Obesity-Associated Hepatic Steatosis, Somatotropic Axis Impairment, and Ferritin Levels Are Strong Predictors of COVID-19 Severity.

The full spectrum of SARS-CoV-2-infected patients has not yet been defined. This study aimed to evaluate which parameters derived from CT, inflammatory, and hormonal markers could explain the clinical variability of COVID-19. We performed a retrospective study including SARS-CoV-2-infected patients hospitalized from March 2020 to May 2021 at the Umberto I Polyclinic of Rome. Patients were divided into four groups according to the degree of respiratory failure. Routine laboratory examinations, BMI, liver steatosis indices, liver CT attenuation, ferritin, and IGF-1 serum levels were assessed and correlated with severity. Analysis of variance between groups showed that patients with worse prognoses had higher BMI and ferritin levels, but lower liver density, albumin, GH, and IGF-1. ROC analysis confirmed the prognostic accuracy of IGF-1 in discriminating between patients who experienced death/severe respiratory failure and those who did not (AUC 0.688, CI: 0.587 to 0.789, p < 0.001). A multivariate analysis considering the degrees of severity of the disease as the dependent variable and ferritin, liver density, and the standard deviation score of IGF-1 as regressors showed that all three parameters were significant predictors. Ferritin, IGF-1, and liver steatosis account for the increased risk of poor prognosis in COVID-19 patients with obesity.

Interleukin 18 and IL-18 BP response to Sars-CoV-2 virus infection.

The immune response to the SARS-CoV-2 infection is crucial to the patient outcome. IL-18 is involved in the lymphocyte response to the disease and it is well established its important role in the complex developing of the host response to viral infection. This study aims at the analysis of the concentrations of IL-18, IL-18BP, INF-γ at the onset of the SARS-CoV-2 infection. The serum levels of measured interleukins were obtained through enzyme-linked immunosorbent assay. Furthermore, the free fraction of IL-18 was numerically evaluated. The enrolled patients were divided in two severity groups according to a threshold value of 300 for the ratio of arterial partial pressure of oxygen and fraction of inspired oxygen fraction and according to the parenchymal involvement as evaluated by computerized tomography at the admittance. In the group of patients with a more severe disease, a significant increase of the IL-18, INF-γ and IL-18BP levels have been observed, whereas the free IL-18 component values were almost constant. The results confirm that, at the onset of the disease, the host response keep the inflammatory cytokines in an equilibrium and support the hypothesis to adopt the IL-18BP modulation as a possible and effective therapeutic approach.

Breast imaging screening in a BRCA1-mutated lactating patient: A potential pitfall mimicking malignancy.

Breast imaging screening during lactation poses a real clinical challenge, especially in high-risk patients. We presented the case of a 34-year-old BRCA1-mutated woman showing marked, asymmetric background parenchymal enhancement on the right breast suspicious for malignancy in the context of annual screening magnetic resonance imaging. The patient revealed that she was still occasionally breastfeeding her two-year-old child only from right side. Ultrasound evaluation reported typical benign lactational findings on the right enhancing breast. An in-depth understanding of expected/ physiologic breast changes during lactation and an accurate clinical-radiological correlation are required to appropriately guide patient management and avoid misdiagnosis.

US-Elastography for Breast Lesion Characterization: Prospective Comparison of US BIRADS, Strain Elastography and Shear wave Elastography.

PURPOSE: To evaluate the diagnostic performance of strain elastography (SE) and 2 D shear wave elastography (SWE) and SE/SWE combination in comparison with conventional multiparametric ultrasound (US) with respect to improving BI-RADS classification results and differentiating benign and malignant breast lesions using a qualitative and quantitative assessment. MATERIALS AND METHODS: In this prospective study, 130 histologically proven breast masses were evaluated with baseline US, color Doppler ultrasound (CDUS), SE and SWE (Toshiba Aplio 500 with a 7-15 MHz wide-band linear transducer). Each lesion was classified according to the BIRADS lexicon by evaluating the size, the B-mode and color Doppler features, the SE qualitative (point color scale) and SE semi-quantitative (strain ratio) methods, and quantitative SWE. Histological results were compared with BIRADS, strain ratio (SR) and shear wave elastography (SWE) all performed by one investigator blinded to the clinical examination and mammographic results at the time of the US examination. The area under the ROC curve (AUC) was calculated to evaluate the diagnostic performance of B-mode US, SE, SWE, and their combination. RESULTS: Histological examination revealed 47 benign and 83 malignant breast lesions. The accuracy of SR was statistically significantly higher than SWE (sensitivity, specificity and AUC were 89.2 %, 76.6 % and 0.83 for SR and 72.3 %, 66.0 % and 0.69 for SWE, respectively, p = 0.003) but not higher than B-mode US (B-mode US sensitivity, specificity and AUC were 85.5 %, 78.8 %, 0.821, respectively, p = 1.000). CONCLUSION: Our experience suggests that conventional US in combination with both SE and SWE is a valid tool that can be useful in the clinical setting, can improve BIRADS category assessment and may help in the differentiation of benign from malignant breast lesions, with SE having higher accuracy than SWE.

Breast Cancer and Multiple Primary Malignant Tumors: Case Report and Review of the Literature.

Multiple primary malignant neoplasms are multiple tumors with different pathogenetic origin. They may be synchronous or metachronous. The management of these conditions represents an interesting clinical scenario. A crucial aspect is the decision regarding which tumor to treat initially, and how to schedule further treatments according to individual tumor risk. This process involves a multidisciplinary physician team to ensure favorable outcomes. We describe a case report of a female patient affected by primary synchronous tumors of the breast and pectoral skin, which raised a series of diagnostic, etiological and therapeutic issues persuading us to carry out a critical review of the literature.

Morphological and Semiquantitative Kinetic Analysis on Dynamic Contrast Enhanced MRI in Triple Negative Breast Cancer Patients.

RATIONALE AND OBJECTIVES: The aim of this study was to retrospectly investigate the association between different breast cancer (BC) immunohistochemical subtypes and morphological and semiquantitative kinetic analysis on breast magnetic resonance imaging (MRI) performed before surgery treatment. Specifically we aimed to assess MRI features of triple-negative breast cancer (TNBC) compared to the other BC subtypes (nTNBC). MATERIALS AND METHODS: Patients undergone to breast MRI and then diagnosed with BC by core-needle biopsy were included. The MRI morphological and kinetic features were studied. Parametric and non-parametric tests were used, as appropriate. RESULTS: Seventy-five BC patients were considered, 30 patients included in TNBC Group and 45 patients included in nTNBC Group. We found in TNBC Group a greater mean lesion size (P <0.001), a rim enhancement imaging (P=0.003), and a higher intratumoral signal intensity on T2-weighted images (P=0.03) with respect to nTNBC Group. We noticed that TNBC patients presented a lower grade of BPE when compared to the nTBC Group (P< 0.02). TNBC Group showed lower EPeak values (P=0.003) and higher SER values (P=0.02) with respect to the nTNBC Group. In addition, stratifying kinetics parameters according to the tumor grade, the TNBC Group presented higher tumor grade (G3) (P< 0.005) and this subgroup had higher SER values when compared to TNBCs showing a lower tumor grade (G1 and G2) (P=0.03). CONCLUSION: After validation by large-scale studies, the morphological and semiquantitative kinetic analysis on dynamic contrast enhanced MRI may help in the pretreatment risk stratification of patients with TNBC and in evidence-based clinical decision support.

The Complementary Role of Imaging and Tumor Biomarkers in Gynecological Cancers: An Update of the Literature

Gynecological tumors, including endometrial, cervical and ovarian cancer, have increased in incidence over time. The widespread introduction of screening programs and advances in diagnostic imaging methods has lead to a progressive increase in gynecological cancer detection. Accurate diagnosis and proper monitoring of disease remain the primary target for a successful treatment. In the last years, knowledge about cancer biomarkers has considerably increased providing great opportunities for improving cancer detection and treatment. In addition, in the last few years there has been an important development of imaging techniques. Nowadays, a multimodal approach including the evaluation of serum tumor biomarkers combined with imaging techniques, seems to be the best strategy for assessing tumor presence, spread, recurrence, and/or the response to treatment in female cancer patients In this review we provide an overview of the application of biomarkers combined with novel imaging methods and highlight their roles in female cancer diagnosis and follow-up.

Highlights on MRI of the fetal body.

Fetal MRI is a level III diagnostic tool performed subsequently a level II prenatal ultrasound (US), in cases of inconclusive ultrasonographic diagnosis or when a further investigation is required to confirm or improve the diagnosis, to plan an appropriate pregnancy management. Fetal MRI plays an increasingly important role in the prenatal diagnosis of fetal neck, chest and abdominal malformations, even if its role has been amply demonstrated, especially, in the field of fetal CNS anomalies. Due to its multiparametricity and multiplanarity, MRI provides a detailed evaluation of the whole fetal respiratory, gastrointestinal and genitourinary systems, especially on T2-weighted (W) images, with a good tissue contrast resolution. In the evaluation of the digestive tract, T1-W sequences are very important in relation to the typical hyperintensity of the large intestine, due to the presence of meconium. The objective of this review is to focus on the application of fetal MRI in neck, chest and abdominal diseases.

Lipofilling Outcomes Mimicking Breast Cancer Recurrence: Case Report and Update of the Literature.

Breast lipofilling uses autologous fat grafting to correct breast defects after radical or conservative surgery. After early concerns regarding its application in reconstruction after breast cancer (BC), in 2009 the American Society of Plastic Surgeons formed a task force to assess the indications, safety and efficacy of autologous fat grafting. We report the case of a woman who came to our attention for a painful swelling of the left breast. She had undergone breast-conserving therapy for BC, followed by lipofilling. The breast ultrasound (US) examination showed diffuse structural alteration and multiple hypoechoic areas with acoustic shadowing, mainly localized in the subcutaneous tissue. After pharmacological treatment and short-term follow-up US examination, considering the persistence of the clinical symptoms and structural alterations, we performed contrast-enhanced magnetic resonance imaging, that showed multiple enhancing areas in the left breast. Suspecting local tumor recurrence, we carried out US-guided breast core-biopsy, whose histological examination documented liponecrosis. This observation raised a series of diagnostic and therapeutic issues highlighting the diagnostic pitfalls that the radiologist may encounter during the evaluation of patients who have undergone BC surgery and breast reconstruction through lipofilling.

Magnetic Resonance Imaging after Breast Oncoplastic Surgery: An Update.

Breast-oncoplastic surgery, allowing local tumor control and a better cosmetic outcome, is oncologically safe when applied to early-stage breast cancer. Breast cancer recurrence following conservative therapy may occur during the first 5 years after treatment, with a peak incidence after 2 years. Therefore, during the follow-up period, patients undergo a series of ultrasound (US) and mammographic examinations. However, after surgery and radiation therapy, several modifications occur in the treated breast, causing difficulties in image interpretation, especially when local recurrence is suspected. Although not included in routine follow-up, magnetic resonance imaging (MRI) is often used in clinical practice, being considered more sensitive than the conventional imaging examinations in discriminating between postsurgical tissue modifications and tumor recurrence. In this review article, we analyze expected and pathologic breast MRI findings after conservative oncoplastic surgery compared to US and mammographic findings in order to distinguish local recurrence and avoid potential pitfalls in image interpretation.

Clinical, histological, and ultrasound follow-up of breast reconstruction with one-stage muscle-sparing "wrap" technique: A single-center experience.

BACKGROUND: Prepectoral implant placement and complete coverage with porcine acellular matrix after mastectomy is a new concept in breast surgery presented in few cases in the literature. This paper aimed to present our single-center experience in one-stage breast reconstruction muscle-sparing "wrap" technique by evaluating clinical and aesthetic outcomes, ultrasound and histological examination, and patient quality of life. METHODS: From January 2014 to January 2017, 52 patients (40 unilateral, 12 bilateral) underwent one-stage muscle-sparing breast reconstructions with Braxon® acellular dermal matrix and implant. In 3 patients, a surgical biopsy and histological examination with immunohistochemical analysis of the periprosthetic tissue were performed. All patients underwent breast ultrasound examination, and the occurrence of capsular contracture was assessed through the Baker classification and by measuring the mammary compliance scores with the Antoon Paar Mammary compliance system. Breast appearance was evaluated using a visual analogue scale (VAS) and in terms of quality of life using the EOCRT QLQ C-30 and QLQ BR-23 questionnaires. RESULTS: Early and late postoperative complications are reported. Histological and ultrasound evaluation showed a complete integration of the matrix. According to the VAS scale, the EOCRT QLQ C-30, and QLQ BR-23, patients' satisfaction resulted in a high score in terms of quality of life and aesthetic outcomes. CONCLUSION: The results of this new surgical technique in selected cases are promising in terms of effectiveness and low rate of postoperative complications, but further long-terms evaluations are required.

Role of Galectin-3 Combined with Multi- Detector Contrast Enhanced Computed Tomography in Predicting Disease Recurrence in Patients with Ovarian Cancer

Galectin-3 (Gal-3) is an endogenous ß-galactoside-binding lectin, playing an important role in the pathogenesis of multiple malignancies. Aim of the study was to evaluate in a group of patients treated for ovarian cancer (EOC), the role of Gal-3 combined with multi-detector contrast-enhanced computed tomography (MDCT), as predictor of recurrence disease. Seventeen follow-up patients with recurrent ovarian cancer and 13 follow-up patients with stable ovarian disease, who performed MDCT at one-year follow-up after cytoreductive treatment, were enrolled. Serum Gal-3 concentrations were determined by using ELISA method. Twenty healthy controls were included in the analysis. Two radiologist blinded to patients status, reviewed MDCT exams, recording the following signs of disease recurrence: local tumor spread, enlarged lymph-nodes, carcinomatosis implants and metastases. We calculated the respective threshold values of Gal- 3 identified by ROC curve analysis for each imaging findings related to disease recurrence : lymphoadenopathies 92.45 ng/ml (AUC: 0.81, Se=91% Spe=73%), carcinomatosis 85.95 ng/ml (AUC:0.93 Se= 93.7%, Spe=92.8%), local tumor spread 99.05 (AUC:0.90, Se=100%, Spe=73% ) and metastasis 99.05ng/ml (AUC :0,78, Se=100% , Spe=70%). A significant correlation between high Gal-3 serum levels and presence of local tumor spread (n=11/17, p:0.001), carcinomatosis (n=16/17, p:0.00), lymphoadenopathies (n=15/17, p:0.00) and metastasis (n=11/17, p:0.003) related with recurrence disease was observed. Patients with recurrence of ovarian cancer presents higher Gal-3 values compared to women with stable diseases. Gal-3 combined to CECT should be used to improve the monitoring of EOC patients.

Magnetic resonance imaging tumor regression shrinkage patterns after neoadjuvant chemotherapy in patients with locally advanced breast cancer: Correlation with tumor biological subtypes and pathological response after therapy.

The objective of this study is to analyze magnetic resonance imaging shrinkage pattern of tumor regression after neoadjuvant chemotherapy and to evaluate its relationship with biological subtypes and pathological response. We reviewed the magnetic resonance imaging studies of 51 patients with single mass-enhancing lesions (performed at time 0 and at the II and last cycles of neoadjuvant chemotherapy). Tumors were classified as Luminal A, Luminal B, HER2+, and Triple Negative based on biological and immunohistochemical analysis after core needle biopsy. We classified shrinkage pattern, based on tumor regression morphology on magnetic resonance imaging at the II cycle, as concentric, nodular, and mixed. We assigned a numeric score (0: none; 1: low; 2: medium; 3: high) to the enhancement intensity decrease. Pathological response on the surgical specimen was classified as complete (grade 5), partial (grades 4-3), and non-response (grades 1-2) according to Miller and Payne system. Fisher test was used to relate shrinkage pattern with biological subtypes and final pathological response. Seventeen patients achieved complete response, 25 partial response, and 9 non-response. A total of 13 lesions showed nodular pattern, 20 concentric, and 18 mixed. We found an association between concentric pattern and HER2+ (p < 0.001) and mixed pattern and Luminal A lesions (p < 0.001). We observed a statistical significant correlation between concentric pattern and complete response (p < 0.001) and between mixed pattern and non-response (p = 0.005). Enhancement intensity decrease 3 was associated with complete response (p < 0.001). Shrinkage pattern and enhancement intensity decrease may serve as early response indicators after neoadjuvant chemotherapy. Shrinkage pattern correlates with tumor biological subtypes.

Wire-guided Localization in Non-palpable Breast Cancer: Results from Monocentric Experience.

BACKGROUND: Breast-conserving surgery (BCS) is considered the gold-standard treatment for early breast cancer. Ultrasound-guided percutaneous biopsy or stereotactic biopsy of a breast lesion allows preoperative histological diagnosis. Various techniques have been proposed for identifying non-palpable breast tumors, but the most popular method is the wire-guided localization (WGL) technique. The aim of this study was to propose an alternative technique for optimizing the WGL procedure, facilitating breast surgery and reducing complications. PATIENTS AND METHODS: We performed a prospective study on 40 patients with a single non-palpable breast lesion. For the preoperative localization of mammary lesions, patients were divided randomly into two groups: 20 patients underwent conventional WGL technique and 20 underwent 'optimized' personalized technique. RESULTS: In the group treated with the optimized technique, dislocation of the wire occurred in only 2/20 cases, whereas in those with the conventional technique, dislocation occurred in 9/20 cases (p=0.03). In 5/20 cases of the conventional WGL technique, the wire was accidentally cut by the surgeon, whereas no similar complications were observed in the group that underwent the optimized technique (p=0.047). Re-excision of the surgical margins was necessary in 6/20 cases with the conventional technique, while re-excision was not required for any case using the optimized technique (p=0.02). CONCLUSION: The proposed optimized technique ensures good esthetic results, enabling the surgeon to identify the lesion and perform oncoplastic breast surgery, and allows surgical time to be reduced.

Biparametric Magnetic Resonance Imaging as an Adjunct to CA125 and HE4 to Improve Characterization of Large Ovarian Masses.

BACKGROUND/AIM: Aim of the present study was to assess the diagnostic value of unenhanced biparametric magnetic resonance imaging (Bp-MRI) as adjunct to CA125 and human epididymis protein 4 (HE4) in the characterization of large ovarian masses. PATIENTS AND METHODS: Bp-MRI and dynamic contrast-enhanced (DCE) imaging of 53 patients with large ovarian masses were retrospectively analyzed and compared to histological diagnosis. The results of Bp-MRI and DCE were assessed by two readers in consensus for each technique individually compared to each other and then with HE4 and CA125. RESULTS: Sensitivity, specificity, negative predictive values and positive predictive values for Bp-MRI and DCE were 92.3%, 91.4%, 94.1%, 88.9% and 84.6%, 94.3%, 89.2%, 91.7%, respectively. Both Bp-MRI and DCE were significant predictors of outcome. Among biomarkers, HE4 was significant. Considering the area under receiver operating characteristic curve the model including Bp-MRI and HE4 was not significantly different from the model including DCE and HE4. CONCLUSION: Bp-MRI in addition to HE4, especially in women of pre-menopausal age, could improve the characterization of large ovarian masses.

Breast MRI in patients with unilateral bloody and serous-bloody nipple discharge: a comparison with galactography.

PURPOSE: Assessing the role of breast MRI compared to galactography in patients with unilateral bloody or serous-bloody nipple discharge. MATERIALS AND METHODS: Retrospective study including 53 unilateral discharge patients who performed galactography and MRI. We evaluated the capability of both techniques in identifying pathology and distinguishing between nonmalignant and malignant lesions. Lesions BIRADS 1/2 underwent follow-up, while the histological examination after surgery has been the gold standard to assess pathology in lesions BIRADS 3/4/5. The ROC analysis was used to test diagnostic MRI and galactography ability. RESULTS: After surgery and follow-up, 8 patients had no disease (15%), 23 papilloma (43%), 11 papillomatosis (21%), 5 ductal cancer in situ (10%), and 6 papillary carcinoma (11%) diagnoses. Both techniques presented 100% specificity; MRI sensitivity was 98% versus 49% of galactography. Considering MRI, we found a statistical association between mass enhancement and papilloma (P < 0.001; AUC 0.957; CI 0.888-1.025), ductal enhancement and papillomatosis (P < 0.001; AUC 0.790; CI 0.623-0.958), segmental enhancement and ductal cancer in situ (P = 0.007; AUC 0.750; CI 0.429-1.071), and linear enhancement and papillary cancer (P = 0.011). CONCLUSIONS: MRI is a valid tool to detect ductal pathologies in patients with suspicious bloody or serous-bloody discharge showing higher sensitivity and specificity compared to galactography.

Beyond laparoscopy: 3-T magnetic resonance imaging in the evaluation of posterior cul-de-sac obliteration.

OBJECTIVES: Endometriosis is the ectopic localization of endometrial glands. Symptoms include a wide variety of chronic pelvic pain. Ovarian endometriosis represents the most frequent site of implantation followed by the Douglas pouch which is undepicted unless peritoneal fluid is present. Pelvic exams may be reported as normal in 40% of evaluations, although multiple nodularities are located in this region. Nowadays, laparoscopy represents the standard technique for endometriosis evaluation. However, magnetic resonance imaging (MRI) remains the best noninvasive technique for the evaluation of pelvic lesions. According to the importance of a precise preoperative diagnosis of deep infiltrative endometriosis involving the Douglas pouch, we evaluated feasibility of a 3-T system in the evaluation of this particular region. METHODS: We enrolled 19 women coming with either ultrasound or anamnestic suspicion of endometriosis. Pelvic MRI examination was performed on the 3-T system. We applied a standard exam protocol including pulse sequences [single-shot fast spin echo (FSE)] and high-resolution T2W and T1W FSE sequences with and without FS. RESULTS: MRI diagnosed posterior cul-de-sac obliteration in 15/19 patients. MRI findings were compared with laparoscopy, thus obtaining the following statistical values: mean sensitivity, specificity, positive predictive value and negative predictive value, respectively, of 93%, 75%, 93% and 75%. Moreover, we calculated an interobserver agreement k value of 0.72 with a substantial degree of agreement between two radiologists of a sensitivity value of 93% and specificity value of 75%. CONCLUSIONS: Precise preoperative mapping of posterior cul-de-sac region is essential for a preoperative planning. In our work, the 3-T MRI was shown to be excellent in the evaluation of posterior cul-de-sac obliteration associated to an optimal evaluation of the uterosacral ligaments due to the higher contrast spatial resolution.

Cystosarcoma phylloides of the breast: a rare diagnosis. A case report and review of the literature.

Sarcoma of the breast is a rare condition, with one possible meaning of relapse ad metastastasize, and behaves biologically as a stromal tumor. Surgery is the first choise and mastectomy is the best procedure adopted in these tumors. The aim of our study was to assess diagnostic and treatment options for PT, based on a review of the literature and our experience with a case of breast sarcoma arising from a phyllodes tumor.

MRI and DWI: feasibility of DWI and ADC maps in the evaluation of placental changes during gestation.

OBJECTIVE: To establish if a correlation exists between apparent diffusion coefficient (ADC) values, obtained by diffusion-weighted imaging (DWI), and placental aging. METHOD: The study is divided into a retrospective phase and a prospective one.In the first phase, 145 pregnant women underwent fetal magnetic resonance imaging (MRI) for suspected disorders in several organs. We performed DWI (b value 0, 200 and 700 s/mm(2)) in all the fetuses, evaluating the patients in whom the whole placenta was visible.In the prospective phase, 50 women (52 fetuses) underwent MRI. We performed, in the same patient, two echo-planar sequences with b values of 0, 200 and 700, and 50, 200 and 700 s/mm(2), including the whole placenta.The ADC maps were calculated for all fetuses, divided into three groups based on gestational age (GA): group I: 20-26 weeks' gestation, II: 27-33, III: 34-40. RESULTS: In the retrospective phase, ADC values had a range from 1 to 2.4 mm(2)/s, showing a significant correlation between ADC values and GA.ADC values obtained by DWI with b value 0, 200 and 700 s/mm(2) had a range from 0.8 to 2.5 mm(2)/s, with an inverse correlation between ADC values and GA, whereas the ADC values with b value 50, 200 and 700 s/mm(2) did not show any statistical correlation (range: 1.5-1.7 mm(2)/s). CONCLUSION: DWI with ADC maps can not be considered markers for placental aging because they are affected by perfusional and circulatory motion.

Congenital stage 1 neuroblastoma evolved into stage 4s.

A newborn with a prenatally detected adrenal mass underwent complete resection of a stage 1 favorable histology neuroblastoma (NB) without MYC-N amplification. Two months later, the infant presented with a local recurrence and multiple hepatic metastases. Close follow-up without therapy was adopted for stage 4s NB. Enlarging tumor lesions were seen until the child was 8 months old, followed by later decrease in size. At 36 months of follow-up, the child is alive and disease-free. We describe this case of NB and its abnormally short evolution from stage 1 to stage 4s, despite initial surgery. Its spontaneous regression may help us understand the natural history of congenital NB.