Lung transthoracic ultrasound elastography imaging and guided biopsies of subpleural cancer: a preliminary report.

BACKGROUND: Despite the usefulness of elastography in assessing the stiffness/elasticity of tissues, and its proven diagnostic accuracy in thyroid, breast, and prostate cancers, among others, it is not yet applied in transthoracic ultrasound (TUS) scans to investigate lung nodules. PURPOSE: To investigate the potential clinical utility of TUS elastography in diagnosing lung cancer proven by fine-needle aspiration biopsy (FNAB). MATERIAL AND METHODS: TUS elastography was performed in 95 consecutive patients (71 men, 24 women; age, 62.84 ± 7.37 years) with lesions suspected of involving the chest wall or the pleura detected on chest X-ray or computed tomography (CT). Patients with pleural effusions were not enrolled, but were further evaluated by pleural fluid cytology. Patients were excluded from the study if a diagnosis had already been made based on sputum cytology and/or bronchoscopic histology (making TUS biopsy unnecessary) or if their lung lesions could not be visualized under standard US. Under FNAB, 34 consolidations were ascribed to pneumonia and 65 to cancer. Under TUS, tissue stiffness, detected using a convex multifrequency 2-8-mHz probe and a MyLab™Twice - ElaXto, was scored from 1 (greatest elasticity) to 5 (no elasticity). Subpleural solid masses (2-5 cm) were initially detected by TUS and subsequently assessed by FNAB. RESULTS: Histological diagnoses were: small cell lung cancer (4/61), adenocarcinoma (29/61), squamous cell carcinoma (SCC) (12/61), large cell lung carcinoma (12/61), and lymphomas (4/61). Patients' age and mass sizes (3.06 ± 0.88 cm) were not significantly associated with any histological type. A significant lower elasticity of SCC (4.67 ± 0.492) was observed versus other types of lung cancer (P < 0.005), and versus pneumonia (2.35 ± 0.48). CONCLUSION: Since only squamous cell lung carcinoma displays the feature of significantly reduced elasticity, and since no clear-cut diagnostic key is yet available, the clinical usefulness of TUS elastography is currently limited with a view to characterizing tumors. Nevertheless, it does enable good non-invasive imaging of lung nodules, providing information on their stiffness, and can improve the accuracy and yield of FNAB.

Thoracic ultrasound combined with low-dose computed tomography may represent useful screening strategy in highly exposed population in the industrial city of Taranto (Italy).

Objectives: We validated a screening protocol in which thoracic ultrasound (TUS) acts as a first-line complementary imaging technique in selecting patients which may deserve a second-line low-dose high resolution computed tomography (HRCT) scan among a population of asymptomatic high-risk subjects for interstitial lung abnormalities (ILA) and lung cancer. Due to heavy environmental pollution burden, the district Tamburi of Taranto has been chosen as "case study" for this purpose. Methods: From July 2018 to October 2020, 677 patients aged between 45 and 65 year and who had been living in the Tamburi district of Taranto for at least 10 years were included in the study. After demographic, clinical and risk factor exposition data were collected, each participant underwent a complete TUS examination. These subjects were then asked to know if they agreed to perform a second-level examination by low-dose HRCT scan. Results: On a total of 167 subjects (24.7%) who agreed to undergo a second-level HRCT, 85 patients (50.9%) actually showed pleuro-pulmonary abnormalities. Interstitial abnormalities were detected in a total of 36 patients on HRCT scan. In particular, 34 participants presented subpleural ILAs, that were classified in the fibrotic subtype in 7 cases. The remaining 2 patients showed non-subpleural interstitial abnormalities. Subpleural nodules were observed in 46 patients. TUS showed an overall diagnostic accuracy of 88.6% in detecting pleuro-pulmonary abnormalities in comparison with HRCT scan, with a sensitivity of 95.3%, a specificity of 81.7%, a positive predictive value of 84.4% and a negative predictive value of 94.4%. The matched evaluation of specific pulmonary abnormalities on HRTC scan (i.e., interstitial abnormalities or pulmonary nodules) with determinate sonographic findings revealed a reduction in both TUS sensibility and specificity. Focusing TUS evaluation on the assessment of interstitial abnormalities, a thickened pleural line showed a sensitivity of 63.9% and a specificity of 69.5%, hypoechoic striae showed a sensitivity of 38.9% and a specificity of 90.1% and subpleural nodules showed a sensitivity of 58.3% and a specificity of 77.1%. Regarding to the assessment of subpleural nodules, TUS showed a sensitivity of 60.9% and a specificity of 81.0%. However, the combined employment of TUS examination and HRCT scans allowed to identify 34 patients with early subpleural ILA and to detect three suspicious pulmonary nodules (of which two were intraparenchymal and one was a large subpleural mass), which revealed to be lung cancers on further investigations. Conclusion: A first-line TUS examination might aid the identification of subjects highly exposed to environmental pollution, who could benefit of a second-line low-dose HRCT scan to find early interstitial lung diseases as well as lung cancer. Protocol registration code: PLEURO-SCREENING-V1.0_15 Feb, 17.

CT-Guided Transthoracic Biopsy of Pulmonary Lesions: Diagnostic versus Nondiagnostic Results.

(1) Background: Despite the high accuracy of CT-guided transthoracic biopsy for diagnosis of pulmonary lesions, in a certain amount of cases biopsy results may indicate the presence of nonspecific findings or insufficient material. We aimed to investigate the effectiveness of CT-guided transthoracic biopsy of pulmonary lesions in providing a specific diagnosis and to analyze the variables affecting biopsy results. (2) Methods: In this retrospective study, a total of 170 patients undergoing 183 CT-guided transthoracic biopsies of pulmonary lesions were included. The clinical, radiological and pathological data were reviewed to classify biopsy results as diagnostic or nondiagnostic and to identify which variables were associated with the two groups. (3) Results: The biopsy results were diagnostic in 150 cases (82.0%), of which 131 (87.3%) positive for malignancy and 19 (12.7%) with specific benign lesions, and nondiagnostic in 33 cases (18.0%). Twenty-two of the thirty-three (66.7%) nondiagnostic cases were finally determined as malignancies and eleven (33.3%) as benign lesions. In the diagnostic group, all the 131 biopsies positive for malignancy were confirmed to be malignant at final diagnosis (87.3%); of 19 biopsies with specific benign lesions, 13 cases were confirmed to be benign (8.7%), whereas six cases had a final diagnosis of malignancy (4%). Multivariate analysis showed increased risk of nondiagnostic biopsy for lesions ≤ 20 mm (p = 0.006) and lesions with final diagnosis of benignity (p = 0.001). (4) Conclusions: CT-guided transthoracic lung biopsy is an effective technique for the specific diagnosis of pulmonary lesions, with a relatively acceptable proportion of nondiagnostic cases. Small lesion size and final benign diagnosis are risk factors for nondiagnostic biopsy results.

Effectiveness and Safety of Real-Time Transthoracic Ultrasound-Guided Thoracentesis.

PURPOSE: The purpose of the present study was to specifically evaluate the effectiveness and safety of real-time ultrasound-guided thoracentesis in a case series of pleural effusion. PATIENTS AND METHODS: An observational prospective study was conducted. From February 2018 to December 2019, a total of 361 consecutive real-time transthoracic ultrasound (TUS)-guided thoracentesis were performed in the Unit of Diagnostic and Interventional Ultrasound of the Research Hospital "Fondazione Casa Sollievo della Sofferenza" of San Giovanni Rotondo, Foggia, Italy. The primary indication for thoracentesis was therapeutic in all the cases (i.e., evacuation of persistent small/moderate pleural effusions to avoid super-infection; drainage of symptomatic moderate/massive effusions). For completeness, further diagnostic investigations (including chemical, microbiological, and cytological analysis) were conducted. All the procedures were performed by two internists with more than 30 years of experience in interventional ultrasound using a multifrequency convex probe (3-8 MHz). For pleural effusions with a depth of 2-3 cm measured at the level of the costo-phrenic sinus was employed a dedicated holed convex-array probe (5 MHz). RESULTS: In all the cases, the attempts at thoracentesis were successful, allowing the achievement of the therapeutic purpose of the procedure (i.e., the complete drying of the pleural space or the withdrawal of fluid till a "safe" quantity [a mean of 1.5 L, max 2 L] producing relief from symptoms) regardless of the initial extent of the pleural effusion. There were only 3 cases of pneumothorax, for a prevalence rate of complications in this population of 0.83%. No statistical difference was recorded in the rate of pneumothorax according to the initial amount of pleural fluid in the effusion (p = 0.12). All the pleural effusions classified as transudates showed an anechoic TUS appearance. Only the exudative effusions showed a complex nonseptated or a hyperechoic TUS appearance. However, an anechoic TUS pattern was not unequivocally associated with transudates. Some chronic transudates have been classified as exudates by Light's criteria, showing also a complex nonseptated TUS appearance. The cytological examination of the drained fluid allowed the detection of neoplastic cells in 15.89% cases. On the other hand, the microbiological examination of effusions yielded negative results in all the cases. CONCLUSIONS: Real-time TUS-guided thoracentesis is a therapeutically effective and safe procedure, despite the diagnostic yield of the cytological or microbiological examinations on the collected liquid being very low. Future blinded randomized studies are required to definitely clarify the actual benefit of the real-time TUS-guided procedure over percussion-guided and other ultrasound-based procedures.

Giant epiphrenic diverticulum: an unusual case from diagnosis to treatment.

Esophageal diverticulum is a rare disease caused by impairment of esophageal motility. The incidence is not known, due to lack of symptoms in many cases. Surgical treatment is reserved to symptomatic patients. In this case report, we describe a rare case of epiphrenic esophageal diverticulum. A 61-year-old male with silent medical history, suffering severe chest pain had a CT scan showing a large esophageal diverticulum. The patient was referred to our hospital, IRCCS "Casa Sollievo della Sofferenza", to complete pre-operative assessment with a CT scan and a Barium swallowing radiography, giving morphodimensional details of the diverticulum. Based on these findings, the surgeons have chosen the appropriate operative strategy. The surgeons adopted a laparoscopic access, completed with robotic-assisted laparotomy due to the morphology of the diverticulum. Radiological evaluation is crucial in the diagnosis and in the treatment planning of symptomatic patients.

Transthoracic ultrasound shear wave elastography for the study of subpleural lung lesions.

PURPOSE: The aim of this study was to assess whether new-generation shear wave elastography (SWE) is suitable for the characterization of lung subpleural lesions. METHODS: In total, 190 consecutive patients with subpleural lung lesions received ultrasonography and SWE. Patients with suspected malignancy underwent ultrasound-guided transthoracic needle biopsy. Final diagnoses were made on the basis of patients' clinical course, microbiological studies, and histological results. SWE was also performed in 25 healthy volunteers. RESULTS: We found no statistically significant differences in stiffness between lung carcinomas, lung metastases, and pneumonia (P=0.296) or between different histological types of lung cancer (P=0.393). Necrosis was associated with reduced stiffness in pneumonia. Excluding necrotic lesions, pneumonia showed higher stiffness than lung carcinomas (2.95±0.68 m/s vs. 2.60±0.54 m/s, P=0.006). Chronic pneumonia showed increased stiffness (3.03±0.63 m/s), probably due to the presence of fibrotic tissue on histology. Pleural effusion was associated with a statistically significant reduction in stiffness, both in lung carcinomas (P=0.004) and lung metastases (P=0.002). The presence of air in healthy lung tissue may lead to incorrect speed estimates due to shear wave reflection (very high values, 14.64±2.19 m/s). CONCLUSION: Transthoracic SWE could not distinguish lung malignancy from pneumonia, or between different histological types of lung carcinomas. In particular, SWE seems unable to resolve the clinical dilemma of chronic subpleural consolidations.

Pulmonary Artery Stump Thrombosis: To Treat or Not to Treat? The Question Is Still Open. Description of a Case and Review of the Literature.

Pulmonary artery stump thrombosis (PAST) represents a possible complication after lung surgery. We report the case of a 59-year-old man who presented with dyspnoea about 4 years after right pneumonectomy due to squamous cell lung cancer. A CT-scan showed the presence of pulmonary artery stump thrombosis. Although there was no evidence of pulmonary embolism, given the clinical features and radiological shape of the thrombus, anticoagulation treatment with low-molecular-weight heparin was started with improvement of symptoms. The patient was discharged on anticoagulant treatment and a pulmonary CT-scan performed 4 months later showed an almost complete resolution of the PAST. Pathophysiological mechanisms of PAST are still unknown, although several hypotheses have been proposed. However, the decision to treat PAST with anticoagulants is still controversial. A review of literature will be provided in order to discuss risk factors, possible etiologies and to highlight clinical and radiological characteristics that could suggest to treat this condition, in particular when there is an increased risk of complications.

Imaging of cranio-cervical junction traumas.

The craniocervical junction (CCJ) or upper cervical spine (UCS) has anatomic features and a biomechanics completely different from the other spinal segment of the spine. Several ligaments and muscles control its motion and function and ensure the maximum mobility and the visual and auditory spatial exploration. UCS traumas represent approximately one-third of all cervical spine injuries. Most of UCS traumas results from blows to the head and sudden deceleration of the body. Thanks to the improvement of the Advanced Trauma Life Support protocols dissociative injuries of CCJ have become less lethal onsite. In other less severe but unstable injuries, patients are neurologically intact at presentation, but they may deteriorate during the stay in hospital, with important clinical and medico-legal consequences. Knowing the peculiarities of UCS is fundamental for the early detection of imaging findings that influences the patient management and outcome. The classification of UCS traumas is mechanistic. More than in any other spinal segment, fractures of CCJ bones can occur without generating instability; on the contrary highly unstable injuries may not be associated with bone fractures. An early and correct diagnosis of occipito-cervical instability may prevent secondary neurological injury. The goal of imaging is to identify which patients can benefit of surgical stabilization and prevent secondary neurologic damage. Actual helical multidetector-CT (MDCT) offers high sensitivity and specificity for bone lesions and displacements in cervical spine traumas, but magnetic resonance imaging (MRI) is increasingly being used to evaluate soft tissues and ligaments, and mainly to identify possible spinal cord injury.

Video-assisted thoracic surgery ultrasound (VATS-US) in the evaluation of subpleural disease: preliminary report of a systematic study.

We provide a pictorial essay examining the preliminary data of an ongoing study whose primary aim is to assess the usefulness and safety of video-assisted thoracic surgery ultrasound (VATS-US) in the identification of different lung diseases. We studied 14 patients (five women and nine men with a mean age of 56.2 ± 8.4 SD years) with indication for VATS. All patients underwent pre-operative imaging of the chest using high-resolution computed-tomography, contrast-enhanced computed-tomography, and/or positron emission tomography and transthoracic ultrasound. VATS-US was performed under general anesthesia with single-lung ventilation through double-lumen endotracheal intubation in all patients, and the Esaote MyLab 25 laparoscope probe with flexible tip and a linear array transducer at frequencies 8.0-12.0 MHz was used. The final histological diagnoses in our cohort were cancer (three cases), usual interstitial pneumonia (five cases), nonspecific interstitial pneumonia (two cases), and hypersensitivity pneumonitis (one case). In patients with pulmonary fibrosis, the VATS-US showed a thick hyperechoic pleural line and no B-lines. Regarding cancer nodules, the VATS-US images showed a uniform hypoechogenic pattern with jagged margins. In patients with hamartochondroma and histocytosis X, VATS-US showed a mixed hyperechoic structure of the margins. In conclusion, we described the US semeiotics of various lung disorders assessed during VATS by reporting the preliminary data of the first study which applies the methodology systematically to all patients undergoing the surgery procedure. Final results from the study will further elucidate how the technique could be of use during the VATS procedure.

Fatal systemic venous air embolism during endoscopic retrograde cholangiopancreatography.

Hepatic portal venous air embolism is the rarest complication of gastrointestinal endoscopy, resulting from penetration of gas into the portal veins, and may occur during endoscopic retrograde cholangiopancreatography and endoscopic biliary sphincterotomy. The likely mechanism is intramural dissection of insufflated air into the portal venous system through duodenal vein radicles transected during the procedure. Hepatic portal air embolism may be fatal. Cerebral air embolism may also occur. So far 13 cases of air embolism after endoscopic retrograde cholangiopancreatography have been reported, with 4 cases of systemic spread that proved fatal. Death was due to pulmonary air embolism in 2 cases, and cerebral air embolism in another 2. We report on an additional such fatal case, concerning a 78-year-old male patient, who several years previously had undergone surgical gastroduodenal resection with cholecystectomy and papillotomy, and was admitted for recurrent ascending cholangitis secondary to bile duct stones. During the third endoscopic cholangioscopic procedure for removal of bile duct stones, sudden cardiopulmonary arrest occurred. Death was due to massive pulmonary air embolism. Cerebral air embolism was also found. Autopsy was performed. A spontaneous duodenobiliary fistula was found. On the basis of bench radiologic investigation (retrograde suprahepatic venography and anterograde portography), it was demonstrated that the air insufflated during duodenal endoscopy, which entered through the spontaneous duodeno-biliary fistula, penetrated into intrahepatic vein radicles injured secondarily to prolonged impaction of biliary sand and stones and infection, resulting in portal and hepatic venous gas and systemic air embolism.

Occult breast cancer in a female with benign lesions.

Occult breast cancer is a carcinoma discovered by the presence of axillary lymph node metastases without the detection of the primary breast tumor. The incidence of this very rare pathology is 0.3%-1.0%. The limited number of these cases does not allow for the precise management of this rare pathology and often, the breast cancer manifestation can take many years to become obvious. We report the case of a 35-year-old woman who presented to our department for annual breast screening examination, without any symptoms. At the time of visit, there were two right and one left tumefactions; unfixed and palpable. Ultrasonography examination confirmed the lesions to be benign. One year later, a palpable hypoechoic axillary left lesion appeared: a lymph node with doubtful morphology. On cytological examination, a biopsy was performed for the axillary left mass which showed irregular masses of large malignant cells with pleomorphism and mitotic figures that suggested a carcinoma. The management of this case is suggestive for cancer of unknown primary syndrome.

Imaging of cervical spine traumas.

Spinal traumas represent a significant proportion of muscle-skeletal injuries worldwide. Spinal injuries involve a complex structure with components having different traumatic susceptibility and variable healing capabilities. The interaction of numerous variables at time of trauma creates a great variety of lesions which makes challenging the creation and comparison of homogeneous groups, with difficulties in classifying spinal lesions, in assessing their instability, and in defining the indication and outcome of different treatment strategies. The evolution of concepts on instability has accompanied that of traumas classification schemes and treatment strategies. The assessment of instability in a spinal injury is actually crucial in front of newer surgical techniques and hardwares. Despite a long history of attempts to classify spinal traumas, it remains some degree of controversy in describing imaging data and a wide variety of treatment strategies. Acute cervical spine injuries affect from 1.9% to 4.6% of subjects reporting a blunt trauma, and up to 5.9% of multiple-injured patients. Most of spinal cord injuries are a consequence of unstable fractures of the cervical spine. An accurate and early diagnosis is mandatory to prevent neurological damage in unstable fractures. Classic and newer classifications are primarily based on features identifiable by using conventional imaging and CT scan, which are the most available modalities at most trauma centers. Even though multidetector-CT remains superior in assessing with high accuracy bone injuries, MRI is the most sensitive modality for detecting soft tissues injuries and spinal cord damage.

Gallbladder and small bowel metastasis of regressive melanoma: a case report.

Malignant melanoma development in gastrointestinal (GI) tract may be primary or secondary. Although small bowel, colon and stomach represent common GI sites affected from metastatic cutaneous malignant melanoma (cMM), more than 90% of the cases are identified only during autoptic examinations. Therefore, the diagnosis in a living patient of gallbladder metastasis from cMM is considered extremely rare. We aimed to describe a case of metastatic melanoma involving the gallbladder, the stomach and the small bowel in a 78-year-old male with diffuse abdominal pain and a history of cMM of the back, which was radically resected 4 years before. Abdominal ultrasound showed intracholecystic multiple nodulations. CT, besides confirming the gallbladder nodules, revealed multiple masses in the stomach, duodenum and ileum. Malignant melanoma lesions were confirmed by histopathological and immunohistochemical analyses of bioptic material obtained from endoscopic examination. In patients with history of melanoma, careful inspection of GI tract should be prompted adopting adequate imaging techniques and endoscopy in order to better influence treatment planning and prognosis.

Tuberous sclerosis complex with polycystic kidney disease of the adult type: the TSC2/ADPKD1 contiguous gene syndrome.

Although different diseases, tuberous sclerosis complex and autosomal dominant polycystic kidney disease have been seen in association, the molecular basis of this being the proximity of tuberous sclerosis complex 2 and polycystic kidney disease 1 genes on the same chromosome (16p13.3). Therefore, the classic autosomal dominant polycystic kidney disease renal phenotype may occur in the context of tuberous sclerosis complex disease as a result of large deletions involving both the polycystic kidney disease 1 and tuberous sclerosis complex 2 genes. This is known as the tuberous sclerosis complex 2/autosomal dominant polycystic kidney disease 1 contiguous gene syndrome. The criteria for this condition are fulfilled when renal lesions typical for classic autosomal dominant polycystic kidney disease phenotype are associated with tuberous sclerosis complex phenotype. We present a new case of the sporadic form of this genetic disorder. The diagnosis of tuberous sclerosis complex in this patient was established on the presence of major and minor features, and the diagnosis of ADPKD was based on the presence of numerous large roundish renal cysts lined by a nondescript tubular epithelium. Sporadic cases of autosomal dominant polycystic kidney disease and tuberous sclerosis complex do occur. Molecular analysis was not performed because the patient's parents refused permission.

[PRES (Posterior Reversible Encephalopathy Syndrome): potential complication of hypertensive crisis. Case report and literature review].

Posterior reversible encephalopathy syndrome (PRES) is a clinical-radiological syndrome, usually reversible, characterized by vasogenic oedema in cerebral posterior regions in patients with autoimmune diseases, nephropathies, hypertensive crisis, eclampsia and exposure to cytotoxic drugs. The main symptoms are: headache, nausea, vomiting, seizures, visual disturbance and altered consciousness. Complications as cerebral hemorrhage and recurrences are rare. We describe a case of a 65 years old woman, affected by chronic kidney disease, recently exacerbated, diabetes and hypertension in treatment, who showed an heterogeneous clinical presentation with vomiting, headache, blurred vision and impaired consciousness during an episode of acute hypertension. After an adjustement of the antihypertensive treatment we observed a regression of symptoms in one week. FLAIR sequences on MRI showed cerebral bilateral vasogenic oedema in posterior regions, typical for PRES. This case was suggestive for PRES and a prompt adjustement of the antihypertensive treatment was critical for clinical recovery. Brain MRI was crucial for diagnosis. It is important for clinicians to recognize PRES as a possible complication of renal disease and hypertensive crisis.

Transperineal ultrasonography: First level exam in IBD patients with perianal disease.

BACKGROUND: A pelvic magnetic resonance imaging (MRI) represents the front-line method for evaluating perianal disease in patients with inflammatory bowel disease (IBD). Recently, transperineal ultrasonography (TPUS) has been proposed as a simple, safe, time-sparing and useful diagnostic technique to assess different pathological conditions of the pelvic floor. AIM: The aim of this prospective single centre study was to evaluate the accuracy of TPUS versus MRI for the detection and classification of perineal disease in IBD patients. METHODS: From November 2013 to November 2014, 28 IBD patients underwent either TPUS or MRI. Fistulae and abscesses were classified according to Parks' and AGA's classification methods. A concordance was assessed by k statistics. RESULTS: Overall, 33 fistulae and 8 abscesses were recognized by TPUS (30 and 7 by MRI, respectively). The agreement between TPUS and MRI was 75% according to Parks' classification (k=0.67) and 86% according to AGA classification (k=0.83), while it was 36% (k=0.34) for classifying abscesses. CONCLUSIONS: TPUS proved to be as accurate as MRI for detecting superficial and small abscesses and for classifying perianal disease. Both examinations may be performed at the initial presentation of the patient, but TPUS is a cheaper, time-sparing procedure. The optimal use of TPUS might be in follow-up patients.

Giant keloid of left buttock treated with post-excisional radiotherapy.

Keloids are defined as excessive scar tissue formation extending beyond the area of the original skin injury and occurring in predisposed individuals. While no single treatment has proven widely effective, several series report excellent outcomes for keloids with post-surgery radiation therapy as described in the literature. We present a patient with recurrent giant keloid of left buttock after several surgical removals, that at physical examination shows the size of 40×22×10 cm in the largest dimension. Patient underwent a surgical excision of gluteal lesion and postoperative radiotherapy using photons at 8 MV of linear accelerator: the total dose delivered was 22 Gy in 11 days, with a daily fraction of 2 Gy. No relapse was showed at 36 months post-therapy. Several methods seem unsatisfactory for preventing keloid recurrence. The combination of surgery and adjuvant radiotherapy seems an excellent strategy to prevent recurrent disease.