Prevalence of patients with lysosomal storage disorders and peroxisomal disorders: A nationwide survey in Japan.

INTRODUCTION: Lysosomal storage disorders and peroxisomal disorders are rare diseases caused by the accumulation of substrates of the metabolic pathway within lysosomes and peroxisomes, respectively. Owing to the rarity of these diseases, the prevalence of lysosomal storage disorders and peroxisomal disorders in Japan is unknown. Therefore, we conducted a nationwide survey to estimate the number of patients with lysosomal storage disorders and peroxisomal disorders in Japan. METHODS: A nationwide survey was conducted following the "Manual of nationwide epidemiological survey for understanding patient number and clinical epidemiology of rare diseases (3rd version)". A questionnaire asking for detailed information, such as disease phenotypes and medical history, was created and sent to 504 institutions with doctors who have experience in treating patients with lysosomal storage disorders and peroxisomal disorders. Result A total of 303 completed questionnaires were collected from 504 institutions (response rate: 60.1%). The number of patients was estimated by calculating the rate/frequency of overlap. The estimated number of patients was 1658 (±264.8) for Fabry disease, 72 (±11.3) for mucopolysaccharidosis I, 275 (±49.9) for mucopolysaccharidosis II, 211 (±31.3) for Gaucher disease, 124 (±25.8) for Pompe disease, 83 (±44.3) for metachromatic leukodystrophy, 57 (±9.4) for Niemann-Pick type C, and 262 (±42.3) for adrenoleukodystrophy. In addition the birth prevalence was calculated using the estimated number of patients and birth year data for each disease, and was 1.25 for Fabry disease, 0.09 for mucopolysaccharidosis I, 0.38 for mucopolysaccharidosis II, 0.19 for Gaucher disease, 0.14 for Pompe disease, 0.16 for metachromatic leukodystrophy, 0.16 for Niemann-Pick type C, and 0.20 for adrenoleukodystrophy. DISCUSSION: Among the diseases analyzed, the disease with the highest prevalence was Fabry disease, followed by mucopolysaccharidosis II, adrenoleukodystrophy, Gaucher disease and metachromatic leukodystrophy. In particular, the high prevalence of mucopolysaccharidosis II and Gaucher disease type II was a feature characteristic of Japan. CONCLUSION: We estimated the number of patients with lysosomal storage disorders and peroxisomal disorders in Japan. The details of the age at diagnosis and treatment methods for each disease were clarified, and will be useful for the early diagnosis of these patients and to provide appropriate treatments. Furthermore, our results suggest that supportive care and the development of an environment that can provide optimal medical care is important in the future.

Detection of novel Fabry disease-associated pathogenic variants in Japanese patients by newborn and high-risk screening.

BACKGROUND: In Japan, newborn and high-risk screening for Fabry disease (FD), an inherited X-linked disorder caused by GLA mutations, using dried blood spots was initiated in 2006. In newborn screening, 599,711 newborns were screened by December 2018, and 57 newborns from 54 families with 26 FD-associated variants were detected. In high-risk screening, 18,235 individuals who had symptoms and/or a family history of FD were screened by March 2019, and 236 individuals from 143 families with 101 FD-associated variants were detected. Totally 3, 116 variants were detected; 41 of these were not registered in Fabry-database.org or ClinVar and 33 were definitely novel. Herein, we report the clinical outcomes and discuss the pathogenicity of the 41 variants. METHODS: We traced nine newborns and 46 individuals with the 33 novel variants, and nine newborns and 10 individuals with eight other variants not registered in the FD database, and analyzed the information on symptoms, treatments, and outcomes. RESULTS: Thirty-eight of the 46 individuals with the 33 novel variants showed symptoms and received enzyme-replacement therapy and/or chaperone treatment. CONCLUSION: Delayed diagnosis should be avoided in patients with FD. Our results will help clinicians diagnose FD and determine the appropriate treatment for patients with these variants.

Otological aspects of Fabry disease in patients with normal hearing.

We investigated the otological aspects of Fabry disease (FD) in patients with normal hearing. Forty-one patients (21 men, 20 women) with bilaterally normal hearing were recruited, and their otological symptoms and hearing evaluations, which included pure tone audiometry (PTA) and distortion product otoacoustic emission (DPOAE), were investigated. Ten of the 21 male (47.6%) and eight of the 20 female (40.0%) patients had otological symptoms, of which tinnitus was the most frequent. Cardiac dysfunction was more frequently observed in female patients. The average thresholds on PTA were below 25 dB at all frequencies, but DPOAE amplitudes were significantly lower in female patients at some frequencies. Otological symptoms were frequently observed in patients with FD, despite their normal hearing levels on PTA. DPOAE might provide useful information regarding cochlear disturbances related to the disease..

Potential prognostic implications of myocardial thallium-201 and iodine-123-beta-methylpentadecanoic acid dual scintigraphy in patients with Anderson-Fabry disease.

OBJECTIVES: Information on the relationship between myocardial damage assessed by myocardial scintigraphy and prognosis in patients with Anderson-Fabry disease (AFD) is lacking. We therefore aimed to investigate the prognostic impacts of myocardial thallium-201 (201Tl) and iodine-123 beta-methyl 15-para-iodophenyl 3(R, S)-methylpentadecanoic acid (123I-BMIPP) dual scintigraphy in patients with AFD. METHODS: Eighteen consecutive patients with AFD underwent resting myocardial 201Tl/123I-BMIPP dual scintigraphy. Total defect scores (TDS) on both images were calculated visually according to the 17-segment model using a 5-point scoring system. The mismatch score (MS) was calculated as 'TDS on 123I-BMIPP-TDS on 201Tl'. RESULTS: Six major adverse cardiac events (MACEs) were recorded during a mean follow-up of 6.7 ± 4.2 years (three heart failure requiring hospitalization and three cardiac deaths). Left ventricular mass index, left atrial diameter, brain natriuretic peptide, TDS on 123I-BMIPP, and MS were all significantly greater in patients with MACEs compared with those without. Kaplan-Meier analysis indicated that high TDS on 123I-BMIPP and high MS were associated with poor event-free survival. CONCLUSION: TDS on 123I-BMIPP was a better prognostic determinant in patients with AFD than TDS on 201Tl. Myocardial 201Tl/123I-BMIPP dual scintigraphy may thus be a useful noninvasive modality for evaluating prognosis in patients with AFD.

[Skin Lesion in Fabry Disease].

Fabry disease is an inborn error metabolisms caused by deficiency of α-galactosidase A activity, and results in glycolipid accumulation of in multiple tissues or organs. Skin lesions occurred in Fabry disease are characterized by angiokeratoma, including acroparesthesia or hypohydrosis, among others. There are important characteristics for the diagnosis of Fabry disease.

Correlations Between Serum Cholesterol and Vascular Lesions in Fabry Disease Patients.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder and shows globotriosylceramide (Gb3) accumulation in multiple organs, resulting from a deficiency of α-galactosidase. In patients with Fabry disease, cardiovascular disease occurs at an early age. Previous studies have shown that serum levels of high-density lipoprotein-cholesterol (HDL-C) increase in this disease, yet its clinical significance for cardiovascular disease remains unclear. Methods and Results: In order to determine why the serum HDL-cholesterol is high in various cardiovascular diseases of Fabry disease patients, we evaluated the serum lipid profiles, ocular vascular lesions, and levels of serum vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 in 69 patients with Fabry disease diagnosed by genetic examination. The serum HDL-C/total cholesterol (T-Chol) ratio was significantly high, especially in male patients (41.5±1.7%) regardless of body mass index. Ocular vascular lesions were more likely to occur in female patients with a high HDL-C/T-Chol ratio compared with most male patients. Female patients with a high HDL-C/T-Chol ratio also presented a high serum VEGF level, suggesting that vascular endothelium dysfunction and arteriosclerotic changes progress more severely than in patients with a normal HDL-C/T-Chol ratio. In most patients, enzyme replacement therapy improved serum Gb3 and lyso-Gb3 levels, but these Gb3 and lyso-Gb3 still remained higher than in healthy controls, which appears to result in continuous vascular arteriosclerotic changes. CONCLUSIONS: We concluded that increased low-density lipoprotein-cholesterol uptake to the vascular wall caused by endothelial dysfunction is likely to contribute to the high HDL-C/T-Chol ratio observed in Fabry disease patients.

Efficacy and safety of enzyme-replacement-therapy with agalsidase alfa in 36 treatment-naïve Fabry disease patients.

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder resulting from the α-galactosidase A gene mutations. Enzyme-replacement-therapy (ERT) products for FD currently used include agalsidase alfa and agalsidase beta. There are many reports on efficacy and safety of ERT. However, most of the previous studies are done as a retrospective medical records analysis. METHODS: The Japan Fabry Research - 002 (JFR-002) was a prospective observational clinical study of 36 ERT-naïve FD patients (14 men and 22 women) at baseline (BL) and after initiation of ERT with agalsidase alfa 0.2 mg/kg every two weeks, a median period 62.5 months. The parameters measured included globotriaosylceramide (Gb3), globotriaosylsphingosine (Lyso-Gb3), left ventricular mass index (LVMI), brain natriuretic peptide (BNP), high-sensitivity troponin I (hs-Trop I), estimated glomerular filtration rate (eGFR), and anti-agalsidase alfa IgG antibody formation. RESULTS: All parameters remained steady during ERT treatment period. BNP levels in 14 patients whose BL levels were within the normal range (<19.5 pg/mL) remained within the same range, while 22 patients whose BL levels were abnormally high (≥19.5 pg/mL) gradually showed decreased levels after start of ERT. Gb3 and Lyso-Gb3 levels remarkably decreased after the initiation of ERT and remained low. CONCLUSION: The JFR-002 suggests that agalsidase alfa is effective in maintaining organ function in FD patients, and that the incidence of infusion reactions related to the treatment with agalsidase alfa is low, indicating the good tolerability to this ERT. TRIAL REGISTRATION: The JFR-002 was retrospectively registered at Japan Medical Association Center for Clinical Trials (Registration number: JMA-IIA00291 ) on May 19th, 2017.

Successful management of enzyme replacement therapy in related fabry disease patients with severe adverse events by switching from agalsidase Beta (fabrazyme(®)) to agalsidase alfa (replagal (®)).

BACKGROUND: Enzyme replacement therapy (ERT) is the only approved therapy for Fabry disease. In June 2009, there was a worldwide shortage of agalsidase beta, necessitating dose reductions or switching to agalsidase alfa in some patients. CASE PRESENTATION: We present two cases of Fabry disease (a parent and a child) who received agalsidase beta for 27 months at the licensed dose and 10 months at a reduced dose, followed by a switch to agalsidase alfa for 28 months. Case 1, a 26-year-old male had severe coughing and fatigue during ERT with agalsidase beta requiring antitussive and asthmatic drug therapy. After switching to agalsidase alfa, the coughing gradually resolved completely. Case 2, a 62-year-old female had advanced cardiac manifestations at the time of diagnosis. Despite receiving ERT with the approved dose of agalsidase beta, she experienced aggravation of congestive heart failure and was hospitalized. After switching to agalsidase alfa with standard care in heart disease, BNP level, echocardiographic parameters, eGFR rate and lyso-Gb3 levels were improved or stabilized. CONCLUSIONS: We report on two Fabry disease patients who experienced severe adverse events while on approved and/or reduced doses of agalsidase beta. Switching to agalsidase alfa associated with standard care in heart disease led to resolution or improvement in the cardiorespiratory status. And reduction in dose associated with standard care in respiratory disease was useful for decrease in cough and fatigue. Plasma BNP level was useful for monitoring heart failure and the effects of ERT.

Laser-induced plasma generation and evolution in a transient spray.

The behaviors of laser-induced plasma and fuel spray were investigated by visualizing images with an ultra-high-speed camera. Time-series images of laser-induced plasma in a transient spray were visualized using a high-speed color camera. The effects of a shockwave generated from the laser-induced plasma on the evaporated spray behavior were investigated. The interaction between a single droplet and the laser-induced plasma was investigated using a single droplet levitated by an ultrasonic levitator. Two main conclusions were drawn from these experiments: (1) the fuel droplets in the spray were dispersed by the shockwave generated from the laser-induced plasma; and (2) the plasma position may have shifted due to breakdown of the droplet surface and the lens effect of droplets.

Clinical course of patients with Fabry disease who were switched from agalsidase-ß to agalsidase-α.

BACKGROUND: Between 2009 and 2012, there was a worldwide shortage of agalsidase-ß for the treatment of Fabry disease. Therefore, alternative treatments were needed, including switching to a different enzyme-replacement therapy. PURPOSE: This is an ongoing observational study assessing the effects of switching from agalsidase-ß (1.0 mg/kg every other week) to agalsidase-α (0.2 mg/kg every other week) in 11 patients with Fabry disease. METHODS: Clinical data were collected for 5 years-2 years before switching and 3 years after switching. RESULTS: Measures of renal function such as estimated glomerular filtration rate remained stable during the 3 years after switching to agalsidase-α. Improvements in cardiac mass were recorded in both male and female patients 12 months after switching to agalsidase-α, and the benefit was maintained during 36 months of follow-up. There was no significant difference in the severity of pain experienced by patients before and after switching enzyme-replacement therapy, and no difference in quality-of-life parameters. Agalsidase-α was generally well tolerated, and no patients experienced allergy or developed antibodies to agalsidase-α. CONCLUSION: This observational study supports the safety of switching from agalsidase-ß to agalsidase-α at the approved doses, with no loss of efficacy. It also suggests that if an infusion-related allergic reaction occurs in a patient receiving agalsidase-ß, switching to agalsidase-α may be a viable option.

Clinical observation of patients with Fabry disease after switching from agalsidase beta (Fabrazyme) to agalsidase alfa (Replagal).

PURPOSE: Fabry disease is a rare, X-linked, inherited lysosomal storage disorder that can be treated with the enzymes agalsidasealfa (Replagal) and agalsidase beta (Fabrazyme). Currently, there is a global shortage of agalsidase beta, and this has increased global demand for agalsidase alfa. We assess the feasibility of switching patients on agalsidase beta treatment to agalsidase alfa instead. METHODS: This analysis is part of an ongoing observational study involving 11 patients with Fabry disease in whom the treatment was switched from agalsidase beta (1 mg/kg every other week) to agalsidase alfa (0.2 mg/kg every other week). Data were collected for a minimum of 36 months: 24 months before and 12 months after the switch. Serial data were evaluated with respect to renal function, cardiac mass, pain, quality of life, and tolerability/safety. RESULTS: Indexes of renal function (estimated glomerular filtration rate) and cardiac mass (left-ventricular mass index), pain (Brief Pain Inventory), and quality of life (EuroQoL-Dimensions) clearly showed that, in patients switched to agalsidase alfa, Fabry disease stabilized during the 12 months of follow-up. CONCLUSION: Despite the limitations of this preliminary observational study, it was found that all the patients maintained disease stability when treated with agalsidase alfa, as evidenced by estimated glomerular filtration rate, left-ventricular mass index,pain scores, and quality-of-life indexes, throughout 12 months of follow-up.

Descriptive epidemiology of Fabry disease among beneficiaries of the Specified Disease Treatment Research Program in Japan.

BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disorder and is included in the Specified Disease Treatment Research Program in Japan, which subsidizes medical care for beneficiaries with rare and other, designated diseases. However, no report on the epidemiologic features of Fabry disease has been published in Japan. METHODS: We used clinical research data reports submitted to the program between 2003 and 2008 to assess the epidemiologic features of 315 beneficiaries with FD. RESULTS: Of the 315 program beneficiaries, 198 were men (mean age, 37.4 years) and 117 were women (mean age, 51.2 years). The overall incidence in Japan was 0.25 cases per 100,000 individuals, and prevalence among men was 1.78 times that among women. More than 80% of beneficiaries were capable of working, going to school, or doing housework; however, 46 beneficiaries (14.6%) required home care, and 9 (2.9%) were living in hospitals or other medical facilities. As compared with the previous year, the clinical course of FD at beneficiary registration was unchanged for 178 of 290 beneficiaries (61.4%), worse for 81 (27.9%), and improved or cured for 31 (10.7%). The distribution of beneficiary-related characteristics was similar between men and women, and no significant difference was observed. CONCLUSIONS: The high percentage (>80%) of individuals with FD who were able to work, attend school, and perform tasks such as housework could reflect an improvement in the clinical course of FD after enzyme replacement therapy. We must continue data collection and conduct further studies to improve our understanding of the descriptive epidemiology of FD.

Clinical observation of patients with Fabry disease after switching from agalsidase beta (Fabrazyme) to agalsidase alfa (Replagal).

PURPOSE: Fabry disease is a rare, X-linked, inherited lysosomal storage disorder that can be treated with the enzymes agalsidase alfa (Replagal) and agalsidase beta (Fabrazyme). Currently, there is a global shortage of agalsidase beta, and this has increased global demand for agalsidase alfa. We assess the feasibility of switching patients on agalsidase beta treatment to agalsidase alfa instead. METHODS: This analysis is part of an ongoing observational study involving 11 patients with Fabry disease in whom the treatment was switched from agalsidase beta (1 mg/kg every other week) to agalsidase alfa (0.2 mg/kg every other week). Data were collected for a minimum of 36 months: 24 months before and 12 months after the switch. Serial data were evaluated with respect to renal function, cardiac mass, pain, quality of life, and tolerability/safety. RESULTS: Indexes of renal function (estimated glomerular filtration rate) and cardiac mass (left-ventricular mass index), pain (Brief Pain Inventory), and quality of life (EuroQoL-Dimensions) clearly showed that, in patients switched to agalsidase alfa, Fabry disease stabilized during the 12 months of follow-up. CONCLUSION: Despite the limitations of this preliminary observational study, it was found that all the patients maintained disease stability when treated with agalsidase alfa, as evidenced by estimated glomerular filtration rate, left-ventricular mass index, pain scores, and quality-of-life indexes, throughout 12 months of follow-up.

Cryptogenic organizing pneumonia after radiotherapy for breast cancer.

We report a case of lasting fever and cough with pulmonary infiltrates progressing 4 months after adjuvant radiotherapy following surgery for breast cancer. Chest radiography and computed tomography demonstrated alveolar opacities outside the irradiated pulmonary area. Laboratory data revealed neutrophilia and increased levels of C-reactive protein. Bronchoalveolar lavage fluid displayed increased lymphocyte counts, and transbronchial lung biopsy revealed histological patterns compatible with cryptogenic organizing pneumonia (COP). Corticosteroid therapy resulted in marked clinical improvement. From the histological and clinical findings, this case was judged to be a case of COP induced after radiotherapy for breast cancer, similar to those reported recently.

Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin.

One Japanese pedigree of familial essential thrombocythemia (FET) inherited in an autosomal-dominant manner is presented. A unique point mutation, serine 505 to asparagine 505 (Ser505Asn), was identified in the transmembrane domain of the c-MPL gene in all of the 8 members with thrombocythemia, but in none of the other 8 unaffected members in this FET family. The Ba/F3 cells expressing the mutant Asn505 acquired interleukin 3 (IL-3)-independent survival capacity, whereas those expressing wild-type Ser505 did not. The autonomous phosphorylation of Mek1/2 and Stat5b was observed in the mutant Ba/F3 cells in the absence of IL-3. The former was also found in platelets derived from the affected individual in the absence of thrombopoietin. These results show that the Asn505 is an activating mutation with respect to the intracellular signaling and survival of the cells. This is the first report of FET deriving from a dominant-positive activating mutation of the c-MPL gene.

T-cell acute lymphoblastic leukemia as a secondary leukemia after a 3-year remission of acute myelocytic leukemia.

Therapy-related myelodysplastic syndrome and therapy-related acute myelocytic leukemia (AML) are now recognized as hematologic malignancies that occur a few years after chemotherapy for primary malignancy with alkylating agents or topoisomerase II inhibitors. The secondary leukemia is usually AML and sometimes is preceded by a myelodysplastic syndrome. Acute lymphoblastic leukemia (ALL) as a secondary leukemia is quite rare, and secondary T-cell ALL after AML is even rarer. We report a case of a 56-year-old woman who developed T-cell ALL after a 3-year remission of AML (M2). We thought that this case would be extremely valuable for studying the etiology and biological characteristics of T-cell ALL as a secondary leukemia after AML.

Lymphoid blastic crisis of chronic myelogenous leukaemia with inv(16)(p13;q22).

We report a case of chronic myelogeneous leukaemia (CML) in B-lineage lymphoid blastic crisis (BC) having chromosome abnormality, inv(16)(p13;q22) in addition to Philadelphia chromosome, in 20/20 marrow metaphase. Inv(16)(p13;q22) was not observed in cells of chronic phase or accelerate phase. Abnormalities of chromosome 16, including inv(16)(p13;q22), del(16)(q22) and t(16;16)(p13;q22), have been reported mostly in acute myelomonocytic leukaemia (AML), (FAB M4-Eo), and some in CML-BC and myelodysplastic syndrome (MDS) cases. Most of the cases showed increase of myelomonocytic components and abnormal eosinophils with dysplastic granules in the bone marrow (BM). However, our case was diagnosed as lymphoid BC without increase of myelomonocytic components, although some abnormal eosinophilia was seen. To date, lymphoid BC of CML having inv(16)(p13;q22) abnormality has not been reported. The case presented here could be a clue to understand the pathophysiology of inv(16)(p13;q22) leukaemia.

Lineage conversion from acute lymphoblastic leukemia to acute myeloid leukemia on rearrangement of the IgH gene in a patient with Down syndrome.

A patient with Down syndrome (DS) at the time of diagnosis of acute lymphoblastic leukemia (ALL) had a relapse with acute myeloid leukemia (AML) after 4 years of complete remission. Although the diagnosis was AML, the leukemic blasts at relapse showed an immunoglobulin H rearrangement that turned out to be identical to that of the initial ALL blasts. It is thought that the leukemic precursor cells of this patient had the potential to differentiate into both lymphoid and myeloid lineages. This case is important for investigating target cells for leukemogenesis in DS.

MUM1/IRF4 expression is an unfavorable prognostic factor in B-cell chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

B-Cell chronic lymphocytic leukemia (B-CLL) / small lymphocytic lymphoma (SLL) consists of heterogeneous diseases that are distinguished by morphological, immunophenotypic and molecular features. MUM1 (multiple myeloma oncogene 1) is a protooncogene that is deregulated as a result of (6;14)(p25;q32) chromosomal translocation in multiple myeloma, and is also expressed in a variety of malignant lymphoma entities. We examined the expression of MUM1 in B-CLL / SLL, and found that 2 of 4 B-CLL-derived cell lines and 14 of 29 patients' specimens expressed MUM1 by immunohistochemical analysis. MUM1 expression was not associated with CD38 expression, somatic hypermutation of immunoglobulin heavy chain gene variable region (IgV(H)), or any other clinical characteristics of the patients. Interestingly, the patients who were positive for MUM1 showed shorter overall survival times than those who were negative for MUM1 (50% survival: 22 months vs. 82 months) (P = 0.0008, log-rank test). Multivariate analysis by Cox's proportional-hazards regression model showed that MUM1 expression and unmutated IgV(H) status were independent unfavorable prognostic factors in patients with B-CLL / SLL. These findings suggest that MUM1 expression is a useful prognostic factor in B-CLL / SLL. The biological role and mechanism of action of MUM1 in B-CLL / SLL need to be clarified for the development of therapies for patients with the poor prognostic subtype.

Successful treatment of nasal T-cell lymphoma with a combination of local irradiation and high-dose chemotherapy.

Nasal natural killer (NK)/T-cell lymphoma is characterized by an aggressive clinical course and poor prognosis. The term "NK/T-cell" lymphoma includes both the NK-cell type and the T-cell type, which are classified by immunophenotyping and according to T-cell receptor (TCR) rearrangement. In addition, CD56+ T-cell lymphoma is defined as NK-like T-cell lymphoma. This report concerns a 54-year-old woman with nasal T-cell lymphoma. Its phenotype showed pure T-cell type with CD3+, CD56-, and TCR+ accompanied by Epstein-Barr virus infection. Although the lesions were localized in the nasal mucosa and facial skin (stage IE), local irradiation could not achieve complete remission (CR). We then administered 5 courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) regimen followed by high-dose chemotherapy with an autologous peripheral blood stem cell transplantation. This therapy resulted in CR. Our results suggest that this lymphoma subtype may be cured by means of intensive treatment soon after diagnosis.