphology, integrity, and surface epitope stability of diverse hematologic cell types” over 72 hours.

However, the researchers also observed platelet activation.

“We are preserving the blood very well, including the coagulation function of platelets,” Dr Wong said. “But, unfortunately, cooling causes profound activation of platelets. Now, we need a targeted approach for platelets so they don’t form nasty clots in the microfluidic blood-sorting device.”

Fortunately, the researchers found that glycoprotein IIb/IIIa inhibitors were able to counter cooling-induced platelet aggregation. And ion chelation treatment with ethylenediaminetetraacetic acid removed activated platelets from leukocytes.

The team said these steps—hypothermic storage, treatment with glycoprotein IIb/IIIa inhibitors, and ion chelation—allowed whole blood preserved for 3 days to be processed as if it were freshly drawn, with very high purity and virtually no loss in CTC numbers.

“The critical achievement here is that the isolated tumor cells contain high-quality RNA that is suitable for demanding molecular assays, such as single-cell qPCR, droplet digital PCR, and RNA sequencing,” Dr Tessier said.

To test their blood preservation method, Dr Tessier and her colleagues used blood specimens from a group of 10 patients with metastatic prostate cancer.

The researchers compared CTC analysis in preserved blood samples and paired fresh samples from the same patients.

There was 92% agreement in the detection of 12 cancer-specific gene transcripts between the fresh and preserved blood samples.

In addition, there was 100% agreement in the detection of a transcript called AR-V7. Recently published studies showed that the presence of AR-V7 mRNA in prostate cancer CTCs predicts resistance to androgen receptor inhibitors, indicating that chemotherapy may be a better option for such patients.

“The ability to preserve the blood for several days and still be able to pick up this clinically relevant biomarker is remarkable,” said study author David Miyamoto, MD, PhD, of MGH Cancer Center.

“This is very exciting for clinicians because AR-V7 mRNA can only be detected using CTCs and not with circulating tumor DNA or other cell-free assays.”

The researchers highlighted the universal nature of their blood preservation approach by pointing to its compatibility with the microfluidic CTC-iChip device, which isolates tumor cells by rapid removal of blood cells. The team said this suggests the potential impact of this work extends beyond cancer detection.

“With exciting breakthroughs in immunotherapy, stem cell transplantation, and regenerative medicine—in which peripheral blood is often the source of cells for functional assays or ex vivo expansion—the ability to preserve live cells will greatly ease logistical timelines and reduce the cost of complex cell-based assays,” Dr Wong said.

Photo by Graham Colm

A new blood stabilization method significantly prolongs the lifespan of blood samples for microfluidic sorting and transcriptome profiling of rare circulating tumor cells (CTCs), according to researchers.

The method involves reducing the storage temperature to 4° C to reversibly slow down cellular processes while also counteracting the platelet activation that can occur because of the low temperature.

The researchers said this work overcomes a significant barrier to the translation of liquid biopsy technologies for precision oncology and other applications.

Keith Wong, PhD, of the Massachusetts General Hospital Center for Engineering in Medicine (MGH-CEM), and his colleagues described this work in Nature Communications.

When isolating CTCs from fresh, unprocessed blood, timing is everything. Even minor changes in the quality of a blood sample—such as the breakdown of red cells, leukocyte activation, or clot formation— can greatly affect cell-sorting mechanisms and the quality of the biomolecules isolated for cancer detection.

According to published studies, factors such as the total number of CTCs in a sample and the number with high-quality RNA decrease by around 50% within the first 4 to 5 hours after the sample is collected.

“At Mass. General, we have the luxury of being so integrated with the clinical team that we can process blood specimens in the lab typically within an hour or 2 after they are drawn,” Dr Wong said.

“But to make these liquid biopsy technologies routine lab tests for the rest of the world, we need ways to keep blood alive for much longer than several hours, since these assays are best performed in central laboratories for reasons of cost-effectiveness and reproducibility.”

With this in mind, Dr Wong and his colleagues set out to preserve blood in its native state with minimal alterations.

“We wanted to slow down the biological clock as much as possible by using hypothermia, but that is not as simple as it sounds,” said study author Shannon Tessier, PhD, also of MGH-CEM.

“Low temperature is a powerful means to decrease metabolism, but a host of unwanted side effects occur at the same time. In some ways, these challenges are similar to those we face in organ preservation, where we have to optimize strategies for a very complex mix of cells.”

To achieve these goals, the researchers first analyzed the effects of hypothermic storage conditions.

The team found that hypothermic storage (4° C) of blood anticoagulated with acid citrate dextrose maintained “cellular morphology, integrity, and surface epitope stability of diverse hematologic cell types” over 72 hours.

However, the researchers also observed platelet activation.

“We are preserving the blood very well, including the coagulation function of platelets,” Dr Wong said. “But, unfortunately, cooling causes profound activation of platelets. Now, we need a targeted approach for platelets so they don’t form nasty clots in the microfluidic blood-sorting device.”

Fortunately, the researchers found that glycoprotein IIb/IIIa inhibitors were able to counter cooling-induced platelet aggregation. And ion chelation treatment with ethylenediaminetetraacetic acid removed activated platelets from leukocytes.

The team said these steps—hypothermic storage, treatment with glycoprotein IIb/IIIa inhibitors, and ion chelation—allowed whole blood preserved for 3 days to be processed as if it were freshly drawn, with very high purity and virtually no loss in CTC numbers.

“The critical achievement here is that the isolated tumor cells contain high-quality RNA that is suitable for demanding molecular assays, such as single-cell qPCR, droplet digital PCR, and RNA sequencing,” Dr Tessier said.

To test their blood preservation method, Dr Tessier and her colleagues used blood specimens from a group of 10 patients with metastatic prostate cancer.

The researchers compared CTC analysis in preserved blood samples and paired fresh samples from the same patients.

There was 92% agreement in the detection of 12 cancer-specific gene transcripts between the fresh and preserved blood samples.

In addition, there was 100% agreement in the detection of a transcript called AR-V7. Recently published studies showed that the presence of AR-V7 mRNA in prostate cancer CTCs predicts resistance to androgen receptor inhibitors, indicating that chemotherapy may be a better option for such patients.

“The ability to preserve the blood for several days and still be able to pick up this clinically relevant biomarker is remarkable,” said study author David Miyamoto, MD, PhD, of MGH Cancer Center.

“This is very exciting for clinicians because AR-V7 mRNA can only be detected using CTCs and not with circulating tumor DNA or other cell-free assays.”

The researchers highlighted the universal nature of their blood preservation approach by pointing to its compatibility with the microfluidic CTC-iChip device, which isolates tumor cells by rapid removal of blood cells. The team said this suggests the potential impact of this work extends beyond cancer detection.

“With exciting breakthroughs in immunotherapy, stem cell transplantation, and regenerative medicine—in which peripheral blood is often the source of cells for functional assays or ex vivo expansion—the ability to preserve live cells will greatly ease logistical timelines and reduce the cost of complex cell-based assays,” Dr Wong said.

Image by Betty Pace

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to voxelotor (previously GBT440) for the treatment of sickle cell disease (SCD).

Voxelotor is being developed by Global Blood Therapeutics, Inc., as a potentially disease-modifying therapy for SCD.

The drug works by increasing hemoglobin’s affinity for oxygen. Since oxygenated sickle hemoglobin does not polymerize, it is believed that voxelotor blocks polymerization and the resultant sickling of red blood cells.

If voxelotor can restore normal hemoglobin function and improve oxygen delivery, the therapy may be capable of modifying the progression of SCD.

The FDA previously granted voxelotor fast track designation, orphan drug designation, and rare pediatric disease designation.

The FDA’s decision to grant breakthrough therapy designation to voxelotor was based on clinical data submitted from the following studies:

• Part A of the phase 3 HOPE study (GBT440-031)
• A phase 1/2 study and open-label extension in adults (GBT440-001/GBT440-024), which was presented at the 2016 ASH Annual Meeting
• The ongoing phase 2 HOPE-KIDS 1 study in children age 6 to 17 (GBT440-007), which was presented at the 2017 ASH Annual Meeting (abstract 689)
• The compassionate access experience in adults with severe SCD who were not eligible for the HOPE study, which was presented at the 2017 ASH Annual Meeting (abstract 3545).

About breakthrough designation

The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Image by Betty Pace

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to voxelotor (previously GBT440) for the treatment of sickle cell disease (SCD).

Voxelotor is being developed by Global Blood Therapeutics, Inc., as a potentially disease-modifying therapy for SCD.

The drug works by increasing hemoglobin’s affinity for oxygen. Since oxygenated sickle hemoglobin does not polymerize, it is believed that voxelotor blocks polymerization and the resultant sickling of red blood cells.

If voxelotor can restore normal hemoglobin function and improve oxygen delivery, the therapy may be capable of modifying the progression of SCD.

The FDA previously granted voxelotor fast track designation, orphan drug designation, and rare pediatric disease designation.

The FDA’s decision to grant breakthrough therapy designation to voxelotor was based on clinical data submitted from the following studies:

• Part A of the phase 3 HOPE study (GBT440-031)
• A phase 1/2 study and open-label extension in adults (GBT440-001/GBT440-024), which was presented at the 2016 ASH Annual Meeting
• The ongoing phase 2 HOPE-KIDS 1 study in children age 6 to 17 (GBT440-007), which was presented at the 2017 ASH Annual Meeting (abstract 689)
• The compassionate access experience in adults with severe SCD who were not eligible for the HOPE study, which was presented at the 2017 ASH Annual Meeting (abstract 3545).

About breakthrough designation

The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Image by Betty Pace

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to voxelotor (previously GBT440) for the treatment of sickle cell disease (SCD).

Voxelotor is being developed by Global Blood Therapeutics, Inc., as a potentially disease-modifying therapy for SCD.

The drug works by increasing hemoglobin’s affinity for oxygen. Since oxygenated sickle hemoglobin does not polymerize, it is believed that voxelotor blocks polymerization and the resultant sickling of red blood cells.

If voxelotor can restore normal hemoglobin function and improve oxygen delivery, the therapy may be capable of modifying the progression of SCD.

The FDA previously granted voxelotor fast track designation, orphan drug designation, and rare pediatric disease designation.

The FDA’s decision to grant breakthrough therapy designation to voxelotor was based on clinical data submitted from the following studies:

• Part A of the phase 3 HOPE study (GBT440-031)
• A phase 1/2 study and open-label extension in adults (GBT440-001/GBT440-024), which was presented at the 2016 ASH Annual Meeting
• The ongoing phase 2 HOPE-KIDS 1 study in children age 6 to 17 (GBT440-007), which was presented at the 2017 ASH Annual Meeting (abstract 689)
• The compassionate access experience in adults with severe SCD who were not eligible for the HOPE study, which was presented at the 2017 ASH Annual Meeting (abstract 3545).

About breakthrough designation

The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Q) What can I tell my kidney patients to increase acceptance of the influenza and pneumonia vaccines during cold and flu season?

The CDC recommends that everyone ages 6 months and older receive an annual flu vaccination, unless contraindicated.¹ Additionally, administration of either the 13-valent pneumococcal conjugate vaccine (PCV13) or the 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for all adults ages 65 and older and for younger adults (ages 19 to 64) with diabetes, chronic kidney disease (CKD), chronic heart disease, and/or solid organ transplant.¹ Despite these recommendations, patients often decline vaccination. What they may not realize is that CKD increases their risk for infection.

In a cohort of more than 1 million Swedish patients, researchers found that any stage of CKD increased risk for community-acquired infection and that the risk for lower respiratory tract infection increased as glomerular filtration rate declined.² Patients on hemodialysis have an increased risk for pneumonia and an incidence of pneumonia-related mortality that is up to 16 times higher than that of the general population.³ Pneumonia also increases the risk for cardiovascular events among all patients with CKD, regardless of stage.⁴

So, can vaccines reduce these risks in our kidney patients? McGrath and colleagues found that patients with end-stage renal disease (ESRD) who were vaccinated against the flu had lower mortality rates than those who were not vaccinated—even when the vaccine was poorly matched to the circulating virus strain.⁵ Additional research has demonstrated that for patients with any stage of CKD, including those on dialysis, the flu vaccine is safe and effective, and its protection may be durable over time.⁶

For pneumonia vaccines, antibody response in patients with CKD may be suboptimal; however, Medicare data have demonstrated that patients with ESRD who are vaccinated against pneumonia have lower rates of all-cause and cardiovascular mortality than unvaccinated patients do.⁵ Given their increased vulnerability to vaccine-preventable respiratory illnesses, it is imperative that our kidney patients receive both the flu and pneumonia vaccines. —NDM

Nicole DeFeo McCormick, DNP, MBA, NP-C, CCTC
Assistant Professor
School of Medicine at the University of Colorado

Q) What can I tell my kidney patients to increase acceptance of the influenza and pneumonia vaccines during cold and flu season?

The CDC recommends that everyone ages 6 months and older receive an annual flu vaccination, unless contraindicated.¹ Additionally, administration of either the 13-valent pneumococcal conjugate vaccine (PCV13) or the 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for all adults ages 65 and older and for younger adults (ages 19 to 64) with diabetes, chronic kidney disease (CKD), chronic heart disease, and/or solid organ transplant.¹ Despite these recommendations, patients often decline vaccination. What they may not realize is that CKD increases their risk for infection.

In a cohort of more than 1 million Swedish patients, researchers found that any stage of CKD increased risk for community-acquired infection and that the risk for lower respiratory tract infection increased as glomerular filtration rate declined.² Patients on hemodialysis have an increased risk for pneumonia and an incidence of pneumonia-related mortality that is up to 16 times higher than that of the general population.³ Pneumonia also increases the risk for cardiovascular events among all patients with CKD, regardless of stage.⁴

So, can vaccines reduce these risks in our kidney patients? McGrath and colleagues found that patients with end-stage renal disease (ESRD) who were vaccinated against the flu had lower mortality rates than those who were not vaccinated—even when the vaccine was poorly matched to the circulating virus strain.⁵ Additional research has demonstrated that for patients with any stage of CKD, including those on dialysis, the flu vaccine is safe and effective, and its protection may be durable over time.⁶

For pneumonia vaccines, antibody response in patients with CKD may be suboptimal; however, Medicare data have demonstrated that patients with ESRD who are vaccinated against pneumonia have lower rates of all-cause and cardiovascular mortality than unvaccinated patients do.⁵ Given their increased vulnerability to vaccine-preventable respiratory illnesses, it is imperative that our kidney patients receive both the flu and pneumonia vaccines. —NDM

Nicole DeFeo McCormick, DNP, MBA, NP-C, CCTC
Assistant Professor
School of Medicine at the University of Colorado

Q) What can I tell my kidney patients to increase acceptance of the influenza and pneumonia vaccines during cold and flu season?

The CDC recommends that everyone ages 6 months and older receive an annual flu vaccination, unless contraindicated.¹ Additionally, administration of either the 13-valent pneumococcal conjugate vaccine (PCV13) or the 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for all adults ages 65 and older and for younger adults (ages 19 to 64) with diabetes, chronic kidney disease (CKD), chronic heart disease, and/or solid organ transplant.¹ Despite these recommendations, patients often decline vaccination. What they may not realize is that CKD increases their risk for infection.

In a cohort of more than 1 million Swedish patients, researchers found that any stage of CKD increased risk for community-acquired infection and that the risk for lower respiratory tract infection increased as glomerular filtration rate declined.² Patients on hemodialysis have an increased risk for pneumonia and an incidence of pneumonia-related mortality that is up to 16 times higher than that of the general population.³ Pneumonia also increases the risk for cardiovascular events among all patients with CKD, regardless of stage.⁴

So, can vaccines reduce these risks in our kidney patients? McGrath and colleagues found that patients with end-stage renal disease (ESRD) who were vaccinated against the flu had lower mortality rates than those who were not vaccinated—even when the vaccine was poorly matched to the circulating virus strain.⁵ Additional research has demonstrated that for patients with any stage of CKD, including those on dialysis, the flu vaccine is safe and effective, and its protection may be durable over time.⁶

For pneumonia vaccines, antibody response in patients with CKD may be suboptimal; however, Medicare data have demonstrated that patients with ESRD who are vaccinated against pneumonia have lower rates of all-cause and cardiovascular mortality than unvaccinated patients do.⁵ Given their increased vulnerability to vaccine-preventable respiratory illnesses, it is imperative that our kidney patients receive both the flu and pneumonia vaccines. —NDM

Nicole DeFeo McCormick, DNP, MBA, NP-C, CCTC
Assistant Professor
School of Medicine at the University of Colorado

GENEVA – Partial results of the first worldwide observational study on the burden of chronic spontaneous urticaria (CSU) and its treatment in real-world clinical practice can be summarized succinctly: “It’s worse than we thought,” Marcus Maurer, MD, said at the annual congress of the European Academy of Dermatology and Venereology.

“We knew it was bad, but what comes out of looking at the daily life and treatment patterns in patients with CSU is a nightmare,” said Dr. Maurer, professor of dermatology and allergy and director of research in the department of dermatology at Charite University Hospital in Berlin.

Bruce Jancin/Frontline Medical News

AWARE study bears bad news

At study enrollment, the 1,550 German participants in the AWARE study had been diagnosed with CSU a mean of 4.9 years previously. Yet fully 78% had uncontrolled CSU as defined by a score below 12 points on the 0-16 UCT. Forty-four percent of patients had experienced angioedema within the previous 6 months, and 56% percent of patients had a baseline Dermatology Life Quality Index (DLQI) score indicating CSU had a moderate, very large, or extremely large effect on their quality of life. Yet 36% of patients weren’t receiving any treatment at baseline, and only 6.5% of patients were receiving guideline-recommended add-on third-line therapy.

In particular, most physicians fail to appreciate the negative impact of angioedema in CSU patients.

“This is not a swollen lip just once a year, this is angioedema weekly or monthly that really impairs quality of life. It’s not just a swollen lip or a swollen eye for the day or for a couple of hours, it’s the fear of going to sleep because in the morning you may wake up looking like that and not be able to go to work,” Dr. Maurer pointed out.

During the first year of the study, the overall situation improved significantly over the course of office visits every 3 months. The prevalence of DLQI scores indicative of a moderate or worse quality of life impact gradually fell from 56% to 28%. The proportion of patients on third-line treatment rose stepwise to 29.5% at 1 year. The rate of uncontrolled CSU as defined by a UCT score below 12 dropped steadily over time to 42%. At 1 year, only 16% of patients reported having an angioedema episode within the prior 12 weeks.

Still, this leaves much room for further improvement, Dr. Maurer commented.

“We’re on the right track, but patients who are in our treatment for a year should have their disease controlled. That’s our job. We have the treatments, and we should provide them. Even after 1 year there are still patients with a DLQI score above 10, and that’s not good,” he said.

Dr. Maurer was first author of the recently published interim results of the German portion of the AWARE study (Clin Exp Allergy. 2017 May;47[5]:684-52). The AWARE study is sponsored by Novartis, manufacturer of omalizumab, which is approved by the Food and Drug Administration for treating CSU. Dr. Maurer reported receiving research grants from and serving as an advisor to and paid speaker for Novartis and numerous other pharmaceutical companies.

[email protected]

GENEVA – Partial results of the first worldwide observational study on the burden of chronic spontaneous urticaria (CSU) and its treatment in real-world clinical practice can be summarized succinctly: “It’s worse than we thought,” Marcus Maurer, MD, said at the annual congress of the European Academy of Dermatology and Venereology.

“We knew it was bad, but what comes out of looking at the daily life and treatment patterns in patients with CSU is a nightmare,” said Dr. Maurer, professor of dermatology and allergy and director of research in the department of dermatology at Charite University Hospital in Berlin.

Bruce Jancin/Frontline Medical News

AWARE study bears bad news

At study enrollment, the 1,550 German participants in the AWARE study had been diagnosed with CSU a mean of 4.9 years previously. Yet fully 78% had uncontrolled CSU as defined by a score below 12 points on the 0-16 UCT. Forty-four percent of patients had experienced angioedema within the previous 6 months, and 56% percent of patients had a baseline Dermatology Life Quality Index (DLQI) score indicating CSU had a moderate, very large, or extremely large effect on their quality of life. Yet 36% of patients weren’t receiving any treatment at baseline, and only 6.5% of patients were receiving guideline-recommended add-on third-line therapy.

In particular, most physicians fail to appreciate the negative impact of angioedema in CSU patients.

“This is not a swollen lip just once a year, this is angioedema weekly or monthly that really impairs quality of life. It’s not just a swollen lip or a swollen eye for the day or for a couple of hours, it’s the fear of going to sleep because in the morning you may wake up looking like that and not be able to go to work,” Dr. Maurer pointed out.

During the first year of the study, the overall situation improved significantly over the course of office visits every 3 months. The prevalence of DLQI scores indicative of a moderate or worse quality of life impact gradually fell from 56% to 28%. The proportion of patients on third-line treatment rose stepwise to 29.5% at 1 year. The rate of uncontrolled CSU as defined by a UCT score below 12 dropped steadily over time to 42%. At 1 year, only 16% of patients reported having an angioedema episode within the prior 12 weeks.

Still, this leaves much room for further improvement, Dr. Maurer commented.

“We’re on the right track, but patients who are in our treatment for a year should have their disease controlled. That’s our job. We have the treatments, and we should provide them. Even after 1 year there are still patients with a DLQI score above 10, and that’s not good,” he said.

Dr. Maurer was first author of the recently published interim results of the German portion of the AWARE study (Clin Exp Allergy. 2017 May;47[5]:684-52). The AWARE study is sponsored by Novartis, manufacturer of omalizumab, which is approved by the Food and Drug Administration for treating CSU. Dr. Maurer reported receiving research grants from and serving as an advisor to and paid speaker for Novartis and numerous other pharmaceutical companies.

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GENEVA – Partial results of the first worldwide observational study on the burden of chronic spontaneous urticaria (CSU) and its treatment in real-world clinical practice can be summarized succinctly: “It’s worse than we thought,” Marcus Maurer, MD, said at the annual congress of the European Academy of Dermatology and Venereology.

“We knew it was bad, but what comes out of looking at the daily life and treatment patterns in patients with CSU is a nightmare,” said Dr. Maurer, professor of dermatology and allergy and director of research in the department of dermatology at Charite University Hospital in Berlin.

Bruce Jancin/Frontline Medical News

AWARE study bears bad news

At study enrollment, the 1,550 German participants in the AWARE study had been diagnosed with CSU a mean of 4.9 years previously. Yet fully 78% had uncontrolled CSU as defined by a score below 12 points on the 0-16 UCT. Forty-four percent of patients had experienced angioedema within the previous 6 months, and 56% percent of patients had a baseline Dermatology Life Quality Index (DLQI) score indicating CSU had a moderate, very large, or extremely large effect on their quality of life. Yet 36% of patients weren’t receiving any treatment at baseline, and only 6.5% of patients were receiving guideline-recommended add-on third-line therapy.

In particular, most physicians fail to appreciate the negative impact of angioedema in CSU patients.

“This is not a swollen lip just once a year, this is angioedema weekly or monthly that really impairs quality of life. It’s not just a swollen lip or a swollen eye for the day or for a couple of hours, it’s the fear of going to sleep because in the morning you may wake up looking like that and not be able to go to work,” Dr. Maurer pointed out.

During the first year of the study, the overall situation improved significantly over the course of office visits every 3 months. The prevalence of DLQI scores indicative of a moderate or worse quality of life impact gradually fell from 56% to 28%. The proportion of patients on third-line treatment rose stepwise to 29.5% at 1 year. The rate of uncontrolled CSU as defined by a UCT score below 12 dropped steadily over time to 42%. At 1 year, only 16% of patients reported having an angioedema episode within the prior 12 weeks.

Still, this leaves much room for further improvement, Dr. Maurer commented.

“We’re on the right track, but patients who are in our treatment for a year should have their disease controlled. That’s our job. We have the treatments, and we should provide them. Even after 1 year there are still patients with a DLQI score above 10, and that’s not good,” he said.

Dr. Maurer was first author of the recently published interim results of the German portion of the AWARE study (Clin Exp Allergy. 2017 May;47[5]:684-52). The AWARE study is sponsored by Novartis, manufacturer of omalizumab, which is approved by the Food and Drug Administration for treating CSU. Dr. Maurer reported receiving research grants from and serving as an advisor to and paid speaker for Novartis and numerous other pharmaceutical companies.

[email protected]