Klinisch-pathologische Studie zur Klassifikation und Prognose von 57 Thymustumoren

Summary The most important prognostic determinants of the thymomas are the gross findings at operation (= the presence or absence of gross invasion of adjacent tissue) and the presence or absence of the thymoma-associated systemic disease, particulary myasthenia gravis. The histologic type of thymoma had no proof value in predicting prognosis with the exception of the so-called atypical thymomas.Thirty-four of 57 patients with thymomas were females and 23 males. The tumors in 40 cases were non-invasive thymomas, and in 17 cases the tumour were invasive of adjacent tissue. 35.1 percent of patients were asymptomatic, the tumours being discovered on roentgenograms done on a routine basis or for an unrelated porpose. 40.3 percent of patients have had a thymomaassociated systemic disease. The most common presenting symptoms were related to myasthenia gravis (26.3%). The 5-year survival rate was 90 percent for non-invasive thymomas without myastenia gravis and 50 percent for invasive thymomas. The 5-year survival rate for patients with myasthenia gravis and encapsulated (non-invasive) thymomas was approximately 60 percent, whereas that for invasive thymomas with myasthenia gravis was 40 percent. The primary form of therapy for all thymomas is the surgical excision. In cases with invasive and/or metastasizing thymomas, postoperative radiation and adjuvanted chemotherapy is indicated, but in most series, the longterm results of this form of therapy are discouraging.

     

胸腺瘤伴重症肌无力患者瘤组织中Bcl-2和Fas的表达水平

目的 探讨凋亡相关基因bcl-2、Fas在胸腺瘤伴重症肌无力患者瘤组织中的表达状况及其临床意义。方法经手术治疗的25例胸腺瘤伴重症肌无力患者的肿瘤组织标本为病例组，25例先天性心脏病患者手术时切取的正常胸腺组织标本为对照组，通过免疫组化的方法检测两组标本中Bcl-2和Fas蛋白的表达水平。结果胸腺瘤中Bcl-2及Fas表达水平均显著高于对照组，经Ridit分析两者差异均有统计学意义（U值分别为2．645、3．200，P均〈0．05），但Bcl-2和Fas的表达水平与胸腺瘤患者的重症肌无力Ossermen分型、术前病程、年龄及性别等临床因素均无显著相关。结论 Bcl-2和Fas在胸腺瘤伴重症肌无力的发病中可能具有重要作用。     

A comparative clinical and pathological study on the classification and prognostic features of 57 thymomas. II. prognostic features (author's transl)]

The most important prognostic determinants of the thymomas are the gross findings at operation (equal to the presence or absence of gross invasion of adjacent tissue) and the presence or absence of the thymoma-associated systemic disease, particulary myasthenia gravis. The histologic type of thymoma had no proof value in predicting prognosis with the exception of the so-called atypical thymomas. Thirty-four of 57 patients with thymomas were females and 23 males. The tumors in 40 cases were non-invasive thymomas, and in 17 cases the tumour were invasive of adjacent tissue. 35.1 percent of patients were asymptomatic, the tumours being discovered on roentgenograms done on a routine basis or for an unrelated porpose. 40.3 percent of patients have had a thymoma-associated systemic disease. The most common presenting symptoms were related to myasthenia gravis (26.3%). The 5-year survival rate was 90 percent for non-invasive thymomas without myastenia gravis and 50 percent for invasive thymomas. The 5-year survival rate for patients with myasthenia gravis and encapsulated (non-invasive) thymomas was approximately 60 percent, whereas that for invasive thymomas with myasthenia gravis was 40 percent. The primary form of therapy for all thymomas is the surgical excision. In cases with invasive and/or metastasizing thymomas, postoperative radiation and adjuvanted chemotherapy is indicated, but in most series, the longterm results of this form of therapy are discouraging.     

A case of post-thymomectomy myasthenia gravis after extrapleural pneumonectomy for invasive thymoma which necessistated long-term mechanical ventilation]

The patient was a 58-year-old male with invasive thymoma which had disseminated in the left thorax and was histologically a polygonal cell type lesion. While the serum value of anti-acetylcholine receptor antibody was high before surgery, there were signs of myasthenia gravis. After preoperative chemotherapy, a thymectomy and left panpleuropneumonectomy were conducted. Forty days after surgery, the patients suffered post-thymomectomy myasthenia gravis, which necessitated mechanical ventilation for 6 months. Despite steroid therapy and 17 plasmapheresis procedures the tidal volume increased by little more than 200-250 ml during that time. The causes of ventilatory failure, therefore, were probably decreased pulmonary function due to extrapleural pneumonectomy and the myasthenia gravis. According to the literature, polygonal cell type thymomas with high serum levels of anti-acethycholine receptor antibody have higher incidences of post-thymomectomy myasthenia gragvis than other ones. Therefore, the risk of post-thymomectomy myasthenia gravis should be kept in mind when extrapleural pneumonectomy for invasive thymoma is being considered, especially in the cases of this type.     

Disorders of the thymus. A review

The thymus remains one of the least understood organs in the body. It has gone from the villain to the hero. For many years, it was blamed for what is now recognized as the sudden infant death syndrome; now, its role of immunosurveillance is being recognized. In spite of the fact that there are only two predominant cell types within the thymus, there are nearly 15 histologically different neoplasms of the thymus. These, in turn, are associated with more than 20 parathymic syndromes that affect approximately 40% of patients with thymoma. The three most common of these syndromes associated with thymic disorders are myasthenia gravis (MG), pure red cell aplasia (PRCA), and hypogammaglobulinemia. Thymomas are found in 15% of patients with MG, 50% of those with PRCA, and 10% of those with adult-onset hypogammaglobulinemia. Of all thymomas, 35% are malignant, that is, invasive or metastatic.     

Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease

Thymomas are the only tumors that are proven to generate mature T cells from immature precursors. It is unknown, however, whether intratumorous thymopoiesis has an impact on the peripheral T-cell pool and might thus be related to the high frequency of thymoma-associated myasthenia gravis. This study shows, using fluorescence-activated cell sorting-based analyses and T-cell proliferation assays, that thymopoiesis and T-cell function in thymomas correspond with immunologic alterations in the blood. Specifically, the proportion of circulating CD45RA(+)CD8(+) T cells is significantly increased in patients with thymoma compared with normal controls, in accordance with intratumorous T-cell development that is abnormally skewed toward the CD8(+) phenotype. Moreover, it is primarily the proportion of circulating CD45RA(+)CD8(+) T cells that decreases after thymectomy. The results also demonstrate that T cells reactive toward recombinant autoantigens are distributed equally between thymomas and blood, whereas T-cell responses to foreign antigen (ie, tetanus toxoid) are seen only among circulating T cells and not among thymoma-derived T cells. These functional studies support the hypothesis that thymopoiesis occurring within thymomas alters the peripheral T-cell repertoire. Because many thymomas are enriched with autoantigen-specific T cells, a disturbance of circulating T-cell subset composition by export of intratumorous T cells may contribute to paraneoplastic autoimmune disease arising in patients with thymoma. (Blood. 2000;96:3872-3879)     

THE THYMUS: EXPERIMENTAL PHYSIOLOGY,AND PATHOLOGY IN MAN

The thymus is an integral part of the immunological system. It is a site of intense lymphopoiesis, especially in early life. Neonatal thymectomy in mice causes runting and death due to gross immunological deficiencies. These deficiencies are determined by lymphopenia, and by lack of a lymphotrophic hormone secreted by the epithelial cells of the medulla; this hormone confers on lymphocytes the capacity to respond to antigenic stimulation. The thymus may be the main source of lymphoid cells carrying new or primary patterns of immune reactivity; it is thus “first-level” or “central” lymphoid tissue, which seeds cells to “second-level” or “peripheral” lymphoid tissues in the lymph nodes and spleen. Pathological lesions of the thymus in man include aplasia, hyperplasia, dysplasia and neoplasia. Gross aplasia characterizes the immunological deficiency diseases of infancy, including the lymphopenic type of congenital agammaglobulinæmia. Hyperplasia accompanies thyrotoxicosis. Dysplasia refers to the lymph follicle-germinal centre development in myasthenia gravis, probably an autoimmune disease, and to the proliferation in the medulla of spindle-epithelial cells in lupus erythematosus, an autoimmune disease. Neoplasia occurs as benign thymoma, which may be accompanied by extrathymic diseases which are possibly autoimmune in origin; these include myasthenia gravis, red cell aplasia, polymyositis, agammaglobulinæmia and lupus erythematosus. These diseases may in some way be caused by the thymoma; alternatively, the thymoma may represent the result of continuing hyperplasia of the thymus provoked by a primary autoimmune process. The place of thymectomy in the treatment of autoimmune disease is discussed. It is an established procedure in myasthenia gravis, and has been successful in two cases of autoimmune hæmolytic anæmia in infancy. We review our experience with thymectomy for three patients with systemic lupus erythematosus.     

Argyrophilic nucleolar organizer regions in cells of thymoma and thymic carcinoma: correlation with DNA ploidy and clinicopathologic characteristics

STUDY OBJECTIVES: To evaluate the usefulness of argyrophilic nucleolar organizer region (AgNOR) counting and flow cytometric DNA analysis in the differential diagnosis of thymoma and thymic carcinoma, as well as in the differences among various stages and histologic subtypes of these tumors. DESIGN AND INTERVENTIONS: Paraffin-embedded blocks of 64 thymic epithelial tumors (20 noninvasive thymomas, 34 invasive thymomas, and 10 thymic carcinomas) were studied by AgNOR counting and flow cytometric DNA analysis. The thymomas were histologically classified as medullary, cortical, or mixed subtype. MEASUREMENTS AND RESULTS: Invasive thymomas had more AgNORs (-/+ SD) than noninvasive thymomas (7.93+/-2.90 vs 5.97+/-1.77; p < 0.01). The number of AgNORs of thymoma increased progressively with advances in stage (p < 0.01). Cortical thymomas had the highest number of AgNORs among the three subtypes (p < 0.05). Patients with thymoma who presented with myasthenia gravis also had a higher number of AgNORs (8.30+/-3.12 vs 6.50+/-2.03; p < 0.01). The AgNOR number did not correlate with the DNA ploidy of all specimens. CONCLUSIONS: AgNOR counting is useful in differentiating between invasive and noninvasive thymomas, and in predicting the stage of thymomas. A greater number of AgNORs was observed in patients with cortical thymoma and in those who presented with myasthenia gravis.     

Thymomes et maladies auto-immunes

The association between thymoma and autoimmunity is well known. Besides myasthenia gravis, which is found in 15 to 20% of patients with thymoma, other autoimmune diseases have been reported: erythroblastopenia, systemic lupus erythematosus, inflammatory myopathies, thyroid disorders, Isaac's syndrome or Good's syndrome. More anecdotally, Morvan's syndrome, limbic encephalitis, other autoimmune cytopenias, autoimmune hepatitis, and bullous skin diseases (pemphigus, lichen) have been reported. Autoimmune diseases occur most often before thymectomy, but they can be discovered at the time of surgery or later. Two situations require the systematic investigation of a thymoma: the occurrence of myasthenia gravis or autoimmune erythroblastopenia. Nevertheless, the late onset of systemic lupus erythematosus or the association of several autoimmune manifestations should lead to look for a thymoma. Neither the characteristics of the patients nor the pathological data can predict the occurrence of an autoimmune disease after thymectomy. Thus, thymectomy usefulness in the course of the autoimmune disease, except myasthenia gravis, has not been demonstrated. This seems to indicate the preponderant role of self-reactive T lymphocytes distributed in the peripheral immune system prior to surgery. Given the high infectious morbidity in patients with thymoma, immunoglobulin replacement therapy should be considered in patients with hypogammaglobulinemia who receive immunosuppressive therapy, even in the absence of prior infection.     

Malignant thymoma associated with myasthenia gravis, Graves' disease, and SIADH

Patients with thymoma are likely to present with associated autoimmunologic disorders. The occurrence of syndrome of inappropriate antidiuretic hormone (SIADH) attributable to thymoma is extremely rare. We herein present an extremely rare case of a 59-year-old man patient who was discovered to have malignant thymoma associated with myasthenia gravis, Graves' disease, and SIADH. He was admitted for evaluation and treatment of hyponatremia (Na 125 mEq/l). SIADH was diagnosed, and thymoma was identified as its cause. The patient was also found to have both Graves' disease and myasthenia gravis. The hyponatremia was normalized with water restriction and 3% saline therapy before thymectomy. The thymic tumor was a Masaoka stage III thymoma that resulted in direct invasion to the wall of the innominate vein, but there was no finding of invasion to other mediastinal organs. Complete thymectomy with innominate vein graft was performed. Microscopic histopathology findings corresponded to those of a mixed-type thymoma and type B2. However, immunohistochemical stain for antidiuretic hormone was negative in the tumor cells. Adjuvant radiation therapy was employed postoperatively, and the patient's postoperative recovery was uneventful. He subsequently reached a euthyroid state. And the reversal to normal sodium and osmolality levels was continued after the tumor removal without any further management for hyponatremia. The observation of this interesting case and a literature review provided us with the opportunity to explore the pathogenesis and clinical aspects of thymoma-related autoimmune and/or endocrine disorders which must be suspected in patients with thymoma.     

T cell lymphocytosis associated with polymyositis, myasthenia gravis and thymoma

Peripheral T cell lymphocytosis is a rare finding in association with malignant thymomas. In the majority of previous cases, the tumours have behaved aggressively with symptoms arising from local invasion. We describe a patient with ocular myasthenia gravis who presented with a rapidly progressive polymyositis and neuropathy and who was subsequently found to have a thymic mass and a mild T cell lymphocytosis. The thymoma did not give rise to local symptoms and showed no evidence of progression over a 14-month period of follow-up. The possibility of an underlying thymic tumour should be considered in any patient with chronic T cell lymphocytosis if the circulating cells show mature morphology and there is no molecular evidence of monoclonality.     

Myasthenia gravis with thymoma is more common in the Maori and Pacific Island populations in New Zealand

Background: The association of myasthenia gravis (MG) with thymoma is well recognized. Our clinical impression has been that MG associated with thymoma may be more common in patients of Polynesian descent than in other races. Aim: To determine the influence of ethnicity on the association of MG with thymoma in our population. Method: Review of all cases of thymectomy performed at Greenlane Hospital in Auckland for the 20‐year period from June 1978 to June 1998. Results: There were 103 thymectomies performed in the study period. Fifty‐five thymomas were identified, 15 in subjects of Maori or Pacific Island ethnicity and 40 in subjects of other races, predominantly Caucasian. Ten of 15 Maori or Pacific Island subjects with thymoma had MG (67%), compared with 15 of 40 subjects of other races (37.5%, P = 0.05). The mean age of Maori or Pacific Island subjects with thymoma and MG was 42.5 years, compared with 56.3 years in subjects from other races (P = 0.06). All five Maori and Pacific Island subjects with invasive thymoma had MG, whereas only four of 15 subjects (27%) from other races with invasive tumours had MG (P < 0.01). The overall incidence of thymoma and the proportion of thymomas that were invasive did not differ between the ethnic groups. Conclusions: Myasthenia gravis with thymoma occurs more frequently among Maori or Pacific Island people than in other racial groups in our population. This is due to an increase in the proportion of cases with thymoma who have MG in this group, while the overall frequency of cases of thymoma is similar between groups. MG with thymoma in the Maori or Pacific Island populations also presents at a younger age and is more often associated with tumour invasion. (Intern Med J 2001; 31: 206–210)     

Paraneoplastic myasthenia gravis correlates with generation of mature naive CD4(+) T cells in thymomas

Myasthenia gravis (MG) is the leading paraneoplastic manifestation of thymomas and is probably related to the capacity of thymomas to mature and export potentially autoreactive T cells. Why some thymomas are MG associated (MG+) and others are not (MG-) has been unclear. We addressed this question by comparing the percentages of intratumorous naive mature CD45RA+ thymocytes in 9 MG(+) and in 13 MG(-) thymomas by fluorescence-activated cell sorting analysis. Our results show that intratumorous naive CD4 T cells were present in all MG(+) thymomas and in one MG(-) thymoma with the development of MG only 2 months after surgery. By contrast, the percentage of naive CD4(+) T cells was significantly reduced in all 13 MG(-) thymomas (P <.0001). Alterations in intratumorous thymopoiesis were reflected by corresponding alterations of naive T-cell subset composition in the blood, in that only MG(-) patients had significantly decreased levels (P =.02) of naive CD4(+) T cells compared with age- and sex-matched control persons. We conclude that paraneoplastic MG is highly associated with the efficiency of thymomas to produce and export naive CD4(+) T cells. The acquisition of the CD45RA(+) phenotype on CD4(+) T cells during terminal intratumorous thymopoiesis is associated with the presence of MG in most thymoma patients.     

Giant cell myositis and myocarditis revisited

Giant cell myositis (GCMm) and giant cell myocarditis (GCMc) are two rare autoimmune conditions. Among these, GCMc is a life-threatening disease with a 1-year mortality rate of 70%. Lethal ventricular arrhythmias, rapid evolution to heart failure and sudden death risk makes GCMc an emergency condition. It is thought to be mediated by T-cells and characterized by the presence of myofiber necrosis and giant cells in biopsies. Most commonly co-manifesting conditions with GCMm and/or GCMc are thymoma, myasthenia gravis and orbital myositis, all of which are treatable. As suspicion is the key approach in diagnosis, the physician following patients with thymoma with or without myasthenia gravis and with orbital myositis should always be alert. The fatal nature of GCMc associated with these relatively benign diseases deserves a special emergency attention with prompt institution of combined immunosuppressive treatment and very early inclusion of heart failure teams.Key words: giant cell myositis, giant cell myocarditis, thymoma/myasthenia gravis, orbital myositis     

MYASTHENIA GRAVIS : CLINICAL,SEROLOGICAL AND HISTOLOGICAL STUDIES IN RELATION TO THYMECTOMY

In 10 cases of myasthenia gravis correlative studies were made by means of autoimmune serological tests, electromyography, thymic X-ray examination (pneumomediastinography) and assessment of thymic morphology in relation to the effects of thymectomy (nine cases) and thymic irradiation (one case). The 10 patients were placed in three groups, namely (a) three young females with a non-involuted thymus showing “thymitis” and negative results to serological tests who derived benefit from thymectomy, (b) four older females with thymic atrophy and positive results to serological tests who for the most part gained no benefit from thymectomy, and (c) three males with thymomas and positive results to serological tests who obtained benefit from thymectomy in two instances. The presence of the characteristic autoantibody—the myoid antibody which reacted with thymic myoid cells and skeletal muscle—was helpful in diagnosis but did not appear to be related to neuromuscular block, neither was it of value in predicting the response to thymectomy. Electromyography with the decamethonium test showed, with one exception, the characteristic myasthenic responses irrespective of the patient's age, the presence or absence of myoid antibody, or the nature of the microscopic lesion in the thymus. The radiographic outline of the thymus as determined by pneumomediastinography correlated well with the size and shape of the resected thymus. The typical histological appearance in the thymus of abundant cortex and prominent medullary germinal centres and lymphocytosis was termed “thymitis” ; it was characteristic of the thymus of patients in group (a) and the residual thymus of patients with thymoma in group (c). Our clinical observations could be correlated with experimental studies, indicating that myasthenia gravis is associated with a destructive “autoimmune thymitis”. It is suggested that “thymitis” is associated with the release from the medulla of an uncharacterized humoral agent which causes neuro-muscular block.     

Microscopic-sized "microthymoma" in patients with myasthenia gravis

BACKGROUND: In 2005, Cheuk et al reported two patients with microscopic-sized thymomas and proposed the term microthymoma to distinguish it from the nodular hyperplasia of thymic epithelium, so-called microscopic thymoma. Here, we present microthymomas that were found in 196 patients with myasthenia gravis (MG) who had undergone thymectomy. MATERIALS AND METHODS: Thymic tissues in 196 patients with MG who underwent thymectomy or thymothymomectomy were examined. Of these patients, 73 patients had thymoma indicated by CT before surgery, and the other 123 patients had no mediastinal tumors. From the resected thymic tissues, an average of 14 hematoxylin-eosin-stained sections (range, 4 to 55 sections) were prepared for microscopic examination. The histologic type of the thymoma was classified according to the World Health Organization (WHO) classification. RESULTS: From the 196 patients, we found three microthymomas in 3 patients (1.5%). While these three tumors could not be seen grossly in pathology section, they were found microscopically (range, 2 to 4 mm). The histologic subtype according to the WHO classification system was B1 in one patient and B2 in two patients. CONCLUSION: Microthymoma was found in 3 of 196 patients (1.5%) with MG. Microthymoma might exist in thymus of patients with MG, even in patients who have no thymoma indicated by CT.     

Aplastic anemia as a late complication of thymoma in remission

Thymoma has many auto-immune associations, including aplastic anemia and myasthenia gravis. The pathophysiologic relationship between thymoma and its auto-immune sequelae are yet to be fully elucidated, but are thought to be as a result of the production of auto-reactive T cell clones by the thymic epithelium. We report a case in which aplastic anemia did not develop until sometime after remission from thymoma had been induced. This observation suggests that auto-reactive T cells may be produced by the thymoma but not induce clinical auto-immune disease until a later time, even after eradication of thymoma has been achieved.     

The heart in myasthenia gravis

The cardiac changes associated with myasthenia gravis have been reviewed and specific areas explored. There is no doubt concerning the involvement of the myocardium in this disease as indicated by clinical, ECG, vectorcardiographic, and autopsy data. The doubt lies in the precipitating factor for the pathology found. On the one hand the whole picture could be a direct result of the pathologic process of myasthenia gravis. On the other hand the patient with myasthenia gravis, during the natural history of the disease, encounters many iatrogenic and coincidental variables which could influence the nature of the clinical findings and autopsy data. One fact seems reasonably clear: The association of myocardial pathology with thymoma, especially malignant thymoma, is well established for the more severe form of the myocardial disease. Furthermore, the hypothesis that cardiac muscle antibodies give rise to such reactions is attractive, although not fully resolved.If such cases are excluded then there remain others where cardiac pathology could be due to other disease, primarily coronary heart disease, in the older age group. In addition, the mode of death of some patients indicates that intercurrent respiratory problems could play a part. Most patients in this group do not seem to have cardiac abnormalities due to the pathologic process of myasthenia. There is in addition a small group where very striking cardiovascular findings suggestive of myocarditis are found. There is not necessarily a thymoma and no other specific etiologic factors can be found. These are rare cases and might still be related to disorders of immune mechanisms.In conclusion it can be stated that, although there is now a considerable body of evidence concerning the heart in myasthenia gravis, the implication of specific pathology for this neuromuscular disorder affecting the heart must be considered, in the traditional Scottish legal sense, as “not proven.”     

Increased frequency of thymic T follicular helper cells in myasthenia gravis patients with thymoma

Background

To investigate the presence of T follicular helper (TFH) cells and their associated molecules in myasthenia gravis (MG) patients with thymoma.

Methods

TFH cells are detected in thymus around the thymoma region of 50 patients and atrophic thymus in 10 patients as control. The percentage of TFH cells among CD4⁺ T cells and the expression level of surface markers CXC chemokine receptor 5 (CXCR5), inducible co-stimulator (ICOS), programmed cell death 1 and the cytoplasmic marker B cell lymphoma 6 (Bcl-6) were analyzed by immunohistochemistry (IHC) staining, immunofluorescence (IF) and western blotting (WB).

Results

Higher percentage of thymic TFH cells was found in MG patients with thymoma compared with both thymoma patients without MG and control group. The expression levels of the four markers in thymoma of MG patients were significantly higher than thymoma patients without MG and control group. No significant difference was found in the levels of programmed cell death 1 (PD-1) and Bcl-6 between thymoma patients without MG and the control, while the levels of CXCR5 and ICOS in thymoma patients without MG were higher than control group.

Conclusions

These results suggested thymic TFH cells might involve in the pathogenesis of MG with thymoma. However, it needs further study to test if the inhibition of the function of TFH cells could effectively alleviate the severity of MG.     

Pleural dissemination of thymoma showing tumor regression after combined corticosteroid and tacrolimus therapy

We present the case of an elderly woman with myasthenia gravis who had pleural dissemination of thymoma reduced by treatments with a moderate dose of corticosteroids and a conventional dose of tacrolimus. A maintenance dose of prednisolone for myasthenia gravis could not shrink the size of the disseminated thymoma, but prednisolone (>30 mg daily) succeeded in reducing the size of the tumor. Moreover, a combination with tacrolimus enabled the daily dose of prednisolone to be tapered off without recurrence of myasthenia gravis, and the disseminated thymoma almost disappeared. A moderate or higher dosage of corticosteroids with tacrolimus may, in some cases, be an effective procedure for pleural dissemination of thymoma. Treatment should be undertaken on a trial basis for patients not indicated for surgery, radiotherapy, or chemotherapy.