Atypical Tongue Abscesses Mimicking Submucosal Malignancies: A Review of the Literature Focusing on Diagnostic Challenges.

Tongue abscesses are rare conditions that usually follow mucosal disruption due to mechanical trauma or foreign body impaction. They typically manifest abruptly as a rapidly growing, hard mass or swelling in the context of tongue muscles; the patient frequently complains of pain, difficulties in swallowing or speaking, and fever. Nonetheless, the features of its presentation, together with accurate clinical evaluation, blood tests, and appropriate imaging tests, are usually sufficient to easily discern a tongue abscess from a malignancy. However, in rare cases, they may occur with slowly progressing and subtle symptoms, nuanced objective and laboratory findings, and inconclusive radiological evidence, leading to difficult differential diagnosis with submucosal malignancy. Herein, we review the literature, available on Pubmed, Embase, and Scopus, on publications reporting tongue abscesses, with atypical presentation suggesting an oral tumor. Our review confirms that tongue abscesses may manifest as a slowly growing and moderately painful swelling without purulent discharge and minimal mucosal inflammation; in this case, they may constitute an actual diagnostic challenge with potentially severe impact on correct management. Atypical tongue abscesses must therefore be considered in the differential diagnosis of tongue malignancy with submucosal extension, even when other diagnostic elements suggest a neoplasia; in this case, a deep biopsy under general anesthesia is essential for differential diagnosis, and simultaneous drainage of the necrotic and abscessual material may resolve the condition.

18F-Fluorocholine PET/CT in the Detection of Hyperfunctioning Transplanted Parathyroid Tissue.

ABSTRACT: A 54-year-old woman diagnosed with multiple endocrine neoplasia syndrome type 1 and primary hyperparathyroidism underwent total parathyroidectomy with autotransplantation of parathyroid tissue fragments in the right forearm in 1999. Since several years later, follow-up laboratory examinations showed the relapse of hypercalcemia; the patient started cinacalcet therapy. To exclude the presence of hyperfunctioning parathyroid glands in ortotopic or ectopic sites, a PET/CT scan with 18F-fluorocholine was performed. The PET/CT scan excluded the presence of ortotopic and ectopic parathyroid glands but showed a hyperplastic parathyroid fragment in the right forearm, responsible for the patient's persistent hypercalcemia.

Current evidence on diagnosis and treatment of parotid gland lymphomas: a systematic review.

BACKGROUND AND PURPOSE: Parotid gland lymphoma (PGL) is a rare and challenging diagnosis. Different lymphomas can develop in the parotid gland, with the most common being the mucosa-associated lymphoid tissue (MALT) lymphoma, which originates directly from the glandular parenchyma. Other histologic subtypes arise from both intraglandular and extraglandular parotid lymph nodes. A consensus on diagnosis and treatment of PGL is still lacking, and published data is scarce and heterogeneous. METHODS: We performed a systematic review of the literature, including studies published after 2001, when the WHO classification of lymphoid tumours was introduced. RESULTS: Twenty retrospective studies were included in the analyses, eight of which focused exclusively on MALT lymphomas. Final analysis included 612 cases of PGL, with a 1.68:1 F/M ratio. MALT lymphoma was the most common histology, followed by follicular and diffuse large B-cell lymphoma. Most cases were low stages (IE/IIE acc. Ann Arbour, 76.5%) and only 10% of patients presented with symptoms, most commonly pain (4.8%) and B symptoms (2.2%). A high prevalence of associated autoimmune diseases was found, particularly Sjögren's syndrome, that affected up to 70% of patients with MALT lymphoma. In most cases diagnosis was achieved through parotidectomy (57.5%), or open biopsy (31.2%). Treatment strategies were either surgical, non-surgical or a combination of modalities. Surgery as a single-modality treatment was reported in about 20% of patients, supposing it might be a valuable option for selected patients. CONCLUSIONS: Our review showed that the diagnosis and treatment of PGLs is far from being standardized and needs further, more homogeneous reports to reach consensus.

The impact of near-infrared autofluorescence on postoperative hypoparathyroidism during total thyroidectomy: a case-control study.

PURPOSE: Near-infrared autofluorescence is a new technology in thyroid surgery to better localize and preserve parathyroid glands. The purpose of this study is to assess if the adoption of NIR-AF can improve in short-, medium-, and long-term post-operative calcium and PTH levels compared to conventional "naked eye" surgery in patients undergoing TT for benign or malignant conditions. METHODS: 134 patients undergone total thyroidectomy between January 2020 and June 2022; 67 were treated with conventional thyroidectomy, the other 67 underwent surgery adopting an autofluorescence detecting device. RESULTS: Significant differences were found between the two groups in percentage of patients with short-term hypocalcemia (p = 0.04) and short-term hypoparathyroidism (p = 0.011). Median short-term (p = 0.01) and medium-term (p = 0.03) PTH levels were significantly higher in autofluorescence group, while, short- (p = 0.001), medium- (p < 0.001) and long-term (p = 0.019) percentage variation of PTH levels from baseline were significantly higher in the standard-care group. Finally, the prescription of oral calcium (p < 0.01) after surgery were significantly lower in the autofluorescence group. CONCLUSION: The adoption of near-infrared autofluorescence during total thyroidectomy is related to lower short-term hypocalcemia and hypoparathyroidism rates, decreased variation of post-operative PTH levels in short- and medium- and long-term, reducing the necessity of supplementation therapy with oral calcium compared to conventional surgery.

The use of near-infrared autofluorescence during total laryngectomy with hemi- or total thyroidectomy.

PURPOSE: The aim of this study is to describe the use of near-infrared autofluorescence (NIR-AF) to identify and preserve parathyroid glands (PGs) in a group of patients with advanced hypopharyngeal/laryngeal cancer undergone total (pharyngo)laryngectomy with hemi- or total thyroidectomy. METHODS: At San Raffaele Hospital, Milan (Italy), from January 2021 to May 2021, 7 patients affected by cT4a laryngeal squamous cell carcinoma (SCC) underwent surgery using an autofluorescence detection system (Fluobeam-Fluoptics®). For proper surgical planning, the demolition phase envisaged extension of the intervention to 4 hemithyroidectomies and 3 total thyroidectomies associated, respectively, with homolateral or bilateral CCND. Serum calcium, ionized calcium, and parathyroid hormone (PTH) levels at post-operative day (POD) 1 and 2 and at 2 weeks after surgery were monitored. Finally, we compared the data obtained with a cohort of patients who underwent surgery without the adoption of NIR-AF. RESULTS: With the use of NIR-AF, 18/20 PGs were identified, of which 7/18 were preserved exclusively thanks to the use of autoflorescence. The technique also made it possible to identify and isolate three PGs from the surgical specimen, which were subsequently transplanted only after intraoperative histological confirmation. On POD-1, 3/7 patients (42.8%) were hypocalcemic; on POD-2 and after 2 weeks only 1/7 patient (14.2%) was hypocalcemic. Comparing the two groups, we highlighted that the utilization of NIR-AF was related to a significant decrease of median serum (p = 0.026) and ionized calcium levels (p = 0.017) 2 weeks after surgery. Using this new technology, in no case did definitive histological examination reveal the presence of PGs in the surgical specimen, reaching an accuracy of 100%. CONCLUSIONS: In our cohort of patients who underwent total (pharyngo)laryngectomy with hemi- or total thyroidectomy, the use of near-infrared autofluorescence improved medium term postoperative hypocalcemia rates. This new technology helps to achieve a better calcemic outcome compared to the standard naked eye approach, since it helps the surgeon to identify and preserve parathyroid glandular tissue with a lower incidence of post-operative hypocalcemia.

Benign Peripheral Non-cranial Nerve Sheath Tumors of the Neck.

Benign peripheral non-cranial nerve sheath tumors are rare lesions, including both schwannomas and neurofibromas. These tumors arise from Schwann cells, and may originate from any peripheral, cranial, or autonomic nerve. Most of them are localized and sporadic but multifocal systemic forms can occur. Cervical sympathetic chain, brachial plexus, cervical plexus and spinal roots and nerves are the major nerve systems commonly affected. Dumbbell-shaped intra- and extradural tumors occur most commonly in the cervical spine, as well as purely extradural and paravertebral tumors. The management of these tumors has improved greatly owing to the developments in imaging techniques and surgical innovations such as endoscopically assisted approaches and robotic surgery. Microsurgical intracapsular excision of the tumor helped by the use of intraoperative fluorescent dyes and intraoperative neurophysiological monitoring minimize postoperative neural deficit, since most schwannomas are encapsulated. Most tumors can be removed with a low rate of complications and recurrence. Radiotherapy should be considered for growing lesions that are not amenable to surgery. In asymptomatic patients, observation and serial scans is an option for elderly infirm patients.

Skeletal Muscle Depletion and Major Postoperative Complications in Locally-Advanced Head and Neck Cancer: A Comparison between Ultrasound of Rectus Femoris Muscle and Neck Cross-Sectional Imaging.

Skeletal muscle mass (SMM) depletion has been validated in many surgical fields as independent predictor of complications through cross-sectional imaging. We evaluated SMM depletion in a stage III-IV head and neck cancer cohort, comparing the accuracy of CT/MRI at C3 level with ultrasound (US) of rectus femoris muscle (RF) in terms of prediction of major complications. Patients submitted to surgery were recruited from 2016 to 2021. SMM was estimated on CT/MRI by calculating the sum of the cross-sectional area (CSA) of the sternocleidomastoid and paravertebral muscles at C3 level and its height-indexed value (cervical skeletal muscle index, CSMI) and on US by computing the CSA of RF. Specific thresholds were defined for both US and CT/MRI according to ROC curve in terms of best prediction of 30-day major complications to detect sarcopenic subjects (40-53%). Sixty-five patients completed the study. At univariate analysis, major complications were associated to lower RF CSA, lower CSA at C3 level and lower CSMI, together with previous radiotherapy, higher ASA score and higher modified frailty index (mFI). At multivariate analysis RF CSA (OR 7.07, p = 0.004), CSA at C3 level (OR 6.74, p = 0.005) and CSMI (OR 4.02, p = 0.025) were confirmed as independent predictors in three different models including radiotherapy, ASA score and mFI. This analysis proved the value of SMM depletion as predictor of major complications in a head and neck cancer cohort, either defined on cross-sectional imaging at C3 or on US of RF.

Early diagnosis of oral squamous cell carcinoma may ensure better prognosis: A case series.

Oral squamous cell carcinoma is an extremely malignant tumour: in order to reduce mortality and morbidity, early diagnosis and treatment is the clinician's best weapon.

The importance of the patient's perspective in function-sparing parotid surgery for benign neoplasms: clinical reappraisal.

OBJECTIVE: Function-sparing surgery is the cornerstone for the treatment of benign parotid neoplasms. We assessed the incidences and determinants of the main postoperative complications, reappraising their influence on the patient's quality of life (QoL). METHODS: Patients who underwent parotid surgery for benign neoplasms were reviewed (2016-2019). Parotidectomy Outcome Inventory-8 (POI-8) and condition-specific questionnaires were used to investigate the patient's perspective. RESULTS: We enrolled 211 patients. Preservation of the posterior branch of the great auricular nerve (GAN) seemed to reduce early dysfunction (87% vs 96%, p = 0.053), but not the late one. Deep lobe dissection and resection of more than one parotid segment favoured first bite syndrome (FBS) and Frey's syndrome (FS), respectively (16% vs 3%, p = 0.003; 37% vs 15%, p = 0.003). Neither GAN impairment, FBS, nor FS influenced patient QoL. Facial weakness affected 19 patients (9%), being more likely after total parotidectomy (23% vs 7%, p = 0.034). According to POI-8, QoL was mainly jeopardised by fear of revision surgery, especially in females (p = 0.005) and those experiencing early complications (p = 0.004). CONCLUSIONS: Reappraisal of the patient's perspective after functional parotid surgery is fundamental to tailor preoperative counselling.

Cocaine-Induced Midline Destructive Lesions: A Real Challenge in Oral Rehabilitation.

Cocaine abuse is associated with severe local effects on mucosal and osteocartilaginous structures, with a centrifugal spreading pattern from the nose, a condition known as cocaine-induced midline destructive lesions (CIMDL). When the soft or hard palate is affected, a perforation may occur, with subsequent oro-nasal reflux and hypernasal speech. Both diagnosis and therapy (surgical or prosthetic) constitute a serious challenge for the physician. The cases of three patients affected by cocaine-induced palatal perforation and treated with a palatal obturator at San Raffaele Dentistry department between 2016 and 2019 are presented. In addition, the literature was reviewed in search of papers reporting the therapeutic management in patients affected by cocaine-induced palatal perforation. All the patients in our sample suffered from oro-nasal reflux and hypernasal speech, and reported a significant impact on interpersonal relationships. The results at the delivery of the obturator were satisfactory, but the duration of such results was limited in two cases, as the progression of the disease necessitated continuous modifications of the product, with a consequent increase in costs and a reduction in patient satisfaction. In conclusion, the therapy for palatal defects in CIMDL includes both reconstructive surgery and prosthetic obturators, the latter being the only possibility in the event of active disease. It successfully relieves symptoms, but the long-term efficacy is strongly related to the level of disease activity.

Mucosal Melanoma of the Hard Palate: Surgical Treatment and Reconstruction.

Mucosal melanomas of the head and neck region are uncommon pathologies that can affect the oral cavity, and are characterized by a high rate of mortality. Considering the lack of knowledge regarding risk and prognostic factors, current best clinical practice is represented by a large surgical excision with disease-free margins, eventually associated with a reconstructive flap. Indeed, given the frequent necessity of postoperative radiotherapy and fast healing process, a reconstruction of the surgical gap is advisable. Even if several flaps have been most commonly used, the submental island flap represents a valid alternative thanks to local advantages and similar oncologic outcomes compared to free flaps.

High-risk early-stage oral tongue squamous cell carcinoma, when free margins are not enough: Critical review.

Oral tongue squamous cell carcinoma (OTSCC) is a quite peculiar disease from an anatomical and biological standpoint. An increasing amount of literature highlights the existence of a small subset of T1-T2N0 OTSCC, properly resected on a margin-dependent basis, which conversely proved higher than expected rates of loco-regional/distant failure and disease-specific mortality. These specific high-risk tumors might not have a margin-dependent disease and could possibly benefit from a more aggressive upfront loco-regional treatment, especially addressing the so-called T-N tract. Widespread adoption of a histopathological risk model would allow early recognition of these high-risk diseases and, consequently, intensification of the traditional treatment strategies in that specific niche. We reviewed the available knowledge trying to shed light on the potential determinants of the dismal prognosis of these high-risk OTSCC, with special reference to the role of overlooked T-N tract involvement and possible alternatives in terms of elective neck management and risk stratification.

Trends in the Management of Non-Vestibular Skull Base and Intracranial Schwannomas.

The aim of this review is to analyze the latest trends in the management of non-vestibular skull base and intracranial schwannomas in order to optimize tumor control and quality of life. Non-vestibular cranial nerve schwannomas are rare lesions, representing 5-10% of cranial nerve schwannomas. Management decisions should be individualized depending on tumor size, location and associated functional deficits. Generally, large sized schwannomas exerting significant mass effect with increased intracranial pressure are treated surgically. In some cases, even after optimal skull base resection, it is not possible to achieve a gross total resection because tumor location and extent and/or to reduce morbidity. Thus, subtotal resection followed by stereotactic radiosurgery or fractioned radiotherapy offers an alternative approach. In certain cases, stereotactic radiosurgery or radiotherapy alone achieves good tumor control rates and less morbidity to gross total resection. Finally, given the slow growth rate of most of these tumors, observation with periodic radiographic follow-up approach is also a reasonable alternative for small tumors with few, if any, symptoms.

Oral Cancer and Precancer: A Narrative Review on the Relevance of Early Diagnosis.

Oral cancer (OC) is an uncommon malignancy in Western countries, being one of the most common cancers in some high-risk areas of the world. It is a largely preventable cancer, since most of the different risk factors identified, such as tobacco use, alcohol consumption, and betel nut chewing, are behaviors that increase the likelihood of the disease. Given its high mortality, early diagnosis is of utmost importance. Prevention and the anticipation of diagnosis begin with identification of potentially malignant lesions of the oral mucosa and with local conditions promoting chronic inflammation. Therefore, every lesion must be recognized promptly and treated adequately. The clinical recognition and evaluation of oral mucosal lesions can detect up to 99% of oral cancers/premalignancies. As stated by the World Health Organization, any suspicious lesion that does not subside within two weeks from detection and removal of local causes of irritation must be biopsied. Surgical biopsy remains the gold standard for diagnosis of oral cancer. Adjunctive tools have been developed and studied to help clinicians in the diagnostic pathway, such as toluidine blue vital staining and autofluorescence imaging. In the near future other methods, i.e., identification of salivary markers of progression may help in reducing mortality due to oral cancer.

Low skeletal muscle mass as predictor of postoperative complications and decreased overall survival in locally advanced head and neck squamous cell carcinoma: the role of ultrasound of rectus femoris muscle.

PURPOSE: Skeletal muscle mass (SMM) depletion and sarcopenia as predictors of postoperative complications and poorer overall survival (OS) have been validated in many surgical fields through cross-sectional imaging (CT, MRI), with potential limitations. We evaluated it in a stage III-IV head and neck squamous cell carcinoma (HNSCC) surgical cohort through ultrasound (US) of rectus femoris muscle (RF), a quick, cheap, repeatable alternative. METHODS: Patients submitted to surgical treatment with curative purpose were recruited and prospectively evaluated through clinical, biometric, biochemical, surgical, pathological and functional prognosticators and with preoperative US of RF with regards to 30-day complications and OS. RESULTS: Forty-seven patients completed the study. RF cross-sectional area (RF-CSA) was used to identify patients with low SMM (CSA ≤ 0.97 cm2: 18/47, 38.3%). RF-CSA was lower in complicated cases (0.95 ± 0.48 vs 1.41 ± 0.49 cm2; p = 0.003), remaining the only independent predictor of postoperative complications at multivariate analysis, with a model including ASA score and modified Frailty index (OR 9.84; p = 0.004). SMM depletion significantly impaired OS (13.6 ± 2.9 vs 26.3 ± 2.1 months; p = 0.017), being its only independent prognosticator at multivariate Cox regression analysis (OR 4.42; p = 0.033). CONCLUSION: RF-CSA, evaluated with US, seems a reliable method for identification of patients with low SMM in a stage III-IV HNSCC cohort, defining a subset at high-risk of 30-day complications and poorer OS.

Pre-operative transnasal endoscopy as a predictor of difficult airway: A prospective cohort study.

BACKGROUND: Consequences of failed endotracheal intubation can be catastrophic and predicting difficulty is therefore a critical issue. There is no consensus on the best way to predict difficulty. OBJECTIVE: To evaluate the role of transnasal flexible endoscopic laryngoscopy (TFEL), a minimally invasive procedure, in the prediction of difficult intubation. DESIGN: Prospective cohort study. SETTING: San Raffaele Hospital, Milan, a tertiary university hospital. PATIENTS: One hundred and sixty nine adults scheduled for elective ear, nose and throat surgery under general anaesthesia with pre-operative TFEL. INTERVENTION: In addition to routine pre-operative evaluation by an anaesthesiologist, glottis exposure during TFEL was assessed with a scoring system similar to the modified Cormack-Lehane (MCL). MAIN OUTCOME MEASURES: The extent to which TFEL improves the prediction of difficult direct laryngoscopy, measured with the MCL score, and of difficult intubation, measured with the intubation difficulty scale score. RESULTS: When added to bedside evaluation, TFEL performed during tongue protrusion significantly (P = 0.005) improved the prediction of MCL. The area under the receiver operating characteristics curve was 0.75 [95% confidence interval (CI) 0.67 to 0.83] vs. 0.65 (95% CI 0.58 to 0.74). For the intubation difficulty scale (P = 0.049), the area under the receiver operating characteristics curve was 0.70 (95% CI 0.61 to 0.80) vs. 0.66 (95% CI 0.58 to 0.74). CONCLUSION: TFEL is a useful tool in predicting difficult intubation, improving predictability of routine bedside evaluation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02671877.

The prognostic value of anterior commissure involvement in T1 glottic cancer: A systematic review and meta-analysis.

OBJECTIVE: The anterior commissure is considered a laryngeal subsite, but it is not taken into account in the current T-staging system. The impact of anterior commissure involvement (ACI) on the oncologic outcomes of T1 glottic tumors has not been well defined and remains controversial. The aim of this study was to assess the influence of ACI in the prognosis of T1 glottic tumors. METHODS: A systematic review and meta-analysis of observational studies was performed by including studies published up to July 2019. Studies were selected if they had investigated the local control rate (LCR) at 5 years of clinical stage I (T1 and N0) glottic squamous cell carcinoma with and without ACI. The difference in LCR at 5 years between T1 glottic tumors without and with ACI was evaluated. RESULTS: The meta-analysis showed that the difference in LCR at 5 years between T1 glottic tumors without and with ACI is 12% (95% confidence interval: 8%-16%, p < 0,0001, I2 = 34.81%). CONCLUSIONS: Our study pointed out that the anterior commissure involvement is a negative prognostic factor in LCR at 5 years for T1 glottic tumors. Our results suggest the need to consider ACI in the T staging of glottic tumors. Laryngoscope, 130:1932-1940, 2020.

Fine needle aspiration cytology for parotid neoplasms: risk of malignancy through inconclusive results and lower grade tumors.

PURPOSE: Fine needle aspiration cytology (FNAC) is a commonly performed procedure for parotid masses, although its accuracy in detecting malignancies widely varies through different series. We evaluated our single-center cohort of parotidectomies to highlight possible limitations of preoperative FNAC. METHODS: Seven hundred and eighteen consecutive patients submitted to parotid surgery at San Raffaele Scientific Institute (Milan) were retrospectively evaluated (2002-2018). Five hundred and fifty four FNAC were analyzed. FNAC accuracy was assessed with and without inclusion of "inconclusive" results. The peculiar role of lower grade primary parotid cancers was investigated. RESULTS: FNAC reports were "diagnostic" in 502 cases (90.4%) and "inconclusive" in 52 (9.6%). Histopathology revealed 488 benign lesions (88.1%) and 66 malignancies (11.9%). FNAC sensitivity, specificity, PPV, NPV and accuracy in detecting malignancies were 59%, 99%, 89%, 95%, and 95%, respectively. Sensitivity fell to 48%, when "inconclusive" FNAC was computed. Within 66 parotid cancers, FNAC could discriminate malignancy in 32 cases (48.5%), provide proper grading in 21 (31.8%), and precise histopathological diagnosis in 15 (22.7%). Malignancy was more likely in patients with "inconclusive" FNAC than in those with "diagnostic" cytologies (23.1% vs 10.8%, p = 0.003). Low-intermediate-grade primary parotid cancers were associated to a higher rate of FNAC failure in comparison with high-grade ones (86.4% vs 19.0%; p < 0.001). CONCLUSION: FNAC is an important tool for preoperative assessment of parotid masses, though its sensitivity in detecting malignancy remains poor. "Inconclusive" FNAC results could further jeopardize FNAC accuracy and should elicit resorting to additional tests, especially when a lower grade parotid cancer is suspected.

Long-term Swallowing Function, Pulmonary Complications, and Quality of Life after Supracricoid Laryngectomy.

OBJECTIVES: Long-term effects of supracricoid laryngectomies are nowadays under discussion. The purpose of this study was to detect the prevalence of chronic aspiration and incidence of pulmonary complications, to investigate possible influencing factors, and to analyze dysphagia-related quality of life in a cohort of patients who recovered swallowing function after undergoing supracricoid laryngectomies. STUDY DESIGN: Retrospective observational study. SETTING: San Raffaele Hospital, Vita-Salute University, Milan, Italy. METHODS: A cohort of 39 patients who recovered swallowing function free of disease after a minimum 3-year follow-up period was retrospectively investigated between October and December 2017-clinically with the Pearson's Scale and M. D. Anderson Dysphagia Inventory and instrumentally with fiberoptic endoscopic evaluation of swallowing. RESULTS: Chronic aspiration was demonstrated in a significant portion of patients (clinically in 33.3% and instrumentally in 35.9%). Aspiration was influenced by advanced age at surgery (P = .020). Type of surgical procedure, resection of 1 arytenoid cartilage, postoperative rehabilitation with a speech-language therapist, radiotherapy, age at consultation, and length of follow-up did not influence the prevalence of aspiration. Pulmonary complications affected 5 patients; incidence of pulmonary complications was related to aspiration and was favored by poor laryngeal sensation/cough reflex. Aspiration significantly affected quality of life. CONCLUSIONS: Chronic aspiration is frequent and affects patients' quality of life. However, incidence of pulmonary complications is low; therefore, oral feeding should not be contraindicated for aspirating patients. Preservation of laryngeal sensation and cough reflex is mandatory to prevent pulmonary complications.