Mediastinal Mass Research Articles

Unusually severe neonatal presentation of mediastinal bronchogenic cyst.

Bronchogenic cysts are rare congenital malformations that occur in adults and children, with differences in distribution and presentation. We present the case of a newborn who initiated respiratory distress from the first minutes of life, presenting with hypoventilation and rightward displacement of the cardiac impulse, requiring oxygen therapy and intubation. The first radiograph shows a left pulmonary emphysema. The computerized axial tomography revealed a large mediastinal mass causing an obstructive syndrome of the left bronchus. The mass was successfully excised, resulting in a favorable clinical evolution. Although the presentation of our case is exceptional, it is worth noting that while most bronchogenic cysts are asymptomatic, they can occur in childhood, even from birth, as in our case.

A rare clinical case of malignant ectopic retrosternal goiter of a large size in a patient with aberrant right subclavian artery

Background. Ectopic goiter accounts for only 0.2 % to 1 % of all mediastinal goiters. The aberrant right subclavian artery (arteria lusoria) is an extremely rare anomaly of the major vessel, with a prevalence not exceeding 0.3 % in the general population. This paper presents the first case of malignant ectopic retrosternal goiter of a large size in combination with the aberrant right subclavian artery. Clinical case description. A 61-year-old male presented to the thoracic surgery department of P. Herzen Moscow oncology Research institute with a large posterior mediastinal mass measuring 108×106×79 mm and adjacent to the right lobe of the thyroid gland. The tumor displaced the trachea and esophagus. Open biopsy through a thoracotomy incision revealed thyroid gland cells without signs of atypia. A detailed examination revealed mediastinal vascular anomaly – retrotracheal position of the right subclavian artery. a complete longitudinal sternotomy, complemented by a right-sided thoracotomy at the 3rd intercostal space, served as the surgical approach. The operation lasted 320 minutes, with a blood loss of 3500 ml. The postoperative period was uneventful. The morphological examination of the surgical specimen revealed nodular hyperplasia of the ectopic thyroid tissue with the growth of well-differentiated follicular carcinoma without metastatic involvement of removed lymph nodes. Considering the identified follicular carcinoma, total thyroidectomy was performed. Conclusion. In surgical planning, it is crucial to assess the location of major mediastinal vessels and their relationship with the goiter. Therefore, all patients with mediastinal lesions should undergo preoperative contrast-enhanced ct. Retrosternal goiter predisposes to a higher rate of malignancy compared to cervical goiter. If the lower edge of the goiter is at the level of or below the aortic arch, cervical access should be supplemented with sternotomy. In cases of a massive thoracic component, additional thoracotomy is justified.

Clinical usability of 3D gradient-echo-based ultrashort echo time imaging: Is it enough to facilitate diagnostic decision in real-world practice?

Background With recent advances in magnetic resonance imaging (MRI) technology, the practical role of lung MRI is expanding despite the inherent challenges of the thorax. The purpose of our study was to evaluate the current status of the concurrent dephasing and excitation (CODE) ultrashort echo-time sequence and the T1-weighted volumetric interpolated breath-hold examination (VIBE) sequence in the evaluation of thoracic disease by comparing it with the gold standard computed tomography (CT). Methods Twenty-four patients with lung cancer and mediastinal masses underwent both CT and MRI including T1-weighted VIBE and CODE. For CODE images, data were acquired in free breathing and end-expiratory images were reconstructed using retrospective respiratory gating. All images were evaluated through qualitative and quantitative approaches regarding various anatomical structures and lesions (nodule, mediastinal mass, emphysema, reticulation, honeycombing, bronchiectasis, pleural plaque and lymphadenopathy) inside the thorax in terms of diagnostic performance in making specific decisions. Results Depiction of the lung parenchyma, mediastinal and pleural lesion was not significant different among the three modalities (p > 0.05). Intra-tumoral and peritumoral features of lung nodules were not significant different in the CT, VIBE or CODE images (p > 0.05). However, VIBE and CODE had significantly lower image quality and poorer depiction of airway, great vessels, and emphysema compared to CT (p < 0.05). Image quality of central airways and depiction of bronchi were significantly better in CODE than in VIBE (p < 0.001 and p = 0.005). In contrast, the depiction of the vasculature was better for VIBE than CODE images (p = 0.003). The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were significant greater in VIBE than CODE except for SNRlung and SNRnodule (p < 0.05). Conclusions Our study showed the potential of CODE and VIBE sequences in the evaluation of localized thoracic abnormalities including solid pulmonary nodules.

Single-Port Robotic Trans-Subxiphoid Surgery for Anterior Mediastinal Disease: A Pilot Trial.

In recent years, there has been an increasing focus on minimally invasive mediastinal surgery using a trans-subxiphoid single-port thoracoscopic approach. Despite its potential advantages, the widespread adoption of this method has been hindered by the intricate surgical maneuvers required within the confined retrosternal space. Robotic surgery offers the potential to overcome the limitations inherent in the thoracoscopic technique. This was a clinical trial (NCT05455840) to evaluate the feasibility and safety of utilizing the da Vinci® SP system (Intuitive Surgical, Sunnyvale, CA, USA) for trans-subxiphoid single-port surgery in patients with anterior mediastinal disease. The primary endpoints encompassed conversion rates and the secondary endpoints included the occurrence of perioperative complications. Between August 2022 and April 2023, a total of 15 patients (7 men and 8 women; median age = 56 years, interquartile range [IQR]: 49 to 65 years) underwent trans-subxiphoid robotic surgery using da Vinci SP platform for maximal thymectomy (n = 2) or removal of anterior mediastinal masses (n = 13). All surgical procedures were carried out with success, with no need for conversion to open surgery or the creation of additional ports. The median docking time was 2 min (IQR: 1 to 4 min), while the console time had a median of 152 min (IQR: 95 to 191 min). There were no postoperative complications and patients experienced a median postoperative hospital stay of 2 days with no unplanned 30-day readmission. This study shows that trans-subxiphoid single-port robotic surgery employing the da Vinci SP system in patients with anterior mediastinal disease is clinically viable with acceptable safety and short-term outcomes.

Thymic carcinoid with multiple bone metastases: A case report

BACKGROUND Thymic carcinoid (TC) is a rare entity among anterior mediastinal malignancies. TCs are neuroendocrine carcinomas that constitute approximately 2%–5% of all thymic epithelial tumors. CASE SUMMARY The study reported a rare TC with multiple bone metastases. A 77-year-old man presented with a 2-month history of lower back pain and weight loss of 5 kg. Magnetic resonance imaging scans revealed damage to the lumbar spine, sacrocaudal vertebrae and iliac crest, suggesting bone metastasis; computed tomography (CT) scan of the thorax showed a calcified anterior mediastinal mass; positron emission tomography-CT demonstrated multiple abnormal bone signals; and laboratory work-up showed no endocrine abnormalities. Fine-needle aspiration biopsy revealed predominantly single small, round to oval cells with scant cytoplasm and some loose clusters, suggesting endocrine manifestations. The pathological diagnosis was atypical carcinoid, which tend to originate from the thymus and was classified as intermediate-highly invasive. The patient underwent anlotinib-targeted therapy. Anlotinib (12 mg) was administered daily for 2 wk, after which the patient was allowed to rest for 21 d. Follow-up CT after one year demonstrated that the tumor had shrunk by approximately 29% after therapy. Treatment has a long stable disease benefit of more than 2.5 years. CONCLUSION These findings demonstrated that anlotinib is a promising treatment regimen for patients with TC and multiple bone metastases.

Computed tomographic findings in canine and feline heart base tumors (25 cases).

Tumors located at the heart base are rare in dogs and cats and aortic body tumors (chemodectoma/paraganglioma), hemangiosarcoma, ectopic thyroid carcinoma, lymphoma, and other uncommon neoplasia can be found at that location. The objective of this retrospective case series was to describe the CT characteristics of canine and feline heart base tumors. CT studies of 21 dogs and four cats with histologically or cytologically confirmed heart base tumors were reviewed for size, location, shape, margination, contrast enhancement, adjacent neovascularization, invasion, mass effect, cavitary effusions, and metastasis. Neuroendocrine tumors (15 aortic body tumors, three ectopic thyroid carcinoma, and three nonspecific neuroendocrine) were more commonly observed than hemangiosarcoma (4) and were frequently located between the cranial vena cava and aortic arch (12/21; 57%) and or dorsal to the pulmonary trunk bifurcation/pulmonary arteries (10/21; 48%). Hemangiosarcoma was more commonly found cranioventral to the aortic arch and cranial to the right auricular appendage (3/4; 75%). Mediastinal and peritumoral neovascularization was associated with 16/21 (76%) neuroendocrine tumors but none of the hemangiosarcoma. Median postcontrast attenuation in Hounsfield units (HU) was higher in neuroendocrine (110 HU) than in hemangiosarcoma (51 HU). Pericardial effusion was frequently observed with hemangiosarcoma (3/4; 75%) and infrequently in neuroendocrine (3/21; 14%). In four cases (all neuroendocrine), concurrent cranial mediastinal masses were present. CT provides useful information regarding the characteristics of heart base tumors, indicating differences between the appearance of neuroendocrine tumors and hemangiosarcoma. However, no differences were found between aortic body tumors and ectopic thyroid carcinoma.

Insights into Uncommon Presentation—Acute T-cell Lymphoma with Mediastinal Mass and Pericardial Effusion: Exploring the Rare Phenomenon of Spontaneous Tumor Lysis

Insights into Uncommon Presentation—Acute T-cell Lymphoma with Mediastinal Mass and Pericardial Effusion: Exploring the Rare Phenomenon of Spontaneous Tumor Lysis

Advantages of robot-assisted resection of large mediastinal tumors: a single-center preliminary study.

Current study aims to assess the safety and efficacy of robot-assisted thoracoscopic surgery (RATS) for sizable mediastinal masses with a minimum diameter ≥6cm, compared with video-assisted thoracoscopic surgery (VATS) and open surgery. This study enrolled 130 patients with mediastinal tumors with no less than 6 cm diameter in Zhongnan Hospital, Wuhan University, including 33 patients who underwent RATS, 52 patients who underwent VATS and 45 patients who underwent open surgery. After classifying based on mass size and whether it has invaded or not, we compared their clinical characteristics and perioperative outcomes. There was no significant difference in age, gender, mass size, myasthenia gravis, mass location, pathological types (p>0.05) in three groups. Patients undergoing open surgery typically presenting at a more advanced stage (p<0.05). No obvious difference was discovered in the average postoperative length of stay, operation duration, chest tube duration and average postoperative day 1 drainage output between RATS group and VATS group (p>0.05), while intraoperative blood loss in RATS group was significantly lower than VATS group (p=0.046). Moreover, the postoperative length of stay, operation duration, chest tube duration and intraoperative blood loss in RATS group were significantly lower than open surgery group (p<0.001). RATS is a secure and efficient approach for removing large mediastinal masses at early postoperative period. In comparison with VATS, RATS is associated with lower intraoperative blood loss. Compared with open surgery, RATS is also associated with shorter postoperative length of stay, operation duration, chest tube duration and intraoperative blood loss.

Safety and Efficacy of Transsternal Core Biopsy of Anterior Mediastinal Masses

Safety and Efficacy of Transsternal Core Biopsy of Anterior Mediastinal Masses

Pulmonary Infundibular Stenosis Secondary to a Mediastinal Hodgkin Lymphoma Tumor Invasion in a Young Adult Male: What a Rare Occurrence!

Introduction: Cardiac involvement is a rare unusual localization of Hodgkin lymphoma, as it’s known that primary lymphomas of the heart are rare. They develop primarily in the right atrium, and extend to the pericardium in about one third of the cases. Pulmonary infundibular stenosis secondary to mediastinal mass Hodgkin lymphoma invasion is rare but not impossible especially in relapse cases. Case Report: A rare case of a young adult patient diagnosed with Hodgkin Lymphoma under chemotherapy presents a relapse of his pathology associated with heart failure; predominantly, right heart failure due to extension of the mediastinal mass tumor to the right cavities of the heart causing pulmonary infundibular stenosis which is a rare occurrence. He was put under an intense chemotherapy and symptomatic heart failure treatment with close follow-up after multi-disciplinary discussions including cardiologist, onco-hematologists and cardiothoracic surgeons. Three months later, a significant reduction of the mass was observered. Conclusion : Pulmonary infundibular stenosis secondary to mediastinal Hodgkin lymphoma invasion is a rare entity of secondary tumors of the heart. Multimodal imagery is the key tool for diagnosis. There prognosis depend on multiple factors but generally good in younger adult patients compared to aged individuals.

Sternotomic resection of an anterior mediastinal cystic teratoma with pericardial fistula

Background: Mediastinal teratomas are rare tumors and the majority of them are mature teratomas, benign lesions characterized by slow growth and low malignant potential. Signs and symptoms are infrequent; hence the diagnosis is often incidental. Complicated cases are rare and are traditionally treated with elective surgery. Our case report presents a patient with a teratoma complicated by pericardial fistulization requiring emergency surgery: the only case described in the literature. Case presentation: A 36-year-old male with no relevant medical history reported acute thoracic pain. Chest CT scan shows a mediastinal mass (compatible with cystic teratoma) compressing the superior vena cava, the heart, and pericardial involvement. The patient was first subjected to pericardiocentesis and then an en-bloc resection of the mediastinal lesion was performed via sternotomy. Discussion and conclusion: Mediastinal lesions require an accurate differential diagnosis, despite the diagnosis often being incidental in the absence of clinical symptoms. Conversely, if symptomatic, complicated cases can lead to life-threatening situations, where the exeresis of such lesions might require urgent, complex, and multidisciplinary surgical intervention.

Extracorporeal membrane oxygenation (ECMO) assisted huge mediastinal tumor resection combined with superior vena cava replacement: A case report and literature review.

As to huge solid mediastinal tumor which direct compression or invasion of the superior/inferior vena cava (SVC/IVC), surgical resection remains the main lifesaving treatment. However, it would present formidable anesthetic challenges due to the extremely high risks of cardiorespiratory compromise, drastic hemodynamic fluctuations and death at all perioperative stages. Here, we report a case of huge anterior mediastinal tumor resection combined with SVC replacement under the assistance of venoarterial extracorporeal membrane oxygenation (VA ECMO), and stable hemodynamics were maintained as well as high internal jugular vein pressure being avoided during the operation procedure. He was weaned off ECMO successfully just after surgery and eventually discharged. No signs of postoperatively neurological complications occurred. Therefore, the use of ECMO assistance in huge mediastinal tumor resection combined with SVC replacement is feasible and safe, which may provide the possibility of surgical treatment for such patients and improve outcomes.

Patient with mediastinal carcinoma of unknown primary with RET fusion achieves durable response with RET inhibition.

Selective RET inhibitors have shown promise in thyroid cancer (TC) and nonsmall cell lung cancer (NSCLC) harboring RET fusions on next-generation sequencing (NGS), although rarity of the rearrangement has led to limited data for certain tumor types, such as carcinoma of unknown primary. We present a 65-year-old female with no history of malignancy, smoking or radiation exposure, who was found to have an anterior mediastinum malignancy of unknown primary, with metastases to supraclavicular lymph nodes. Core biopsy of the mediastinum revealed poorly differentiated carcinoma, while a biopsy of the thyroid revealed atypia of indeterminate significance (Bethesda III). PD-L1 immunohistochemistry was positive (90%), and liquid NGS revealed mutations in TP53 and the TERT promoter (c.-124C>T), as well as a CCDC6-RET fusion. This genetic profile resembled an anaplastic TC vs. NSCLC primary, although thymic primary and poorly differentiated TC remained on the differential. The patient was initiated on selpercatinib, which was held after 3 weeks due to thrombocytopenia and hypertension. At a reduced dosage, patient developed transaminitis, and selpercatinib was switched to pralsetinib. Brain MRI showed a nonenhancing temporal lobe signal abnormality, which on biopsy proved to be glioblastoma (GBM) with TERT promoter c.-124C>T mutation and FGFR3-TACC3 fusion by NGS. Pralsetinib was held during adjuvant chemoradiation for the GBM, and again for 4 weeks due to pneumonitis that resolved with steroids, and pralsetinib was restarted at a reduced dose. The patient has since demonstrated a stable reduction of the mediastinal mass for >15 months with RET inhibition therapy, despite several treatment interruptions.

Asymptomatic mature intrapericardial teratoma in an adult: a case report of a rare condition

BackgroundBenign mature teratomas are the most common type of anterior mediastinal germ cell tumor. Mature intrapericardial teratomas are generally diagnosed during infancy because of symptoms of cardiac compression. In contrast, mature adult intrapericardial teratomas are extremely rare, accounting for less than 1% of mature intrapericardial teratomas. We describe herein a case of a mature intrapericardial teratoma in an asymptomatic adult.Case presentationA 52-year-old woman was found by computed tomography during a health checkup to have an anterior mediastinal mass. She was asymptomatic and hemodynamically stable with no evidence of heart failure. The preoperative provisional radiological diagnosis was a mature intrapericardial teratoma. A median sternotomy revealed an approximately 5-cm diameter protruding intrapericardial mass with a smooth surface. The mass was completely resected. Histopathological examination resulted in a diagnosis of a mature intrapericardial teratoma. The patient did well and has no evidence of recurrence 5 years after surgery.ConclusionsMature intrapericardial teratomas in adults are extremely rare. Given the risks of malignant transformation, rupture, compression of the heart, and infection, excision is indicated to prevent development of serious manifestations.

Video assisted thoracoscopy surgery a viable alternative for duplication cyst excision: a case report on foregut duplication cyst

Alimentary tract duplication is a relatively uncommon congenital abnormality. It can be found anywhere from the mouth to the anus and can be symptomatic or undetectable. Although congenital duplication can happen anywhere in the gastrointestinal tract, the ileum, oesophagus, and colon are the most common locations. The foregut, which includes the stomach, and first and second segments of the duodenum, is the source of one-third of all duplications. When foregut duplication involves the bronchial tree, respiratory symptoms are often present. Furthermore, excision through surgery is required for pathological examination of the resected specimen for definitive diagnosis. The most promising surgical approach for cyst excision has been thought to be open surgical resection through a posterolateral thoracotomy incision. However, video assisted thoracoscopy surgery has recently emerged as a viable surgical option for duplication cyst removal In paediatric surgery, video assisted thoracoscopy surgery has been established to facilitate the removal of mediastinal masses. However there is a limitation of research in the literature regarding the best surgical technique for oesophageal duplication cyst excision. In girls, foregut duplication is more common, especially in cases when bronchopulmonary involvement is present. While many duplications result in issues in early development, some are discovered by accident. When foregut duplication involves the bronchial tree, respiratory symptoms are often present. Haemoptysis and respiratory distress may be present in specific cases of the patient. Here, we described a 5-year-old male infant's case of foregut duplication with bronchial involvement and its management.

Giant immature teratoma resection at Dong Nai General Hospital: A case report

Introduction: Mediastinal teratoma is a disease that develops silently and can reach large sizes asymtomatically. Computed tomography is a gold standard for diagnosis and treatment strategy. We report a case of radical surgical resection of an immature mediastinal teratoma. Case report: A 18 year-old male patient admitted to the hospital due to shrotness of breath. Contrast-enhanced computed tomography showed a mediastinal tumor of 132 x 135 x 200 mm. The tumor occupied nearly the entire left pleural space, compressed the heart and its large blood vessels to the right. The tumor was entirely resected via the median sternotomy. The pathology result was immature teratoma. Postoperative course was favorable, the patient was discharged from the hospital on postoperative day 7. Conclusion: Immature teratoma is a malignant disease with poor long-term prognosis. Surgery is a proven effective treatment. Initial successful results at a provincial hospital contribute to helping the surgical team develop techniques and continue to perform complex surgeries, the patients need not to travel long distances and thus decrease the treatment cost.

Selpercatinib for treating recurrent mixed medullary and follicular cell-derived thyroid carcinoma: a case report

BackgroundMixed medullary and follicular cell-derived thyroid carcinoma (MMFCC) is characterized by the coexistence of follicular and C cell–derived tumour cell populations within the same lesion. Due to its rarity, its etiology and clinical course remain unclear, and treatment for advanced or recurrent cases has not been established.Case presentationWe report a case of MMFCC treated with selpercatinib. The patient was a 69-year-old male presenting with tumors in the right thyroid lobe and in the upper mediastinum. Fine-needle aspiration (FNA) cytology of the right thyroid lobe tumor revealed a medullary carcinoma; germline RET mutations were not detected. After resection of the right thyroid lobe with central node dissection, rapid intraoperative diagnosis of the mediastinal mass confirmed malignancy, leading to total thyroidectomy with excision of the upper mediastinal tumor. Histologically, the tumor in the right thyroid lobe and the pretracheal lymph node revealed a mixture of medullary and follicular carcinoma components, diagnosed as MMFCC. The mediastinal lymph node exhibited only medullary carcinoma components. At 11 months postoperatively, computed tomography scans showed enlargement of the right supraclavicular and upper mediastinal lymph nodes. FNA cytology of the right supraclavicular lymph node suggested the recurrence of medullary thyroid carcinoma. The gene panel testing (The Oncomine Dx Target Test Multi-CDx system®, Thermo Fisher SCIENTIFIC) of metastatic lymph node revealed RET somatic mutation (M918T). Treatment with selpercatinib was initiated, and both the cervical and mediastinal lymph nodes showed a reduction in size.ConclusionsWe report a rare case of selpercatinib use for MMFCC. Since RET mutations may occur frequently in MMFCC, selpercatinib could be effective in treating MMFCC.

Video-Assisted Thoracoscopic Surgery Is a Safe and Feasible Technique for Mediastinal Parathyroid Lesions.

Introduction: Hyperfunctional ectopic parathyroid glands in the mediastinum pose a challenge to diagnosis and require optimal surgical management. Video-assisted thoracoscopic surgery (VATS) has emerged as a promising minimally invasive approach, offering potential benefits in terms of both patient comfort and oncological principles. This study aimed to evaluate the effectiveness and safety of VATS for the treatment of hyperfunctional ectopic parathyroid glands in the mediastinum. Methods: Among the 538 patients with mediastinal tumors who underwent thoracoscopic surgery at Istanbul University (2008-2021), 11 exhibited hyperfunctional ectopic parathyroid glands. The localization of the glands was performed using various diagnostic techniques, including neck ultrasound, sestamibi scan, CT (computerized tomography), and SPECT (Single-photon emission computed tomography). VATS (Video-assisted thoracoscopic surgery) was used to remove ectopic parathyroid glands in all 11 patients, with no need for conversion to open surgery. Results: The pathological results showed that VATS successfully removed the ectopic glands in all 11 patients. Serum parathyroid hormone (PTH) levels were monitored intraoperatively, and frozen sections were used to confirm the presence of parathyroid adenomas in all cases. Postoperative analysis showed that PTH levels dropped by at least 50% within 10-15 minutes after adenoma removal. Conclusion: VATS is a safe and effective method for the treatment of hyperfunctional ectopic parathyroid glands in the mediastinum with a low risk of complications.

The Clinico-pathology Loci, Diagnosis and Management of Mediastinal Masses: A Retrospective Study in a Tertiary Care Hospital

The Clinico-pathology Loci, Diagnosis and Management of Mediastinal Masses: A Retrospective Study in a Tertiary Care Hospital

A proof-of-concept study: advantages of the subxiphoid over the lateral intercostal approach.

The study was designed to evaluate the superiority of the subxiphoid approach comparing with the lateral intercostal approach during the process of operation, and other perioperative indices. Patients diagnosed anterior mediastinal disease in our hospital between January 2018 and October 2019 were prospectively assigned into two groups, receiving the lateral intercostal approach or the subxiphoid approach VATS to resect the disease. The PaCO2, SaO2, PaO2 and circulation changes were recorded during the operation, neutrophil-to-lymphocyte ratio, and other perioperative outcomes, including clinical and surgical results, operation time, blood loss, postoperative complication, postoperative pain score were compared. A total 59 patients diagnosed anterior mediastinal tumour or myasthenia gravis underwent the resection by VATS. 31 patients were treated with the subxiphoid approach, 28 patients were treated with the lateral intercostal approach. PaCO2 increased significantly and SaO2 remained stable in the subxiphoid group during the operation, while PaCO2 increased significantly and SaO2 decreased at the same time in the lateral intercostal group. Operations were more frequently interrupted for the hypoxia or circulation disturbance during the process of dissecting the thymus in the lateral intercostal approach. Compared with the lateral intercostal approach, patients in the subxiphoid approach experienced less inflammation reaction, and yielded lower pain score and shorter postoperative hospital stay. There were no significant differences in postoperative complications between the two groups. All these patients recovered well when discharged. Our study suggested that subxiphoid approach will influence pulmonary and circulation lesser than the lateral intercostal approach, and the whole procedure will be safer and easier, and the subxiphoid approach may be the ideal choice for the anterior mediastinal disease.