Preoperative Evaluation of Thyroid Cancer: A Review of Current Best Practices.

OBJECTIVE: The incidence of thyroid cancer has significantly increased in recent decades. Although most thyroid cancers are small and carry an excellent prognosis, a subset of patients present with advanced thyroid cancer, which is associated with increased rates of morbidity and mortality. The management of thyroid cancer requires a thoughtful individualized approach to optimize oncologic outcomes and minimize morbidity associated with treatment. Because endocrinologists usually play a key role in the initial diagnosis and evaluation of thyroid cancers, a thorough understanding of the critical components of the preoperative evaluation facilitates the development of a timely and comprehensive management plan. The following review outlines considerations in the preoperative evaluation of patients with thyroid cancer. METHODS: A clinical review based on current literature was generated by a multidisciplinary author panel. RESULTS: A review of considerations in the preoperative evaluation of thyroid cancer is provided. The topic areas include initial clinical evaluation, imaging modalities, cytologic evaluation, and the evolving role of mutational testing. Special considerations in the management of advanced thyroid cancer are discussed. CONCLUSION: Thorough and thoughtful preoperative evaluation is critical for formulating an appropriate treatment strategy in the management of thyroid cancer.

Thyroid Carcinoma, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Differentiated thyroid carcinomas is associated with an excellent prognosis. The treatment of choice for differentiated thyroid carcinoma is surgery, followed by radioactive iodine ablation (iodine-131) in select patients and thyroxine therapy in most patients. Surgery is also the main treatment for medullary thyroid carcinoma, and kinase inhibitors may be appropriate for select patients with recurrent or persistent disease that is not resectable. Anaplastic thyroid carcinoma is almost uniformly lethal, and iodine-131 imaging and radioactive iodine cannot be used. When systemic therapy is indicated, targeted therapy options are preferred. This article describes NCCN recommendations regarding management of medullary thyroid carcinoma and anaplastic thyroid carcinoma, and surgical management of differentiated thyroid carcinoma (papillary, follicular, Hürthle cell carcinoma).

Factors Associated With Radioactive Iodine Therapy-Acquired Nasolacrimal Duct Obstruction.

OBJECTIVE: To identify factors associated with radioactive iodine (RAI)-acquired nasolacrimal duct obstruction (NLDO). METHODS: Retrospective chart review and telephone surveys of patients who received RAI therapy for thyroid carcinoma at an academic institution were conducted. Telephone surveys were used to screen for post-RAI NLDO diagnoses. Databases were reviewed for documented NLDO, demographics, RAI dose, total number of RAI treatments, and sialadenitis. Routine post-RAI whole-body scintigraphy (WBS) images were analyzed for the presence or absence of 131I sodium iodide (I-131) in the nasolacrimal duct. Intranasal I-131 activity was graded as none, low, moderate, and high; those with moderate or high activity were considered to have "increased" activity. Logistic and ordinal logistic regression models were used to evaluate the associations with NLDO while adjusting for I-131 dose. RESULTS: Of the 209 patients who completed the survey, 15 (7%) had NLDO diagnoses. Increased intranasal I-131 activity on WBS, presence of nasolacrimal I-131 WBS activity, presence of documented post-RAI sialadenitis, and history of >1 RAI treatment were associated with the development of NLDO from univariate analyses (P ≤ .013). After adjusting for the administered dose of I-131, the presence of sialadenitis and nasolacrimal I-131 activity on WBS were the remaining 2 factors significantly associated with NLDO development (P < .001 and P = .01, respectively). CONCLUSIONS: The presence of sialadenitis and nasolacrimal I-131 activity on WBS are I-131 dose-independent correlative factors for RAI-associated NLDO. Patients with these characteristics should be counseled on their increased risk of NLDO after RAI therapy for thyroid carcinoma.

Combined administration of anti-IL-13 and anti-IL-17A at individually sub-therapeutic doses limits asthma-like symptoms in a mouse model of Th2/Th17 high asthma.

BACKGROUND: Recent studies have demonstrated that Th2 responses have the ability to antagonize Th17 responses. In mouse models of allergic asthma, blockade of Th2-effector cytokines results in elaboration of Th17 responses and associated increases in pulmonary neutrophilia. While these can be controlled by simultaneous blockade of Th17-associated effector cytokines, clinical trials of anti-IL-17/IL-17RA blocking therapies have demonstrated increased of risk of bacterial and fungal infections. Identification of minimally effective doses of cytokine-blocking therapies with the goal of reducing the potential emergence of infection-related complications is a translationally relevant goal. OBJECTIVE: In the current report, we examine whether combined blockade of IL-13 and IL-17A, at individually sub-therapeutic levels, can limit the development of allergic asthma while sparing expression of IL-17A-associated anti-microbial effectors. METHODS: House dust mite was given intratracheally to A/J mice. Anti-IL-13 and anti-IL-17A antibodies were administered individually, or concomitantly at sub-therapeutic doses. Airway hyper-reactivity, lung inflammation, magnitude of Th2- and Th17-associated cytokine production and expression of IL-13- and IL-17A-induced genes in the lungs was assessed. RESULTS: Initial dosing studies identified sub-therapeutic levels of IL-13 and IL-17A blocking mAbs that have a limited effect on asthma parameters and do not impair responses to microbial products or infection. Subsequent studies demonstrated that combined sub-therapeutic dosing with IL-13 and IL-17A blocking mAbs resulted in significant improvement in airway hyperresponsiveness (AHR) and expression of IL-13-induced gene expression. Importantly, these doses neither exacerbated nor inhibited production of Th17-associated cytokines, or IL-17A-associated gene expression. CONCLUSION: This study suggests that combining blockade of individual Th2 and Th17 effector cytokines, even at individually sub-therapeutic levels, may be sufficient to limit disease development while preserving important anti-microbial pathways. Such a strategy may therefore have reduced potential for adverse events associated with blockade of these pathways.

NCCN Guidelines Insights: Thyroid Carcinoma, Version 2.2018.

The NCCN Guidelines for Thyroid Carcinoma provide recommendations for the management of different types of thyroid carcinoma, including papillary, follicular, Hürthle cell, medullary, and anaplastic carcinomas. These NCCN Guidelines Insights summarize the panel discussion behind recent updates to the guidelines, including the expanding role of molecular testing for differentiated thyroid carcinoma, implications of the new pathologic diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features, and the addition of a new targeted therapy option for BRAF V600E-mutated anaplastic thyroid carcinoma.

A Pilot Nonrandomized Controlled Trial Examining the Use of Artificial Tears on the Radioactivity of Tears After Radioactive Iodine Treatment for Thyroid Cancer.

Background: Nasolacrimal duct obstruction (NLDO) is an adverse effect of high dose radioactive iodine (RAI) therapy for thyroid carcinoma. There are currently no established preventive measures. This study assesses whether preservative free artificial tears (PFATs) can decrease the 131I sodium iodide (131I) activity in the tears of patients following RAI therapy for thyroid carcinoma, and potentially serve as a preventive measure for RAI-associated NLDO. Methods: This non-randomized prospective pilot clinical trial recruited contact-lens wearing patients undergoing RAI therapy for thyroid cancer to self-administer PFATs into the right eye for four days starting on the day of RAI ingestion. Left eyes were the controls. While wearing contacts, patients self-administered PFATs per the following-Day 1: every 15 minutes for 2 hours, then every 30 minutes until bedtime, day 2: every hour for at least 12 hours, day 3: four times a day, and day 4: two times a day. Contact lenses were changed daily, and all lenses were collected one week later. Levels of 131I activity were measured by a well counter, decay-corrected, and converted to units of becquerel. Statistical analyses were performed to compare the 131I activities of the experimental and control eyes. Results: Sixteen eyes of eight patients treated with an average of 145.7 mCi (range 108-159) of 131I for papillary thyroid cancer were included. On day 1, artificial tears decreased the geometric mean 131I activity by 26% in the experimental eyes (p = 0.008). Artificial tears also decreased the geometric mean area under the curve over four days by 23% (p = 0.002). Conclusions: 131I is present in the tears following RAI therapy for thyroid carcinoma. Frequent PFATs starting on the day of RAI ingestion may decrease the level of 131I in the tears. This finding could have implications for lowering the risk of NLDO. Future multi-center clinical trials are needed to determine whether the use of artificial tears after RAI therapy may decrease the risk of NLDO. Clinical Trial Registration: NCT04327999.

Molecular Alterations and Comprehensive Clinical Management of Oncocytic Thyroid Carcinoma: A Review and Multidisciplinary 2023 Update.

Importance: Oncocytic (Hürthle cell) thyroid carcinoma is a follicular cell-derived neoplasm that accounts for approximately 5% of all thyroid cancers. Until recently, it was categorized as a follicular thyroid carcinoma, and its management was standardized with that of other differentiated thyroid carcinomas. In 2022, given an improved understanding of the unique molecular profile and clinical behavior of oncocytic thyroid carcinoma, the World Health Organization reclassified oncocytic thyroid carcinoma as distinct from follicular thyroid carcinoma. The International Thyroid Oncology Group and the American Head and Neck Society then collaborated to review the existing evidence on oncocytic thyroid carcinoma, from diagnosis through clinical management and follow-up surveillance. Observations: Given that oncocytic thyroid carcinoma was previously classified as a subtype of follicular thyroid carcinoma, it was clinically studied in that context. However, due to its low prevalence and previous classification schema, there are few studies that have specifically evaluated oncocytic thyroid carcinoma. Recent data indicate that oncocytic thyroid carcinoma is a distinct class of malignant thyroid tumor with a group of distinct genetic alterations and clinicopathologic features. Oncocytic thyroid carcinoma displays higher rates of somatic gene variants and genomic chromosomal loss of heterozygosity than do other thyroid cancers, and it harbors unique mitochondrial DNA variations. Clinically, oncocytic thyroid carcinoma is more likely to have locoregional (lymph node) metastases than is follicular thyroid carcinoma-with which it was formerly classified-and it develops distant metastases more frequently than papillary thyroid carcinoma. In addition, oncocytic thyroid carcinoma rarely absorbs radioiodine. Conclusions and Relevance: The findings of this review suggest that the distinct clinical presentation of oncocytic thyroid carcinoma, including its metastatic behavior and its reduced avidity to radioiodine therapy, warrants a tailored disease management approach. The reclassification of oncocytic thyroid carcinoma by the World Health Organization is an important milestone toward developing a specific and comprehensive clinical management for oncocytic thyroid carcinoma that considers its distinct characteristics.

MEK inhibition reduced vascular tumor growth and coagulopathy in a mouse model with hyperactive GNAQ.

Activating non-inherited mutations in the guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) gene family have been identified in childhood vascular tumors. Patients experience extensive disfigurement, chronic pain and severe complications including a potentially lethal coagulopathy termed Kasabach-Merritt phenomenon. Animal models for this class of vascular tumors do not exist. This has severely hindered the discovery of the molecular consequences of GNAQ mutations in the vasculature and, in turn, the preclinical development of effective targeted therapies. Here we report a mouse model expressing hyperactive mutant GNAQ in endothelial cells. Mutant mice develop vascular and coagulopathy phenotypes similar to those seen in patients. Mechanistically, by transcriptomic analysis we demonstrate increased mitogen activated protein kinase signaling in the mutant endothelial cells. Targeting of this pathway with Trametinib suppresses the tumor growth by reducing vascular cell proliferation and permeability. Trametinib also prevents the development of coagulopathy and improves mouse survival.

Molecular signature incorporating the immune microenvironment enhances thyroid cancer outcome prediction.

Genomic and transcriptomic analysis has furthered our understanding of many tumors. Yet, thyroid cancer management is largely guided by staging and histology, with few molecular prognostic and treatment biomarkers. Here, we utilize a large cohort of 251 patients with 312 samples from two tertiary medical centers and perform DNA/RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence to identify biomarkers of aggressive thyroid malignancy. We identify high-risk mutations and discover a unique molecular signature of aggressive disease, the Molecular Aggression and Prediction (MAP) score, which provides improved prognostication over high-risk mutations alone. The MAP score is enriched for genes involved in epithelial de-differentiation, cellular division, and the tumor microenvironment. The MAP score also identifies aggressive tumors with lymphocyte-rich stroma that may benefit from immunotherapy. Future clinical profiling of the stromal microenvironment of thyroid cancer could improve prognostication, inform immunotherapy, and support development of novel therapeutics for thyroid cancer and other stroma-rich tumors.

Approach to the Patient With Thyrotoxicosis Using Telemedicine.

CONTEXT: The potential for endocrine care via telemedicine has been recognized since the early 2000s when clinical outcome data demonstrated improvements in glycemic control with telemedicine. The widespread use of telemedicine during the COVID-19 pandemic has pushed telemedicine beyond diabetes care and into clinical areas with a paucity of published data. The evaluation and treatment of thyrotoxicosis heavily relies on laboratory assessment and imaging with physical exam playing a role to help differentiate the etiology and assess the severity of thyrotoxicosis. CASE DESCRIPTION: We describe a patient presenting for evaluation of new thyrotoxicosis via telemedicine, and describe modifications to consider for thorough, safe evaluation via telemedicine. CONCLUSION: Telemedicine may be an ideal way to assess and treat patients with thyrotoxicosis who are not able to physically attend a visit with an endocrinologist but still have access to a laboratory for blood draws. Potential challenges include access to imaging and high-volume surgeons if needed. Clinical and economic outcomes of telemedicine care of thyrotoxicosis should be studied so that standards of care for endocrine telemedicine can be established.

INCIDENTAL PULMONARY METASTASES REVEALING SUBCENTIMETER PAPILLARY THYROID CARCINOMA.

OBJECTIVE: Here we present 2 cases of papillary thyroid microcarcinomas (PMCs) that had metastasized at presentation. The 2015 American Thyroid Association and the American College of Radiology Thyroid Imaging Reporting and Data System (TI-RADS) criteria do not recommend biopsy of the majority of subcentimeter thyroid nodules, as PMCs are mostly indolent with excellent prognosis. However, the paradigm of active surveillance presents a conundrum on how to identify the rare patient with distant metastatic disease while avoiding unnecessary intervention in the majority. METHODS: After initial discovery of incidental lesions on chest computed tomography, core or wedge biopsies of the lung lesion were performed. Thyroid nodules on ultrasound were classified by TI-RADS. Tumor DNA was sequenced, annotated, filtered on 119 known cancer genes, and filtered for variants with an exome allele frequency of <0.001. RESULTS: A 70-year-old woman and a 29-year-old woman presented with incidental pulmonary lesions on computed tomography scan. Lung biopsy revealed lung metastases from papillary thyroid carcinoma. The thyroid nodules in both patients were TI-RADS 3 and American Thyroid Association low-suspicion. Molecular testing showed a c.1721C>G mutation (p.Thr574Ser) in the TSHR gene in patient 1 and a codon 61 mutation in the NRAS gene in patient 2. Both patients were iodine-avid, with complete structural remission in one patient and ongoing treatment with evidence of structural response in the other. CONCLUSION: The 2 presentations demonstrate unexpected and concerning behavior of PMCs. Both thyroid tumors were subcentimeter in diameter, meaning they would have escaped detection using traditional risk-stratification algorithms in active surveillance. Further knowledge of tumor genetics and microenvironment may assist in predicting tumor behavior in PMCs.

Wnt Signaling in Thyroid Homeostasis and Carcinogenesis.

The Wnt pathway is essential for stem cell maintenance, but little is known about its role in thyroid hormone signaling and thyroid stem cell survival and maintenance. In addition, the role of Wnt signaling in thyroid cancer progenitor cells is also unclear. Here, we present emerging evidence for the role of Wnt signaling in somatic thyroid stem cell and thyroid cancer stem cell function. An improved understanding of the role of Wnt signaling in thyroid physiology and carcinogenesis is essential for improving both thyroid disease diagnostics and therapeutics.

Papillary-Type Carcinoma of the Thyroglossal Duct Cyst: The Case for Conservative Management.

OBJECTIVES: Thyroglossal duct cyst (TGDC) is the most common congenital neck mass, presenting in up to 7% of the population. TGDC carcinoma is much less common, occurring in roughly 1% of patients diagnosed with TGDC. The vast majority of these tumors are papillary-type thyroid cancer. Given its rarity, there is wide variation in management recommendations for this disease. Extent of surgical management and need for adjuvant therapy including radioactive iodine ablation (RAI) are particularly debated, with some authors arguing aggressive therapy including RAI for any patients who undergo concurrent thyroidectomy with the Sistrunk procedure for TGDC carcinoma. We present a series of patients treated for TGDC carcinoma at our institutions and discuss our management algorithm. METHODS: This is a retrospective chart review of patients with TGDC treated at 2 separate institutions. Factors reviewed included patient age, sex, preoperative diagnosis, preoperative work-up, extent of therapy, and use of adjuvant therapy. RESULTS: Six patients who were treated for TGDC carcinoma at our institutions were identified. One patient was excluded because the patient had been treated at an outside facility prior to referral. All patients had papillary-type thyroid cancer. One patient underwent the Sistrunk procedure alone, and the remaining 4 underwent the Sistrunk procedure plus total thyroidectomy. Two of 4 patients were noted to have malignancy in the thyroid. Two of 4 patients who underwent thyroidectomy additionally received adjuvant RAI. CONCLUSION: Thyroglossal duct cyst carcinoma is uncommon and management is controversial. In low-risk patients (single tumor focus, negative margins, normal preoperative neck/thyroid imaging, no extension of TGDC carcinoma beyond the cyst wall), the Sistrunk procedure alone with observation of the thyroid may be sufficient. In this patient population, RAI is unlikely to be of any substantial benefit.

The physician-hospital team: a successful approach to improving care in a large academic medical center.

Initiatives to improve the quality and efficiency of care in academic medical centers (AMCs, teaching hospitals) can benefit the performance of academic departments as well as the hospital. However, the value of performance improvement programs in an AMC is often challenging. At Jefferson Medical College, clinical efficiency and bed availability are important priorities to the Department of Medicine. To this end, a multidisciplinary program was designed to (1) improve the quality and consistency of care by adapting and adopting national guidelines for patients with heart failure and acute coronary syndrome; (2) identify and improve hospital operational supports and maximize resource utilization; (3) increase hospital functional capacity to make way for increased volume; and (4) improve housestaff education and practice by using evidence-based approaches and by optimizing teaching relationships between housestaff and attending faculty. The eight-month project (November 2002 to July 2003) resulted in improvement in several quality measures including increased use of beta blockers and angiotensin converting enzyme inhibitors for heart failure patients, reduced length of stay for heart failure and acute coronary syndrome patients, and increased satisfaction of the clinicians involved in caring for these patients. However, the project was not without barriers including individual physician's unwillingness to embrace change and an inability to incentivize change. Development of faculty leadership skills and enhanced physician accountability helped in overcoming the challenges of change.

Management of Hyperthyroidism during the Preconception Phase, Pregnancy, and the Postpartum Period.

Hyperthyroidism can occur during pregnancy and the postpartum period, and the treatment of hyperthyroidism should be considered in the preconception phase. Pregnancy has multiple normal physiologic effects on thyroid hormone, which is a separate process distinct from syndromes such as transient hyperthyroidism of hyperemesis gravidarum. The rationale regarding antithyroid drug use during different stages of pregnancy is reviewed, including the literature regarding adverse neonatal outcomes such as aplasia cutis and methimazole embryopathy in the setting of first trimester maternal methimazole use. The use of treatment modalities for hyperthyroidism during pregnancy such as surgery is also discussed. Studies of maternal, fetal, and neonatal complications of hyperthyroidism are examined in this article. Moreover, the evidence regarding antithyroid drugs, specifically methimazole and propylthiouracil, during lactation is considered. Other disease conditions that can take place during pregnancy and the postpartum period such as hyperemesis gravidarum, subclinical hyperthyroidism, gestational trophoblastic disease, and postpartum thyroiditis and their treatments are also presented.

Thyroid Cancer in Pregnancy.

Owing to the young median age of diagnosis, thyroid cancer in women can coincide with pregnancy and affect its management. The evaluation of a thyroid nodule in pregnant women is similar to that in nonpregnant women, but special consideration must be taken for the impact of a cancer diagnosis and its sequelae in pregnancy. The initial comprehensive exam for pregnant and nonpregnant women includes evaluation of the biochemical function and structure of the thyroid gland, and then fine-needle aspiration biopsy of any suspicious nodule. Management diverges after biopsy and diagnosis, as pregnancy affects timing of thyroidectomy and radioiodine exposure. Owing to the indolent nature of differentiated thyroid cancers, surgery can often be delayed to the immediate postpartum period without change in recurrence or mortality rate. However, for more aggressive thyroid cancers or if the patient wishes to pursue surgery during pregnancy, a discussion about maternal health, fetal risk, and disease prognosis is needed between the physician and patient. This review serves to discuss the evaluation of the thyroid nodule and management of thyroid cancers in the pregnant population, as well as address thyroid cancer surveillance in pregnant women with a previous history of thyroid cancer.

Is above age 45 appropriate for upstaging well-differentiated papillary thyroid cancer?

OBJECTIVE: Age greater than 45 years old is a prognostic marker in well-differentiated papillary thyroid cancer (PTC) using the American Joint Cancer Committee/Union Internationale Contre le Cancer Tumor Nodes Metastasis (AJCC/UICC TNM) staging system. Our clinical observation has been that patients aged 45 to 64 years have similar outcomes when compared to patients younger than 45 years, and we questioned the origin and accuracy of this prognostic variable. METHODS: Using SEERstat software, we analyzed the Surveillance, Epidemiology, and End Result (SEER) database for PTC using the following International Classification of Diseases for Oncology (ICD-O) codes: 8050, 8260, 8340, 8341, 8342, 8243, and 8344. Data were stratified in 5-year categories by age at diagnosis from 20 to 84 years old, with patients 85 years old and above categorized together. Survival is reported as cause specific. RESULTS: A total of 53,581 patients were identified. The 5-year survival rate decreased with each increasing age category with no inflection point at age 45 in the survival curve. While the prognosis was less favorable in each advancing age group, survival remained above 90% for all age groups under 65 years. CONCLUSION: A review of the literature reveals a lack of data supporting the use of age 45 as a prognostic variable. Our SEER database review revealed a continuum of disease-specific mortality for each incremental 5-year time period above age 45. We conclude that the current use of age 45 as a single prognostic age marker does not accurately reflect the progressive mortality risk that is apparent with each 5-year increment in age.

Eosinophilic fasciitis: demographics, disease pattern and response to treatment: report of 12 cases and review of the literature.

BACKGROUND: Eosinophilic fasciitis is a rare scleroderma-like illness. The clinical spectrum of the disease has evolved since its initial description. METHODS: We identified all patients diagnosed with eosinophilic fasciitis over the past 10 years at our scleroderma clinic. Demographics, disease pattern, serologies, tissue pathology and reponse to treatment were all recorded. RESULTS: Twelve patients with eosinophilic fasciitis were identified in our clinic over the past 10 years. The mean age at diagnosis was 49.8 +/- 9.8 years, with nine female and three male patients. The first symptoms were noticed at an average of 8.8 +/- 6.1 months before diagnosis. The mean initial absolute peripheral blood eosinophil count was 1188 +/- 1059 cells/L. Two patients had a monoclonal gammopathy, and two had positive ANA titers. All patients received corticosteroids, 10 of whom received the equivalent dose of > 20 mg/day of prednisone for more than a month. Five patients received hydroxychloroquine, two received methotrexate, one received cyclosporine, one received topical tacrolimus, and one received sulfasalazine. At a mean follow up of 17.6 months (range 2-94 months), 8 patients had a good response to treatment, 2 patients had no effect, and 2 patients had a poor response to treatment. CONCLUSION: High dose corticosteroid treatment lasting longer than a month with or without an immunosuppressive agent helped most patients with eosinophilic fasciitis, best results seen in those patients who were initiated treatment early on after their first symptoms.

Scleroderma lung disease: treatment with cyclophosphamide.

Evaluation of: Tashkin, Elashoff, Clements PJ et al. Cyclophosphamide versus placebo in scleroderma lung disease. N. Engl. J. Med. 354(25), 2655-2666 (2006). Interstitial lung disease has become one of the leading causes of morbidity and mortality in systemic sclerosis. Currently, there remains a void in proven effective treatment strategies to provide clinical benefit to affected patients. The article under evaluation pioneers the efforts of investigating oral cyclophosphamide in treating scleroderma lung disease by designing a prospective, double-blinded, placebo-controlled study examining the drug's effect on outcome measures of forced vital capacity, patient subjective health assessment questionnaire disability scores, among others. We review the methods, results and overall conclusion of the study, which shows a significant, yet modest, result demonstrating the benefit of oral cyclophosphamide in the context of this disease setting. We conclude that although the study provides an excellent starting point for examining the efficacy of cyclophosphamide in certain forms of scleroderma lung disease, the study's high drop-out rate, choice of forced vital capacity as a primary outcome, side-effect profile of the drug and overall significance of the results make the conclusions difficult to incorporate into clinical practice.