Ponatinib-Related Vasospastic Angina.

Tyrosine kinase inhibitors (TKIs) are essential drugs for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Cardiovascular or arteriothrombotic adverse events have been reported in patients treated with TKIs. We report 3 cases of Ponatinib-related vasospastic angina, in which prophylactic administration of nitrates or calcium channel blockers was effective.

Impact of COVID-19 Pandemic on Advanced Non-small Cell Lung Cancer Treatment at a Japanese Hospital.

Background/Aim: The COVID-19 pandemic has forced medical institutions to scale back their practice. Changes in patient behavior seemed to be having an impact. We conducted a survey with the aim of reviewing lung cancer treatment during the pandemic period and identifying problems. Patients and Methods: We examined the medical records of all patients pathologically diagnosed with non-small cell lung cancer (NSCLC) in our hospital from 2017 to 2022. NSCLC patients were divided into two groups: those diagnosed between 2017 and 2019 (first period) and those diagnosed between 2020 and 2022 (second period). Results: Within the study period, 267 NSCLC patients (first period: 147 patients, second period: 121 patients) were diagnosed in our hospital. The patients in the two study periods did not differ significantly in age (p=0.613), ECOG performance status (p=0.125), and clinical stage (p=0.354). Tumor size was significantly larger in the second period with a mean of 5.88 cm ± 3.02, compared to 4.24 cm ± 1.76 in the first period (p<0.001). In the standard treatment group, the median survival time was 457 days in the first period and 313 days in the second period (p=0.063). In the best supportive care group, median survival time was 122 days in the first period and 57 days in the second period (p=0.004). Conclusion: Patients themselves refrained from seeking consultation for lung cancer treatment during the pandemic period. It is inconclusive how to reduce the delay due to the suppression of consultations, but this is an important issue for the future.

Refusal of Subsequent Treatment in Patients With EGFR-mutant Non-small-cell Lung Cancer After Response to EGFR-TKIs.

BACKGROUND/AIM: During the course of effective and long-term treatment with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), some elderly patients might decline further treatment after EGFR-TKI. We conducted a study to try and understand the reasons for this treatment decision. PATIENTS AND METHODS: We analyzed the medical records of all patients diagnosed with non-small-cell lung cancer with EGFR mutations between 2016 and 2021. RESULTS: There were 108 patients who received EGFR-TKIs. Of these, 67 patients responded to TKI. These responding patients were divided into two groups according to whether they received subsequent TKI treatment. At their request, 24 patients (group A) did not receive further anticancer treatment following TKI. The other 43 patients (group B) received anticancer therapy following TKI. Progression-free survival in group A patients was significantly longer (median=18 months, range=1-67 months) than in group B patients. The reasons for not wanting subsequent treatment after TKI were older age, reduced general condition, deterioration of physical comorbid disease and dementia. Dementia was the most common reason for patients over 75 years of age. CONCLUSION: Some elderly patients with well-controlled disease might express their refusal of all subsequent anticancer therapy after TKIs. Medical staff should respond seriously to these requests.

Xanthine oxidase inhibitors treatment or discontinuation effects on mortality: evidence of xanthine oxidase inhibitors withdrawal syndrome.

Objectives: This study investigates the impact of xanthine oxidase inhibitors (XOI) on mortality in patients with cardiovascular diseases. XOI withdrawal has been reported to increased mortality risk due to rapid adenosine triphosphate (ATP) deficiency. This study aims to determine whether XOI treatment reduces mortality and whether XOI withdrawal increases mortality. Methods: This is a real-world database study using the Japanese Registry of All Cardiac and Vascular Diseases (J-ROAD). We analyzed 1,648,891 hospitalized patients aged 20-90 with acute coronary syndrome or heart failure. In the first study, mortality rates were compared between patients without urate-lowering agents (n = 1,292,486) and those with XOI agents (n = 315,388, excluding 41,017 on other urate-lowering agents). In the second study, mortality rates were compared between the XOI continuous medication group (n = 226,261) and the XOI withdrawal group (n = 89,127). Results: After multiple adjustments, XOI treatment group showed significantly lower mortality compared with that without any urate-lowering agent (odds ratio (OR), 0.576, 95% confidence interval (CI), 0.567-0.587, p < .001). In the sub-analysis, the group with allopurinol (OR, 0.578; 95% CI, 0.557-0.600), febuxostat (OR, 0.610; 95% CI, 0.599-0.622), and topiroxostat (HR, 0.545; 95% CI, 0.473-0.628) showed lower OR of mortality compared with that without any urate-lowering agent. XOI withdrawal group led to significantly higher death rates compared to XOI continuous group (19.8% vs. 0.03%; p < .001). Conclusion: XOI treatment for patients with cardiovascular diseases is associated with reduced mortality. Conversely, XOI withdrawal is linked to elevated mortality risk. This emphasizes the importance of both prescribing and discontinuing XOI carefully to optimize patient outcomes.

Impediments to Heart Transplantation in Adults With MELASMT-TL1:m.3243A>G Cardiomyopathy.

BACKGROUND: The heart is commonly involved in maternally inherited mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome caused by the MT-TL1 m.3243A>G mutation of the mitochondrial DNA. Heart transplantation (HTx) is controversial and has rarely been performed with conflicting results. OBJECTIVES: We analyzed factors preventing HTx in consecutive adult patients with MELASMT-TL1:m.3243A>G cardiomyopathy diagnosed and followed during the last 23 years in our HTx referral center. METHODS: The series consists of 14 unrelated adult probands who were referred for evaluation of cardiomyopathy from 1998 to 2021. None had a suspected diagnosis of MELAS before referral. All patients underwent clinical and genetic visit and counseling, mitochondrial DNA sequencing, cardiovascular investigation (including right heart catheterization and endomyocardial biopsy in 10), multidisciplinary assessment, and biochemical tests. Family screening identified 2 affected relatives. RESULTS: The cardiac phenotype was characterized by hypertrophic, concentric, nonobstructive cardiomyopathy that often evolved into a dilated cardiomyopathy-like phenotype. Of the 14 probands, 7 were potential candidates for HTx, 2 for heart and kidney Tx, and 1 was on the active HTx list for 3 years. None of the 10 probands underwent HTx. One is currently being evaluated for HTx. All had diabetes, hearing loss, and myopathy, and 10 had chronic kidney disease and progressive encephalomyopathy. During follow-up, 10 died from heart failure associated with multiorgan failure within 5 years of the genetic diagnosis. CONCLUSIONS: High risk of stroke-like episodes, chronic kidney disease, and wasting myopathy in MELASMT-TL1:m.3243A>G patients prevents activation of plans for HTx. As a result, the management of their cardiomyopathy in this syndromic context remains an unmet clinical need.

Discontinuation of Immune Checkpoint Inhibitor and Survival in Patients With Non-small-cell Lung Cancer Without a Driver Gene Mutation.

BACKGROUND/AIM: Patients with non-small-cell lung cancer treated with immune checkpoint inhibitors (ICI) might be forced to discontinue treatment for various reasons. We conducted a retrospective study to evaluate the impact of discontinuation of ICI treatment on patient prognosis. PATIENTS AND METHODS: We performed a retrospective study that reviewed the medical charts of 86 patients treated with ICI monotherapy and 34 patients treated with a combination of ICI and chemotherapy during the period from February 2016 to February 2022 at our two hospitals. 'Discontinuation' was defined as a cessation of ICI treatment for more than two cycles for any reason. RESULTS: The two most common reasons for discontinuation were immune-related adverse events and at the request of the patient. Nineteen patients who had discontinued ICI, resumed ICI or another therapy. Discontinuation of ICI treatment was a favorable factor in overall survival in 84 patients with ICI monotherapy as well as in 34 patients treated with chemotherapy combined with ICI. CONCLUSION: This analysis found discontinuation of ICI treatment did not adversely affect prognosis. This suggests that when treating patients with non-small-cell lung cancer with ICI, chest physicians should respond flexibly, and, with careful monitoring, consider discontinuation of ICI.

Body Weight Change in Non-small Cell Lung Cancer Patients Treated With EGFR-TKI.

BACKGROUND/AIM: Body weight (BW) changes in epidermal growth factor inhibitor-tyrosine kinase (EGFR-TKI) treated non-small cell lung cancer patients has yet to be fully investigated. For the purpose of clarifying changes in body weight in patients who received EGFR-TKI treatment in clinical practice, we performed a retrospective study. In this study, comparison between pretreatment BW and those at 12, 24 weeks, and 12 months in these patients was performed. PATIENTS AND METHODS: We included all the patients diagnosed with EGFR mutated NSCLC in two tertiary hospitals between April 2009 and March 2021. BW records in the medical chart of each patient who was treated with EGFR-TKI for more than 12 weeks were surveyed. In each patient, BW at 12, 24 weeks, and 12 months from the initiation of EGFR-TKI treatment were compared with pretreatment BW. RESULTS: Sixty-three patients obtained TKI treatment for more than 12 weeks and had comparable body weight records. Compared with the pretreatment BW, decreased BW was observed at 12, 24 weeks, and 12 months from the initiation of TKI treatment. CONCLUSION: Even in patients treated with EGFR-TKI, which is evaluated as less toxic and a more effective therapy, there might be patients who lose weight during the treatment period. Chest physicians will be required to provide medical care even for EGFR mutated patients, taking into consideration changes in BW.

Left atrial dissection associated with disruption of mitral annular calcification: a case report.

Background: Left atrial dissection is an uncommon entity associated with cardiac surgery, catheter interventional procedures, or cardiac trauma. Spontaneous cases have also been reported. The entry of left atrial dissection often occurs in the posterior annulus of the mitral valve, which is also a favourable site for mitral annular calcification (MAC). We herein report a rare case of spontaneous left atrial dissection caused by a disruption of MAC. Case summary: An 84-year-old woman was admitted to our hospital for chest discomfort. Transthoracic echocardiography showed severe calcification of the posterior mitral annulus and a heterogeneous mass in the posterior wall of the left atrium adjacent to MAC. Transoesophageal echocardiography showed blood flow through MAC from the left ventricle into the mass. Cardiac computed tomography showed the disruption of MAC, which was the entry for left atrial dissection and haematoma. The conservative approach was continued, as the haemodynamic state was stable and because of her frailty and many complications. No further events occurred during 6 months follow-up, although the false cavity did not regress. Discussion: The diagnosis of an intracardiac mass can be challenging. In our case, a detailed anatomical evaluation with multiple imaging modalities allowed us to understand the disease and manage it appropriately.

Association between time to treatment failure and peripheral eosinophils in patients with non-small cell lung cancer treated with immune checkpoint inhibitors.

Introduction: There is an unmet clinical need to identify biomarkers predicting which patients with non­small cell lung cancer (NSCLC) would benefit from treatment with immune checkpoint inhibitors (ICPIs). Objectives: The purpose of this study was to draw a detailed time to treatment failure (TTF) curve with information on the changes in peripheral eosinophil expression during ICPI treatment for NSCLC, and to clarify whether eosinophil expression can predict prolonged TTF. Patients and methods: In 259 patients with NSCLC treated with ICPI therapy, peripheral eosinophil counts and percentages at the time of each ICPI administration were evaluated from the beginning of ICPI treatment up to TTF. Univariable and multivariable analyses were performed to identify clinical factors associated with TTF. Results: Patients receiving ICPI monotherapy (n = 180) were divided into 3 groups (TTF ≤6 weeks, TTF >6 weeks and ≤24 weeks, and TTF >24 weeks) and the number of patients with an eosinophil percentage of 5% or more within 6 weeks of ICPI therapy initiation was significantly different among these groups. In univariable and multivariable analyses, performance status of 0 to 1, immune-related adverse event not requiring ICPI discontinuation as well as an eosinophil percentage of 5% or more and an eosinophil count of 330/µ or more within 6 weeks of ICPI therapy initiation were significant favorable factors for prolonged TTF. In patients treated with combination therapy of ICPI and chemotherapy (n = 79), the number of patients with an eosinophil percentage of 5% or more within 12 weeks of therapy initiation was significantly different between patients with a TTF of up to 12 weeks and those with a more prolonged TTF. However, the only significant favorable factor for TTF was female sex. Conclusions: In NSCLC patients treated with ICPI therapy, particularly ICPI monotherapy, eosinophil measurements during treatment might be useful for predicting prolonged TTF.

Association between peripheral eosinophils and clinical outcomes in patients with non-small cell lung cancer treated with immune checkpoint inhibitors.

INTRODUCTION: Programmed cell death ligand 1 is considered a predictor of the therapeutic effect of immune checkpoint inhibitors (ICPIs), but a more simple and useful predictor is needed. OBJECTIVES: The aim of this study was to identify the relationship between eosinophil counts and percentages and response to ICPI therapy. PATIENTS AND METHODS: In 190 patients with non-small cell lung cancer (NSCLC) treated with ICPI therapy, peripheral eosinophil counts and percentages at the time of ICPI therapy initiation, the maximum counts and percentages of eosinophils during ICPI therapy, response to therapy, and time to treatment failure (TTF) were investigated. RESULTS: Both an increase in the peripheral eosinophil count and an elevation of eosinophil percentage following the initiation of ICPI therapy were observed, regardless of whether the patients had controlled or progressive disease. The median time to the maximum eosinophil percentage was 5 weeks in patients with controlled disease and 2 weeks in those with progressive disease. The cutoff value for the maximum eosinophil counts and percentage during ICPI therapy was set at 300/µl and 5%, respectively, to identify the presence or absence of a therapeutic effect. Time to treatment failure was longer in patients with maximum eosinophil counts exceeding 300/µl and a maximum eosinophil percentage above 5%. In a multivariable analysis, a maximum eosinophil percentage of 5% during ICPI therapy was a significant predictive factor for therapeutic efficacy. CONCLUSIONS: The measurement of peripheral eosinophils up to around 5 weeks following the initiation of treatment, especially the maximum eosinophils count and percentage, might provide useful information about the efficacy of ICPIs.

Absolute Increase in the Number and Proportion of Peripheral Eosinophils Associated With Immune Checkpoint Inhibitor Treatment in Non-small Cell Lung Cancer Patients.

Background/Aim: To clarify the clinical significance of the absolute increase in the number and proportion of peripheral eosinophils associated with immune checkpoint inhibitor (ICPI) treatment in non-small cell lung cancer (NSCLC) patients. Patients and Methods: We performed a retrospective study, by reviewing the medical charts of 191 patients who were treated with ICPI monotherapy and 80 patients treated with the combination of ICPI and chemotherapy during the period from February 2016 and April 2021. Results: In patients treated with ICPI monotherapy, there was a significant difference in time to treatment failure (TTF) between the two groups divided by eosinophils ≥ or <10%. Similarly, a significant difference was found in TTF between the two groups divided by eosinophils ≥ or <1,500/µl. Factors related to both an increase in the number and percentage of peripheral eosinophils were "immune-related adverse effects (irAE) that did not lead to discontinuation of administration". Conclusion: Some patients with irAE might have a 'favorable' absolute increase in peripheral eosinophils.

Treatment of Patients With Non-small-cell Lung Cancer With Uncommon EGFR Mutations in Clinical Practice.

BACKGROUND/AIM: To describe real clinical outcomes in patients with non-small cell lung cancer who have uncommon epidermal growth factor receptor (EGFR) mutations. MATERIALS AND METHODS: We performed a retrospective chart review from 15 medical institutes that cover a population of three million people from April 2008 to March 2019. RESULTS: There were 102 patients with uncommon EGFR mutation. Progression-free survival (PFS) tended to be longer in patients receiving afatinib compared with first-generation EGFR tyrosine kinase inhibitors. PFS in patients treated with afatinib or osimertinib was significantly longer than in patients treated with gefitinib or erlotinib (p=0.030). Multivariate analysis also revealed the contribution of afatinib or osimertinib to increased survival. In patients with exon 20 insertions, chemotherapy was efficacious. CONCLUSION: In treating patients with uncommon EGFR mutations, our results indicate longer-term survival might be achieved with second-generation or later TKIs and cytotoxic chemotherapeutic drugs.

Clinicopathological Features in Elderly ALK-rearranged Non-small Cell Lung Cancer Patients.

AIM: To clarify the clinicopathological features in elderly anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: A retrospective study was performed in 129 ALK rearranged NSCLC patients diagnosed between April 2008 and March 2019 in fifteen Institutions of the Ibaraki prefecture, Japan. RESULTS: Median age of patients was 63 years. In 59 patients aged 65 and older, the proportions of patients with advanced stage and those treated with ALK-tyrosine kinase inhibitor (TKI) were lower than those younger than 65 years. There was no difference in overall survival (OS) between the two age groups. Among the elderly patients, no difference was observed in OS between the patients aged 65-69 and those aged 70 and older. In 89 patients treated with TKI, no significant differences were observed in the progression-free survival of TKIs and OS between patients aged 65 and older and those younger than 65, respectively. CONCLUSION: Evaluation of ALK gene status and TKI treatment are desirable even for elderly patients.

Real Clinical Practice in ALK-rearranged NSCLC Patients: A Retrospective Observational Study.

BACKGROUND/AIM: To describe real clinical outcomes when using systemic therapy to treat non-small cell lung cancer (NSCLC) patients who have anaplastic lymphoma kinase (ALK) fusion gene mutation. PATIENTS AND METHODS: We performed a retrospective chart review from April 2008 to March 2019 sourced from 16 medical institutes that cover a population of three million people. RESULTS: There were 129 ALK rearranged NSCLC patients. Among them, 103 patients including 40 recurrent disease cases received ALK-tyrosine kinase inhibitors (TKI) and chemotherapy. Our treatment results were comparable to previously reported clinical trials and clinical practice studies. First-line alectinib, treatment sequence of ALK-TKI followed by another ALK-TKI, and pemetrexed-containing chemotherapy contributed to the outcome of treatment. CONCLUSION: By arrangement of treatment such as treatment sequence of ALK-TKI and chemotherapy regimen, it might be possible to obtain a treatment outcome almost equivalent to those of clinical trials even in real clinical practice.

Application of Cluster Analysis to Distant Metastases from Lung Cancer.

BACKGROUND/AIM: In patients with lung cancer, there has been no study that treated 'distant metastases' as 'metastatic patterns'. This study aimed to evaluate if specific 'metastatic patterns' exist in lung cancer patients. PATIENTS AND METHODS: Data were collected from lung cancer patients between 2009 and 2018. Metastatic patterns were analyzed using cluster analysis in patients with epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma, those with small cell lung cancer (SCLC), and those with squamous cell lung cancer (SqCLC). RESULTS: In 313 patients (127 patients with EGFR mutation, 87 patients with SCLC, and 99 patients with SqCLC), metastatic patterns existed in each of the three subset groups, and metastatic patterns of these groups were statistically different. CONCLUSION: The knowledge of the metastatic patterns might be useful for clinical practice in the foreseeable future, as it enables a more efficient detection of metastatic disease through imaging, and a more effective treatment at predicted metastatic sites.

The Prognosis of Lung Cancer With Different Metastatic Patterns.

BACKGROUND/AIM: Distant organ metastases do not occur at random in lung cancer. A retrospective study was conducted in order to evaluate 1) what kinds of metastatic patterns exist in three different types of lung cancer, and 2) whether metastatic patterns affected prognosis in the different types of lung cancer. PATIENTS AND METHODS: Data were collected from all consecutive patients with diagnosed lung cancer between April 2009 and October 2018 in our hospitals. Cluster analysis was performed to classify patients. Kaplan-Meier analysis, log-rank test, and Cox proportional hazards model were used. RESULTS: Epidermal growth factor-mutated adenocarcinoma, small cell lung cancer, and squamous cell lung cancer had different 'metastatic patterns', survival, and unfavorable prognostic factors, respectively. CONCLUSION: There might be different metastatic patterns, survival, and unfavorable prognostic factors in each pathological and genetic type of lung cancer. It is worthwhile carrying out diagnostic imaging and treatment considering information on metastatic patterns.

An autopsied NSCLC patient with huge adrenal gland metastasis with rapid growth and local invasion.

The adrenal gland is a common site for metastasis from non-small-cell lung cancer (NSCLC). Adrenal metastases are usually solitary, asymptomatic and diagnosed incidentally during staging of patients with lung adenocarcinoma. Huge but sole adrenal gland metastasis with rapid growth and local invasion is extremely rare and those occurring in the setting of NSCLC have not been reported previously. Herein we describe a 66 year old male patient with NSCLC who had huge but sole adrenal gland metastasis with rapid growth and local invasion and extension into stomach, pancreas and left kidney. Interestingly there was no increase in the primary lesion of NSCLC. These findings were confirmed by autopsy. Despite the occurrence of an adrenal gland metastasis with considerable size being rare, it should be considered in the differential diagnosis, even if there is no involvement of the other organ and the primary lesion is of a small size.

Acquired EGFR T790M Mutation After Relapse Following EGFR-TKI Therapy: A Population-based Multi-institutional Study.

AIM: To describe the prevalence and determinants of acquired epidermal growth factor receptor (EGFR) T790M gene mutation in a clinical practice setting. MATERIALS AND METHODS: We performed a retrospective chart review study between January 2013 and November 2017 across multiple institutes, covering a population of 3 million people. RESULTS: We reviewed the charts of 233 patients non-small cell lung cancer with EGFR mutations. Of them, 99 (42.5%) patients had acquired T790M mutations in EGFR. Patients ≥75 years old and patients with an exon 19 deletion had higher rates of acquired T790M mutation than did younger patients and those with an exon 21 L858R mutation. In 75 patients treated with afatinib, 34 (45.3%) patients had acquired T790M mutation. The sensitivity of T790M mutation detection was lower in plasma specimens than in biopsy specimens. CONCLUSION: This population-based study confirms previous studies and highlights potential determinants of acquired T790M mutation to be considered in clinical practice.

Management of afatinib-induced stomatitis.

Severe stomatitis may lead to the need to interrupt or discontinue cancer therapy and, thus, may affect control of the primary disease. Stomatitis may also increase the risk of local and systemic infection and significantly affects the quality of life and the cost of care. The present study was conducted to evaluate the efficacy of two traditional herbal medicines in controlling treatment-induced stomatitis in a small cohort of lung cancer patients treated with afatinib. All patients who were treated with afatinib for epidermal growth factor receptor (EGFR) mutated nonsmallcell lung cancer (NSCLC) between January, 2015 and March, 2016, were included in this study. During the study period, a total of 14 NSCLC patients were treated with afatinib, an EGFR-tyrosine kinase inhibitor (TKI). Two patients already had stomatitis at the time of initiation of afatinib therapy; among the remaining 12 NSCLC patients, 2 (16.7%) developed stomatitis. All the lesions in the 4 patients who developed stomatitis were completely alleviated after 2 weeks of therapy with Aznol mouthwash, a chamomile extract with anti-inflammatory effects, and Hangeshashinto, a traditional herbal (Kampo) medicine. Afatinib therapy was re-initiated, but none of the patients developed stomatitis thereafter. To the best of our knowledge, this is the first report evaluating oral care and management of stomatitis. This type of care and treatment may reduce the incidence of complications associated with EGFR-TKI therapy.

Genetic Screening of Anderson-Fabry Disease in Probands Referred From Multispecialty Clinics.

BACKGROUND: Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disease, caused by defects of the alpha-galactosidase A (GLA) gene. AFD can affect the heart, brain, kidney, eye, skin, peripheral nerves, and gastrointestinal tract. Cardiology (hypertrophic cardiomyopathy), neurology (cryptogenic stroke), and nephrology (end-stage renal failure) screening studies suggest the prevalence of GLA variants is 0.62%, with diagnosis confirmation in 0.12%. OBJECTIVES: This study sought to expand screening from these settings to include ophthalmology, dermatology, gastroenterology, internal medicine, pediatrics, and medical genetics to increase diagnostic yield and comprehensively evaluate organ involvement in AFD patients. METHODS: In a 10-year prospective multidisciplinary, multicenter study, we expanded clinical, genetic, and biochemical screening to consecutive patients enrolled from all aforementioned clinical settings. We tested the GLA gene and α-galactosidase A activity in plasma and leukocytes. Inclusion criteria comprised phenotypical traits and absence of male-to-male transmission. Screening was extended to relatives of probands harboring GLA mutations. RESULTS: Of 2,034 probands fulfilling inclusion criteria, 37 (1.8%) were carriers of GLA mutations. Cascade family screening identified 60 affected relatives; clinical data were available for 4 affected obligate carriers. Activity of α-galactosidase A in plasma and leukocytes was diagnostic in male subjects, but not in female subjects. Of the 101 family members harboring mutations, 86 were affected, 10 were young healthy carriers, and 5 refused clinical evaluation. In the 86 patients, involved organs or organ systems included the heart (69%), peripheral nerves (46%), kidney (45%), eye (37%), brain (34%), skin (32%), gastrointestinal tract (31%), and auditory system (19%). Globotriaosylceramide accumulated in organ-specific and non-organ-specific cells in atypical and classic variants, respectively. CONCLUSIONS: Screening probands with clinically suspected AFD significantly increased diagnostic yield. The heart was the organ most commonly involved, independent of the clinical setting in which the patient was first evaluated.