[The clinicopathological features and curative effect of the bronchoscopic interventional therapy combined with radiotherapy for the treatment of locally recurrent lung adenoid cystic carcinoma].

Objective: To explore the clinical value of endoscopic interventional therapy for locally recurrent primary lung adenoid cystic carcinoma (ACC). Methods: The clinical data of 42 patients with locally recurrent ACC were retrospectively analyzed, and the differences of tracheal and bronchial diameter, airway scoring grade and airway obstruction degree before and after treatment were compared among three treatment methods: bronchoscopic interventional therapy + palliative radiotherapy, interventional therapy alone, and non-interventional therapy. Log rank test and Cox proportional risk model multi-factor analysis were used to determine the prognostic factors of ACC patients with local recurrence, and the long-term effect of bronchoscopic interventional therapy on ACC with local recurrence was determined. Results: The median overall survival of 42 patients was 59 months and 5-year survival rate was 54.2%.Univariate analysis showed that vascularized cancer, pleural invasion, pulmonary atelectasis, incisal margin, microscopic classification, tumor diameter, initial TNM stage, ki-67 index, and treatment after local recurrence were associated with long-term survival of ACC patients with local recurrence (all P<0.05). Cox multivariate regression analysis showed that margin status (RR=0.272, P=0.011), tumor diameter (RR=2.586, P=0.005), initial TNM staging (RR=0.369, P=0.035), ki-67 index (RR=3.569, P<0.001), and treatment methods after local recurrence (RR=0.126, P<0.001) were independent factors influencing the prognosis of ACC patients with local recurrence. After three months of treatment, the tracheal bronchus diameters, rating of shortness of breath, and degree of airway obstruction were all improved significantly (all P<0.05), both in the interventional therapy + palliative radiotherapy group [(14.5±2.8 mm, 0.86±0.45, (14.50±10.67)%, respectively], and the interventional therapy alone group [(13.7±2.3) mm, 0.97±0.25, (15.38±12.02)%, respectively]. Meanwhile, the difference before and after non-interventional therapy was not statistically significant (all P>0.05). 5-year overall survival rates were 55.8%, 46.6% and 42.6% for patients undergoing interventional therapy+ palliative radiotherapy, interventional therapy alone, and non-interventional therapy after recurrence, with statistically significant differences (P=0.015). Patients underwent bronchial endoscopic interventional therapy and palliative radiotherapy had the best efficacy of treatment. Conclusion: Endoscopic interventional therapy plus palliative radiotherapy is an effective local palliative treatment for locally recurrent ACC patients, which can rapidly relieve airway stenosis, improve the quality of life of patients and prolong the survival time of patients.

Successful treatment of a recurrent granulation polyp in the airways with high-dose-rate brachytherapy: a case report.

BACKGROUND: Benign central airway tumors are very rare diseases. Their unspecific symptoms are responsible for late diagnosis. Endoscopic interventions with different techniques and tools are widely used for their treatment. However, in certain cases interventional endoscopy might be unsuccessful and therefore other methods such as high-dose-rate brachytherapy could be a therapeutic option. CASE PRESENTATION: A 76-year-old white German woman was referred to our clinic for an endoscopic treatment of a recurrent granulation polyp in her left main bronchus. She had dyspnea, coughing, and mucus retention. Three times resections via bronchoscopy were performed within less than a year. After each intervention the polyp regrew inside her left main bronchus causing a repeat of the initial symptoms. She presented to our clinic less than 1 month since the last intervention. Twice we performed a rigid bronchoscopy in total anesthesia where we resected the granulation polyp with a snare wire loop and did an argon plasma coagulation of its base. Due to the recurrent growing of the granuloma, we performed a high-dose-rate brachytherapy in conscious sedation after another interventional bronchoscopy with a resection of the polyp and argon plasma coagulation of the base. Three months after brachytherapy our patient came to our clinic for a follow-up with none of the initial symptoms. Only a small remnant of the polyp without a significant occlusion of her bronchus was visualized by bronchoscopy. Furthermore, 6 months after brachytherapy she was not presenting any of the initial symptoms. CONCLUSIONS: This case report shows that high-dose-rate brachytherapy is a therapeutic option for the treatment of benign airway stenosis when other interventional treatments are not or are less than successful. However, further investigations are needed to prove the effectiveness and reliability of the method.

Palliative radiotherapy for patients with tracheobronchial and esophageal compression due to intrathoracic malignant tumors.

AIMS: To evaluate palliative outcomes of patients with extrinsic malignant tracheobronchial or esophageal stenosis treated with radiation. Mediastinal or hilar lymphadenopathy surrounding the tracheobronchi or esophagus may cause compression, presenting as dyspnea and dysphagia respectively. Treatment is important for symptom relief and maintaining patients' quality of life. METHODS: Dyspnea and dysphagia were assessed using the Hugh-Jones score and a modified dysphagia scale, respectively. A total of 13 patients (median age, 60 years) with dyspnea received palliative radiotherapy. The primary organs were lung (n = 6), colorectum (n = 5), hypopharynx (n = 1) and uterine cervix (n = 1). Three patients received concurrent chemotherapy. The median time-adjusted biological effective dose (BED) was 33.0 Gy(10) . Ten patients (median age, 61) with dysphagia received palliative radiotherapy. The primary organs were lung (n = 7), esophagus (n = 2) and hypopharynx (n = 1). Three patients received concurrent chemotherapy. The median time-adjusted BED was 32.1 Gy(10) . RESULTS: Palliation of dyspnea and dysphagia occurred in seven (54%) and five (50%) patients, respectively. Patients treated with doses over 35 Gy(10) had greater score improvements than those treated with less than 35 Gy(10) in both groups. Patients who received concurrent chemoradiotherapy had greater score improvements than those treated with radiotherapy alone. Dyspnea patients with pretreatment scores of 2 (n = 5) had greater score improvements than those with scores of 3 or more (n = 8). CONCLUSION: External beam radiotherapy should be considered for patients with tracheobronchial or esophageal stenosis before their symptoms worsen. The prescription dose should be over 35 Gy(10) .

Long-term results of conformal radiotherapy for progressive airway amyloidosis.

PURPOSE: To evaluate the efficacy of conformal external beam radiotherapy (RT) for local control of progressive airway amyloidosis. METHODS AND MATERIALS: We conducted a retrospective review of patients with biopsy-proven progressive airway amyloidosis treated with conformal RT between 2000 and 2006 at Boston Medical Center. The patients were evaluated for performance status and pulmonary function, with computed tomography and endoscopy after RT compared with the pretreatment studies. Local control was defined as the lack of progression of airway wall thickening on computed tomography imaging and stable endobronchial deposits by endoscopy. RESULTS: A total of 10 symptomatic airway amyloidosis patients (3 laryngeal and 7 tracheobronchial) received RT to a median total dose of 20 Gy in 10 fractions within 2 weeks. At a median follow-up of 6.7 years (range, 1.5-10.3), 8 of the 10 patients had local control. The remaining 2 patients underwent repeat RT 6 and 8.4 months after initial RT, 1 for persistent bronchial obstruction and 1 for progression of subglottic amyloid disease with subsequent disease control. The Eastern Cooperative Oncology Group performance status improved at a median of 18 months after RT compared with the baseline values, from a median score of 2 to a median of 1 (p = .035). Airflow (forced expiratory volume in 1 second) measurements increased compared with the baseline values at each follow-up evaluation, reaching a 10.7% increase (p = .087) at the last testing (median duration, 64.8 months). Acute toxicity was limited to Grade 1-2 esophagitis, occurring in 40% of patients. No late toxicity was observed. CONCLUSIONS: RT prevented progressive amyloid deposition in 8 of 10 patients, resulting in a marginally increased forced expiratory volume in 1 second, and improved functional capacity, without late morbidity.

HDR endobronchial brachytherapy (HDRBT) in the management of advanced lung cancer--comparison of two different dose schedules.

PURPOSE: The aim of this work is to compare the results of various treatment protocols used in palliative HDRBT with the view of analyzing differences in survival and diminishing breathing difficulties. MATERIAL AND METHODS: A total of 648 patients with advanced lung cancer were divided into two groups according to their clinical stage and the Zubrod-ECOG-WHO score. 303 (46.8%) patients received a total dose of 22.5 Gy in 3 fractions once a week, and 345 (53.2%) patients received a single fraction of 10 Gy. They were under clinical and endobronchial observation taking into consideration survival rates, local remission and duration of symptom relief such as dyspnoea, breathing, cough and haemoptysis. RESULTS: There was no difference in the length of survival time between the two groups of patients (log-rank test, p=0.055). Patients showing improvement (objective response) survived longer than those who showed no change or progression (F Cox, p=0.000001). In multivariate analysis the other statistically important prognostic factors were: clinical stage of primary tumor (F Cox, p=0.000002), Zubrod-ECOG-WHO score (F Cox, p=0.002) and age of patients (F Cox, p=0.004). CONCLUSIONS: The two treatment protocols showed similar efficiency in overcoming difficulties in breathing. Prognostic factors that significantly correlated with survival length were: grade of remission after treatment, clinical stage and performance status.

Tracheobronchial amyloidosis: utilization of radiotherapy as a treatment modality.

Tracheobronchial amyloidosis (TBA) is a rare disease. No general consensus exists with regard to its optimal treatment, resulting in a variety of modalities used to manage this condition. In this article, we present a case of TBA treated with external beam radiation therapy with encouraging results. A brief literature review of this rare ailment is also included.

Liquid (188)Re-filled balloon dilation for the treatment of refractory benign airway strictures: preliminary experience.

PURPOSE: To present the preliminary results of beta irradiation with use of liquid rhenium 188 ((188)Re)-filled balloon dilation in the treatment of refractory benign airway strictures. MATERIALS AND METHODS: Ten sessions of beta irradiation by using liquid (188)Re-filled balloon dilation were prospectively performed in nine patients with refractory bronchial strictures between 2003 and 2006. Indications for treatment were dyspnea caused by repeat stricture or no response to previous treatment (ie, balloon dilation and/or temporary stent placement or laser therapy) in seven patients and dyspnea caused by exuberant granulation tissue formation at the distal end of the placed stent in two. To assess the treatment efficacy, the authors calculated and compared the mean intervals of interventional treatments before and after dilation with (188)Re and mercaptoacetyltriglycine (MAG(3))-filled balloons. RESULTS: Liquid (188)Re-filled balloon dilation was successfully performed in all nine patients, with no procedure-related complications. Immediately after the procedure, all patients showed resolution of their dyspnea. Five patients remained asymptomatic at 5-25-month follow-up. Four patients experienced dyspnea caused by recurrent stricture 1-10 months after dilation. The mean intervals between interventional treatments increased significantly from 3.1 months +/- 2.1 before (188)Re-MAG(3)-filled balloon dilation to 10.8 months +/- 8.8 after (188)Re-MAG(3)-filled balloon dilation in all nine patients (Wilcoxon signed rank test, P = .025). CONCLUSIONS: beta irradiation with liquid (188)Re-filled balloon dilation can be safely used for refractory benign airway strictures. A large study with longer follow-up is needed to draw a definite conclusion.

Tracheobronchial amyloidosis: a case report of successful treatment with external beam radiation therapy.

Tracheobronchial amyloidosis (TBA) refers to the deposition of localized amyloid deposits within the upper airways. Treatments have historically focused on bronchoscopic techniques including debridement, laser ablation, balloon dilation, and stent placement. Local excisions often prove temporarily effective, with multiple local recurrences and progressive compromise pulmonary function occurring frequently. We present a case of TBA managed with definitive external beam radiation therapy. Eighteen months after moderate-dose radiation, the patient demonstrated improvements in functional status, pulmonary function, bronchoscopic visualization, and CT-based luminal diameters. The literature involving the role of radiation therapy in the treatment of TBA is reviewed.

Short-course palliative radiotherapy for airway stenosis in non-small cell lung cancer.

BACKGROUND: The majority of patients with non-small cell lung cancer have inoperable disease that is already too advanced for radical treatment at the initial diagnosis. But patients who suffer from symptoms caused by intrathoracic tumor often require palliative treatment to relieve the symptoms. We investigated, retrospectively, the outcome of short-course palliative radiotherapy for airway stenosis in non-small cell lung cancer. METHODS: Between October 1997 and June 2001, 24 patients were treated by palliative radiotherapy to relieve airway stenosis caused by intrathoracic tumor. The short-course radiotherapy consisted of a total dose of 30 Gy given in ten fractions over 2 weeks. The effect of treatment was assessed by improvement of radiographic findings. The duration of palliation and this duration as a percentage of the remaining survival time were also investigated. RESULTS: Palliation of airway stenosis was achieved in 13 (54.2%) patients. The time until palliation was achieved ranged from 11 to 44 days (median, 24 days). The duration of palliation ranged from 44 to 351 days (median, 116 days). In the palliated patients, the median survival time was 192 days, while that of the non-responders was 43 days. The duration of palliation as a percentage of the remaining lifetime ranged from 41% to 96% (median, 66%). CONCLUSIONS: Short-course palliative radiotherapy of 30 Gy in ten fractions over 2 weeks achieved good palliation without severe acute toxicities in over half of the patients. It is suggested that, in the palliated patient, the airway can be, potentially, maintained over the long term.

External-beam radiation therapy in the treatment of diffuse tracheobronchial amyloidosis.

Tracheobronchial amyloidosis is characterized by deposits of amyloid in airway walls. No effective treatment is known. We describe a 59-year-old woman who presented with increasing symptoms of airway obstruction due to diffuse deposition of amyloid throughout her tracheobronchial tree. She was treated with external-beam radiation therapy (20 Gy) with marked improvement in her symptoms, effort tolerance, bronchoscopic appearance, and forced expiratory volume in 1 second (1.39 L to 1.97 L [42%]). This improvement was maintained during 21 months of follow-up.

Successful use of high dose rate brachytherapy for non-malignant bronchial obstruction.

High dose rate (HDR) endobronchial brachytherapy is a palliative treatment for symptomatic airway obstruction by malignant tumours. We report a novel use of HDR brachytherapy for treating non-malignant bronchial obstruction. The patient had a metal stent placed in a reconstructed airway after a bronchial tear to ensure patency. Granulation tissue formation in and around the stent caused symptomatic occlusion of the airway, necessitating multiple laser applications. A single treatment of HDR brachytherapy (1000 cGy) was delivered following laser therapy. The patient remains well 15 months after treatment with no evidence of recurrent granulation tissue formation on bronchoscopy. HDR brachytherapy is an effective treatment for non-malignant airway obstruction.

Treatment of endotracheal or endobronchial obstruction by non-small cell lung cancer: lack of patients in an MRC randomized trial leaves key questions unanswered. Medical Research Council Lung Cancer Working Party.

Symptoms of endotracheal or endobronchial obstruction caused by non-small cell lung cancer (NSCLC) may be relieved with external beam radiotherapy (XRT) or endobronchial treatment. The comparative roles of these two methods need to be established. Patients with predominantly intraluminal obstruction of the trachea, a main bronchus or a lobar bronchus by unresectable NSCLC were randomized to XRT versus the clinician's choice of endobronchial treatment with brachytherapy, laser resection or cryotherapy, according to local availability and practice. Clinicians' assessments included symptoms of obstruction, WHO performance status, lung function tests and adverse effects of treatment. Patients completed a Rotterdam Symptom Checklist at all assessments and a daily diary card to record the severity of major symptoms during the first 4 weeks. To show a difference of 15% in the relief of breathlessness rates at 4 months (from 65% to 80%), 400 patients were required. In spite of our many previously successful lung cancer trials, and initial interest from clinicians in 24 UK centres, who estimated they could randomize 200 patients per year into the present trial, only 75 patients were randomized from seven centres over 3.5 years. Intake to the trial was therefore abandoned in November 1996 although an independent Data Monitoring and Ethics Committee had concluded in April 1996 that the scientific case for the trial was still strong; there were no competing trials; there were no design problems; and much had been done to promote the trial. The main reasons given by centres for the slow intake were: lack of referrals of untreated patients; patients being referred specifically for endobronchial treatment; patients having already received XRT; emergency endobronchial relief of obstruction being necessary; and XRT and endobronchial treatment being considered complementary and not as alternatives. The relative advantages and disadvantages of XRT versus endobronchial treatment remain to be determined. The lack of recruitment to this trial raises the issue of innovative techniques not being given the chance of proving their worth compared with traditional treatments.

Radiation therapy for tracheobronchial amyloidosis.

A 67-year-old man presented with localized tracheobronchial amyloidosis involving the distal trachea and the right-sided airways. The disease caused right middle lobe collapse and threatened the right upper and lower lobes. A variety of bronchoscopic methods, including Nd:YAG laser resection, dilation, and stenting, were used as temporizing methods. External beam radiation therapy, considered because of disease progression, caused a measurable local response. Radiation therapy should be considered as a treatment option for localized tracheobronchial amyloidosis causing airway obstruction.

[A case of left main bronchus obstruction due to recurrent esophageal cancer successfully treated by Nd-YAG laser followed by radiotherapy, low-dose CDDP and continuous infusion of 5-FU].

A 63-year-old female patient with obstruction of left main bronchus due to recurrent esophageal cancer was treated by emergency Nd-YAG laser therapy under bronchoscopy. Severe dyspnea subsided dramatically and she was the given radiotherapy with a total dose of 50 Gy (2 Gy/f and 25 f/5 wks). Concurrent chemotherapy was performed at the 3rd week of radiation therapy. In this chemotherapy of CDDP plus 5-FU, CDDP (10 mg/day) was given for 5 days by intravenous and 5-FU (500 mg/day) for 5 days by continuous infusion the same week. By this treatment, a partial response (PR) was obtained, and the patient returned to normal life. But after 4 months, she had a recurrent lesion at the same place, and underwent only palliative laser therapy. Nd-YAG laser therapy for obstructive lesion of trachea due to recurrent cancer is the most useful one, but some subsequent treatment is required.

[High-dose brachytherapy in endobronchial neoplastic stenoses]. / La brachiterapia con alto rateo di dose nelle stenosi neoplastiche endobronchiali.

Form March, 1991, to September, 1995, twenty-nine patients with endobronchial neoplastic stenosis were treated with high dose rate (HDR) brachytherapy at the Casa Sollievo della Sofferenza Hospital in San Giovanni Rotondo (Foggia, Italy). Fifteen patients had hemoptysis, 10 dyspnea, 6 constant cough and 6 lung atelectasis. The total dose, specified at 1 cm from the source, ranged 5 to 21 Gy and the fraction doses 5 to 15 Gy. Fourteen of 29 patients (48%) died. The mean survival is 7 months, with the follow-up ranging 1 to 22 months. Subjective responses were achieved in 78.4% of cases, with 67.6% complete and 10.8% partial remission rates. Complete remission of hemoptysis was observed in 100% of patients. Dyspnea improved in 70%, cough in 46.4% and atelectasis in 83.2%. Endoscopic findings, 1 month after the end of brachytherapy, showed a response in 79.4% of patients. The complication rate was 13.8% (1 tracheoesophageal fistula, 2 pulmonary hemorrhages and 1 cavitary necrosis). Even though the number of treated patients is small, our experience confirms the efficacy of HDR endobronchial brachytherapy in the palliation of lung cancer-related symptoms. Literature data show that brachytherapy improves the quality of life in the patients with poor prognosis who are otherwise untreatable. The HDR technique is more accurate than the LDR technique and therapy is better tolerated also because execution time is shorter. Prospective clinical trials are needed to investigate the most effective total doses and fractionations and to better define the role of brachytherapy in the curative treatment of lung cancer.

Severe endobronchial obstruction in a girl with relapsing polychondritis: treatment with Nd YAG laser and endobronchial silicon stent.

Relapsing polychondritis (RP) is an uncommon disorder of unknown aetiology characterized by inflammation and destruction of the cartilaginous structures of many organs, including the tracheobronchial tree. When untreated, there is a high mortality rate, usually from respiratory obstructive complications. An 8 year old white girl, with a previous diagnosis of RP, was referred to our department for evaluation of worsening dyspnoea. Bronchoscopy showed localized inflammatory and fibrotic alterations of the mucosa, leading to severe obstruction of the left mainstem bronchus at its origin. The condition was successfully treated by endoscopic neodymium yttrium aluminium garnet (Nd YAG) laser. Re-evaluation of the patient, 7 months later, demonstrated bronchial stenosis and malacia requiring mechanical dilatation and positioning of an endobronchial silicon stent, which was well-tolerated by the patient.

Endobronchial lesions in a non-AIDS patient with disseminated Mycobacterium avium-intracellulare infection.

A 34 year old female developed Mycobacterium avium-intracellulare infection with generalized lymphadenopathy, hepatosplenomegaly, pulmonary infiltration, pleural effusion and endobronchial polypoid lesions. M. avium-intracellulare was identified by means of sputum cultures, pleural effusion culture and lymph node culture. The anti-human immunodeficiency virus (HIV) antibody was negative. The CD4+ cell count was normal. Bronchoscopic examination revealed multiple polypoid lesions, which had nearly occluded the right main bronchus, right middle lobe and left lower lobe bronchi. Neodymium yttrium aluminium garnet (Nd-YAG) laser and antimycobacterial therapy were used effectively to relieve the airway obstruction. The clinical symptoms and signs responded favourably to antimycobacterial therapy.

Endobronchial radiation therapy with or without neodymium yttrium aluminum garnet laser resection for managing malignant airway obstruction.

BACKGROUND: Previous reports have shown low-dose-rate (LDR) afterloading Ir-192 endobronchial radiation therapy (EnBRT) to effectively palliate symptoms in patients with malignant airway obstruction. The authors retrospectively assessed the consequences of LDR EnBRT with or without neodymium yttrium aluminum garnet (Nd:YAG) laser resection in 37 patients. METHODS: Between February 1986 and June 1991, 37 patients with malignant airway obstruction were treated with LDR EnBRT at The Cleveland Clinic Foundation. Inclusion criteria for LDR EnBRT with or without Nd:YAG laser resection were patients with recurrent, symptomatic endobronchial lesions treated previously with external beam irradiation. Of the 37 patients, 21 patients with endobronchial lesions underwent Nd:YAG laser resection; 16 patients with mainly extrinsic lesions received EnBRT only. Before EnBRT, selected patients (7 of 16 in the nonlaser-treatment group and 14 of 21 in the laser-treatment group) received additional external beam treatments of 2000 cGy/10 fractions. The LDR afterloading Ir-192 technique was used to deliver approximately 30 Gy to a 1.0-cm radius target. RESULTS: All patients had one or more of the following symptoms: 1) dyspnea, 2) fever, 3) cough, and 4) hemoptysis. Good-to-excellent symptom relief was apparent in 16 of 21 (76.2%) laser-treated patients and in 12 of 16 (75%) nonlaser-treated patients. Follow-up bronchoscopy in 28 patients revealed tumor regression in 22 (79%). Median survival time was 16.3 weeks in the laser group and 11.7 weeks in the nonlaser group (P = 0.36). Longer median survival times were noted in laser-treated (22.8 weeks) and nonlaser-treated (16.4 weeks) patients receiving additional external beam treatments. Exsanguination occurred in 7 of 21 (33.3%) laser-treated patients and in 4 of 16 (25%) nonlaser-treated patients. The only factor affecting the exsanguination rate was implant location: 6 of 11 (54.5%) patients had lesions in the right or left upper lobe. CONCLUSIONS: EnBRT alone or with Nd:YAG laser resection provided good-to-excellent symptom palliation in these patients although a high rate of exsanguination occurred in both groups.

[Palliative bronchial deobstruction with kinetic radiotherapy in non-small cell lung cancer]. / Disostruzione bronchiale palliativa con radioterapia cinetica nel cancro polmonare non a piccole cellule.

The palliative treatment of lung atelectasis can significantly improve the quality of life in the patients who are unsuitable for cure. The authors present a new transcutaneous radiotherapy technique for treating this complication of lung cancer. After conventional and CT localization, a treatment is scheduled featuring a small (3-5 cm wide and 4-6 cm long) single 180 degrees arc beam giving 14 Gy to the 90% isodose line in two daily fractions. The treatment is repeated 3 weeks later (dosage: 28 Gy). The mean dosage to the ICRU reference point was 34 Gy; the min., max. and mean dosages to the planning target volume were 31, and 35 Gy, respectively, in 4 fractions over a 3-week period. Lesions were localized best by positioning the distal end of a fiberoscope close to the tumor and by checking its position under fluoroscopic guidance, on two orthogonal projections, immediately after every treatment session. Nine patients with histologically-proven non-small cell lung cancer were treated. They relapsed after surgery and/or full-course radiotherapy. Lung reventilation, demonstrated with fiberbronchoscopy and on chest films, was observed in 8/9 patients, in 1 of them lasting for about 40 days. In the extant 7/8 cases, it lasted longer (range: 60-180 days). Of the latter patients, 5 are alive and 2 died 60 and 86 days after treatment, with no atelectasis. The treatment was very well tolerated and severe symptoms were relieved with no complications.