Bronchiolitis after Combination Immunotherapy With Ipilimumab and Nivolumab in a Melanoma Patient.

Therapy with immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of metastatic melanoma but is also associated with various immune-related adverse events (AE), including pulmonary toxicity. Herein, we describe the case of a 60-year-old female with metastasized melanoma with BRAF mutation under combination immunotherapy with ipilimumab and nivolumab, who presented with a persistent, nonproductive cough for the last two months. Her CT-scan showed de novo bronchial inflammation and wall thickening in all lung fields. Initial treatment with antimicrobial treatment and inhalation corticosteroids did not resolve her symptoms, nor the radiologic abnormalities. Additional testing with transbronchial cryobiopsy showed a histologic picture of diffuse ill-formed granulomas and the presence of moderate chronic active inflammation of the respiratory epithelium, consistent with medication-related bronchiolitis. Bronchiolitis, as present in this case, has rarely been reported as an immune-related AE. A thorough diagnostic workup is mandatory as it remains a diagnosis of exclusion. Management consists of discontinuing ICIs and administering systemic corticosteroids. The addition of immunosuppressive agents (e, infliximab, cyclophosphamide, or mycophenolate mofetil) can be considered in refractory cases. In our case, clinical and radiologic resolution was achieved after discontinuing the ICI and treatment with high-dose prednisone. This case shows that although bronchiolitis is a rare immune-related side effect of ICIs, oncologists, and pulmonologists should always be aware of this relatively easily treatable AE.

Yield of Screening for COVID-19 in Asymptomatic Patients Before Elective or Emergency Surgery Using Chest CT and RT-PCR (SCOUT): Multicenter Study.

OBJECTIVE: To determine the yield of preoperative screening for COVID-19 with chest CT and RT-PCR in patients without COVID-19 symptoms. SUMMARY OF BACKGROUND DATA: Many centers are currently screening surgical patients for COVID-19 using either chest CT, RT-PCR or both, due to the risk for worsened surgical outcomes and nosocomial spread. The optimal design and yield of such a strategy are currently unknown. METHODS: This multicenter study included consecutive adult patients without COVID-19 symptoms who underwent preoperative screening using chest CT and RT-PCR before elective or emergency surgery under general anesthesia. RESULTS: A total of 2093 patients without COVID-19 symptoms were included in 14 participating centers; 1224 were screened by CT and RT-PCR and 869 by chest CT only. The positive yield of screening using a combination of chest CT and RT-PCR was 1.5% [95% confidence interval (CI): 0.8-2.1]. Individual yields were 0.7% (95% CI: 0.2-1.1) for chest CT and 1.1% (95% CI: 0.6-1.7) for RT-PCR; the incremental yield of chest CT was 0.4%. In relation to COVID-19 community prevalence, up to ∼6% positive RT-PCR was found for a daily hospital admission rate >1.5 per 100,000 inhabitants, and around 1.0% for lower prevalence. CONCLUSIONS: One in every 100 patients without COVID-19 symptoms tested positive for SARS-CoV-2 with RT-PCR; this yield increased in conjunction with community prevalence. The added value of chest CT was limited. Preoperative screening allowed us to take adequate precautions for SARS-CoV-2 positive patients in a surgical population, whereas negative patients needed only routine procedures.

Accuracy of prediction scores and novel biomarkers for predicting nonalcoholic fatty liver disease in obese children.

BACKGROUND: Accurate prediction scores for liver steatosis are demanded to enable clinicians to noninvasively screen for nonalcoholic fatty liver disease (NAFLD). Several prediction scores have been developed, however external validation is lacking. OBJECTIVE: The aim was to determine the diagnostic accuracy of four existing prediction scores in severely obese children, to develop a new prediction score using novel biomarkers and to compare these results to the performance of ultrasonography. DESIGN AND RESULTS: Liver steatosis was measured using proton magnetic resonance spectroscopy in 119 severely obese children (mean age 14.3 ± 2.1 years, BMI z-score 3.35 ± 0.35). Prevalence of steatosis was 47%. The four existing predictions scores ("NAFLD liver fat score," "fatty liver index," "hepatic steatosis index," and the pediatric prediction score) had only moderate diagnostic accuracy in this cohort (positive predictive value (PPV): 70, 61, 61, 69% and negative predictive value (NPV) 77, 69, 68, 75%, respectively). A new prediction score was built using anthropometry, routine biochemistry and novel biomarkers (leptin, adiponectin, TNF-alpha, IL-6, CK-18, FGF-21, and adiponutrin polymorphisms). The final model included ALT, HOMA, sex, and leptin. This equation (PPV 79% and NPV 80%) did not perform substantially better than the four other equations and did not outperform ultrasonography for excluding NAFLD (NPV 82%). CONCLUSION: The conclusion is in severely obese children and adolescents existing prediction scores and the tested novel biomarkers have insufficient diagnostic accuracy for diagnosing or excluding NAFLD.

US cannot be used to predict the presence or severity of hepatic steatosis in severely obese adolescents.

PURPOSE: To evaluate the diagnostic accuracy of ultrasonography (US) for the assessment of hepatic steatosis in severely obese adolescents, with proton magnetic resonance (MR) spectroscopy as the reference standard, and to provide insight on the influence of prevalence on predictive values by calculating positive and negative posttest probabilities. MATERIALS AND METHODS: This prospective study was institutional review board approved. All participants, and/or their legal representatives, gave written informed consent. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the overall presence of steatosis and for the presence of substantial (moderate to severe) steatosis. Positive and negative posttest probabilities were calculated and plotted against prevalence. RESULTS: A total of 104 children (47 male, 57 female) were prospectively included. Mean age was 14.5 years (range, 8.3-18.9 years) and mean age-adjusted standard deviation body mass index (BMI) score (BMI z score) was 3.3 (range, 2.6-4.1). The overall prevalence of hepatic steatosis was 46.2% (48 of 104). Sensitivity of US was 85.4% (41 of 48), specificity was 55.4% (31 of 56), PPV was 62.1% (41 of 66), and NPV was 81.6% (31 of 38). The prevalence of substantial steatosis was 15.4% (16 of 104), with US sensitivity of 75.0% (12 of 16) and specificity of 87.5% (77 of 88). PPV was 52.2% (12 of 23) and NPV was 95.1% (77 of 81). Plotting of posttest probabilities against prevalence for both disease degrees demonstrated how disease prevalence influences US accuracy. CONCLUSION: Positive US results in severely obese adolescents cannot be used to accurately predict the presence and severity of hepatic steatosis, and additional imaging is required. Negative US results exclude the presence of substantial steatosis with acceptable accuracy. Steatosis prevalence differs among specific populations, strongly influencing posttest probabilities.

Hepatic lipid composition analysis using 3.0-T MR spectroscopy in a steatotic rat model.

PURPOSE: To investigate the feasibility of in vivo assessment of hepatic lipid composition using 3.0-T proton magnetic resonance spectroscopy ((1)H-MRS) in a steatotic rat model and compare it to histopathological and biochemical assessment. MATERIALS AND METHODS: Hepatic steatosis was induced by feeding rats with a methionine/choline-deficient (MCD) diet for 1, 2, 3, 5 or 7 weeks (n=5 per group). At the end of the diet period, (1)H-MRS of the liver was performed, and rats were sacrificed for histopathological and biochemical assessment of the liver. Spectra were acquired in a single voxel (1.2 cc) using a point-resolved spectroscopic sequence with TE/TR=35/2000 ms and 64 signal acquisitions. From the MR spectra, peak area ratios were calculated to estimate hepatic lipid composition. RESULTS: During MCD diet periods, hepatic steatosis significantly increased on histopathology (P<.001). The (1)H-MRS measurements of total hepatic fat content [1.3/(1.3+4.65) ppm] correlated strongly with histological macrovesicular hepatic steatosis (r=0.93, P<.001) and with the biochemical total hepatic fatty acids (r=0.94, P<.001). Total unsaturated fatty acids [TUFA, 5.4/(1.3+4.65) ppm] estimated with (1)H-MRS strongly correlated with the biochemical unsaturated fatty acids (r=0.90, P<.001). Polyunsaturated fatty acids [PUFA, 2.8/(1.3+4.65) ppm] estimated with (1)H-MRS strongly correlated with biochemical PUFA (r=0.91, P<.001). The proportion of total unsaturated fatty acids relative to the amount of total fatty acids (rTUFA, 5.4/1.3 ppm) measured with (1)H-MRS strongly correlated with the biochemical amount of unsaturated relative to total hepatic fatty acids (r=0.81, P<.001). The proportion of PUFA relative to the amount of total fatty acids (rPUFA, 2.8/1.3 ppm) measured with (1)H-MRS correlated with the biochemical amount of PUFA relative to total fatty acids (r=0.59, P=0.005,) and with the biochemical amount of omega-6 PUFA relative to total fatty acids (r=0.73, P<.001). PUFA at (1)H-MRS correlated with the histopathologically assessed degree of lobular inflammation in the liver (r=0.57, P=.001). CONCLUSION: 3.0 T (1)H-MRS is able to measure poly- and unsaturated hepatic fatty acids and this strongly correlates with biochemical assessment. This study provides evidence that 3.0-T (1)H-MRS is a noninvasive technique to assess hepatic lipid composition.

Hepatic steatosis in morbidly obese patients undergoing gastric bypass surgery: assessment with open-system 1H-MR spectroscopy.

OBJECTIVE: The purpose of this study was to assess, with histopathologic control, the use of open-system 1-T (1)H MR spectroscopy for the evaluation of hepatic steatosis in morbidly obese patients undergoing gastric bypass surgery. SUBJECTS AND METHODS: Patients underwent (1)H MR spectroscopy (MRS) for the assessment of steatosis before and 3 months after surgery. Liver biopsy was performed during surgery. Hepatic steatosis was expressed as the ratio of fat peak area to cumulative water and fat peak areas. Histopathologic percentage of steatosis was graded as none (0-5%), mild (5-33%), moderate (33-66%), or severe (> 66%). The accuracy of (1)H-MRS and Spearman correlation coefficient were calculated. Differences between groups were assessed with the Wilcoxon signed rank and Mann-Whitney tests. RESULTS: The study included 38 patients (median age, 45.5 years; median body mass index, 47.7). Before surgery, median steatosis measured with (1)H-MRS was 5.8%. The accuracy of (1)H-MRS was 89% (32/36), and the (1)H-MRS findings correlated with the histopathologic assessment of steatosis (r = 0.85, p < 0.001). With (1)H-MRS, no steatosis was discriminated from mild steatosis (p = 0.011), mild was discriminated from moderate steatosis (p < 0.001), and moderate was discriminated from severe steatosis (p = 0.021). Three months after surgery, steatosis had decreased to 3.1% (p < 0.001). The prevalence of hepatic steatosis measured with (1)H-MRS decreased from 53% to 32%. CONCLUSION: In the care of morbidly obese patients undergoing assessment of hepatic steatosis and changes in steatosis after gastric bypass surgery, (1)H-MRS with an open 1-T MRI system is feasible. Measurements of hepatic fat with (1)H-MRS are accurate and correlate with clinical and histopathologic results.

[No-invasive determination of liver fat with 1H-MR spectroscopy]. / Non-invasieve bepaling levervet met 1H-MR-spectroscopie.

Hepatic steatosis is characterized by accumulation of fat in the liver. The prevalence of hepatic steatosis is increasing wordwide due to the close relation between obesity and insulin resistance in non-alcoholic fatty liver disease (NAFLD). The reference standard for determination of hepatic steatosis is liver biopsy with histological assessment. The objections to this are increased risk of complications, patient discomfort and inter-observer variability. Proton MR spectroscopy (1H-MRS) provides information about the chemical constitution of tissues in a spectrum. In this way, 1H-MRS is able to non-invasively measure the amount of fat in the liver. 1H-MRS is precise and reproducible for the assessment of hepatic fat and is useful in all patients for whom an assessment of hepatic steatosis is required, except for those in which MRI is contra-indicated. 1H-MRS is not difficult to learn, but one has to gain some experience with the data-acquisition to obtain good quality MR spectra.

Reversal of hepatic steatosis by omega-3 fatty acids measured non-invasively by (1) H-magnetic resonance spectroscopy in a rat model.

BACKGROUND AND AIM: Living donors with marked (> 33%) macrovesicular steatosis (MaS) are excluded from living donor liver transplantation procedures. Experimental studies have shown that the development of steatosis can be prevented by supplementation with omega-3 fatty acids (FA), but no studies have investigated the reduction of steatosis using omega-3 FA. The aim of the present study was to investigate whether administration of omega-3 FA is effective in reducing steatosis. METHODS: After fatty liver (FL) induction by a 3-week methionine/choline-deficient (MCD) diet, male Wistar rats were daily administered per gavage omega-3 FA (FL+Omega-3), omega-3-poor lipid solution (FL+Lipid), or NaCl (FL+NaCl) during 2 weeks. Control animals received standard chow without treatment. Determination of steatosis degree was performed before, during, and after treatment by clinical 3.0 T ¹H-magnetic resonance spectroscopy (¹H-MRS) and by histology and gas chromatography at the end of the 2-week treatment period. RESULTS: Hepatic fat content (¹H-MRS) was significantly reduced after 1 and 2 weeks of omega-3 FA treatment. Histological analysis revealed a mild (5-33%) MaS degree in omega-3-treated animals vs severe (> 66%) MaS in the FL+Lipid and FL+NaCl groups. Hepatic omega-6 : 3 FA ratio and total FA content were reduced in the FL+Omega-3 group. Furthermore, de novo lipogenesis (C16, C16 : 1ω7, C18 : 1ω9) was also lowered. The reduction in hepatic fat content was associated with decreased lobular inflammation and hepatic tumor necrosis factor- α and interleukin levels as well as an increased antioxidative capacity. CONCLUSION: Omega-3 FA are capable of reversing severe hepatic MaS and ameliorating pathophysiological features of non-alcoholic steatohepatitis such as hepatocellular damage, lobular inflammation, and a reduced antioxidative capacity.

The diagnostic accuracy of US, CT, MRI and 1H-MRS for the evaluation of hepatic steatosis compared with liver biopsy: a meta-analysis.

OBJECTIVE: To meta-analyse the diagnostic accuracy of US, CT, MRI and 1H-MRS for the evaluation of hepatic steatosis. METHODS: From a comprehensive literature search in MEDLINE, EMBASE, CINAHL and Cochrane (up to November 2009), articles were selected that investigated the diagnostic performance imaging techniques for evaluating hepatic steatosis with histopathology as the reference standard. Cut-off values for the presence of steatosis on liver biopsy were subdivided into four groups: (1) >0, >2 and >5% steatosis; (2) >10, >15 and >20%; (3) >25, >30 and >33%; (4) >50, >60 and >66%. Per group, summary estimates for sensitivity and specificity were calculated. The natural-logarithm of the diagnostic odds ratio (lnDOR) was used as a single indicator of test performance. RESULTS: 46 articles were included. Mean sensitivity estimates for subgroups were 73.3-90.5% (US), 46.1-72.0% (CT), 82.0-97.4% (MRI) and 72.7-88.5% (1H-MRS). Mean specificity ranges were 69.6-85.2% (US), 88.1-94.6% (CT), 76.1-95.3% (MRI) and 92.0-95.7% (1H-MRS). Overall performance (lnDOR) of MRI and 1H-MRS was better than that for US and CT for all subgroups, with significant differences in groups 1 and 2. CONCLUSION: MRI and 1H-MRS can be considered techniques of choice for accurate evaluation of hepatic steatosis.

Assessment of hepatic steatosis in patients undergoing liver resection: comparison of US, CT, T1-weighted dual-echo MR imaging, and point-resolved 1H MR spectroscopy.

PURPOSE: To compare the diagnostic performance of ultrasonography (US), computed tomography (CT), T1-weighted dual-echo magnetic resonance (MR) imaging, and point-resolved proton (hydrogen 1[(1)H]) MR spectroscopy in the assessment of hepatic steatosis in patients undergoing liver resection. MATERIALS AND METHODS: This prospective study was approved by the institutional review board, and patients gave written informed consent. US, CT, T1-weighted MR imaging, and (1)H MR spectroscopy were performed preoperatively in 46 patients. Imaging results were correlated (Spearman correlation coefficient) with histopathologic analysis of results of intraoperative liver biopsies. To assess differences between groups, one-way analysis of variance was used. Sensitivity and specificity were calculated for each imaging modality by using receiver operating characteristic curve analysis, with a histopathologic cut-off value of 5% macrovesicular steatosis. Differences in sensitivity and specificity were assessed by means of McNemar analysis. RESULTS: At histopathologic examination, 23 patients had no (0%-5%) macrovesicular steatosis, 11 had mild (5%-33%), nine had moderate (33%-66%), and three had severe (>66%). MR imaging and (1)H MR spectroscopic measurements of hepatic fat had stronger correlation with histopathologic steatosis assessment (r = 0.85, P < .001 and r = 0.86, P < .001, respectively) than did US (r = 0.66, P < .001) and CT (r = -0.55, P < .001). Only T1-weighted MR imaging and (1)H MR spectroscopy showed differences across steatosis grades: none versus mild (P = .001 for both), mild versus moderate (P < .001 for both), and moderate versus severe (P = .04 and .01, respectively). Sensitivity of US, CT, T1-weighted MR imaging, and (1)H MR spectroscopy was 65% (13 of 20), 74% (17 of 23), 90% (19 of 21), and 91% (21 of 23), respectively, and specificity was 77% (17 of 23), 70% (14 of 20), 91% (20 of 22), and 87% (20 of 23), respectively. CONCLUSION: In contrast to US and CT, T1-weighted MR imaging and (1)H MR spectroscopy strongly correlate with histopathologic steatosis assessment and are able to demonstrate differences across steatosis grades. T1-weighted dual-echo MR imaging and (1)H MR spectroscopy had the best diagnostic accuracy in depicting hepatic steatosis.

The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance.

Intestinal FGF19 has emerged as a novel endocrine regulator of hepatic bile salt and lipid metabolism. In patients with nonalcoholic fatty liver disease (NAFLD) hepatic lipid metabolism is deranged. A possible role of FGF19 in NAFLD has not been reported yet. In this study, we assessed intestinal FGF19 production and the hepatic response to FGF19 in NAFLD patients with and without insulin resistance [homeostasis model of assessment (HOMA) score > or =2.5 (n = 12) and HOMA score <2.5 (n = 8), respectively]. To this end, NAFLD patients received a standardized oral fat challenge. Postprandial excursions of triglycerides, bile salts, and FGF19 were monitored, and plasma levels of a marker for bile salt synthesis (7alpha-hydroxy-4-cholesten-3-one) were determined. Fasted FGF19 levels were comparable in a control group of healthy volunteers (n = 15) and in NAFLD patients (0.26 +/- 0.28 vs. 0.18 +/- 0.09 ng/ml, respectively, P = 0.94). Postprandial FGF19 levels in both controls and NAFLD patients peaked between 3-4 h and were three times higher than baseline levels. The areas under the postprandial FGF19 curve were similar in controls and in the HOMA score-based NAFLD subgroups. In NAFLD patients with HOMA score <2.5, the postprandial increase in plasma FGF19 was accompanied by a lowering of plasma levels of 7alpha-hydroxy-4-cholesten-3-one (-30%, P = 0.015). This anticipated decline was not observed in insulin-resistant NAFLD patients (+10%, P = 0.22). In conclusion, patients with NAFLD show an unimpaired intestinal FGF19 production. However, the hepatic response to FGF19 is impaired in NAFLD patients with insulin resistance (HOMA score > or =2.5). This impaired hepatic response to FGF19 may contribute to the dysregulation of lipid homeostasis in NAFLD.

Reproducibility of 3.0 Tesla magnetic resonance spectroscopy for measuring hepatic fat content.

PURPOSE: To investigate reproducibility of proton magnetic resonance spectroscopy ((1)H-MRS) to measure hepatic triglyceride content (HTGC). MATERIALS AND METHODS: In 24 subjects, HTGC was evaluated using (1)H-MRS at 3.0 Tesla. We studied "between-weeks" reproducibility and reproducibility of (1)H-MRS in subjects with fatty liver. We also studied within liver variability and within day reproducibility. Reproducibility was assessed by coefficient of variation (CV), repeatability coefficient (RC), and intraclass correlation coefficient (ICC). RESULTS: The CV of between weeks reproducibility was 9.5%, with a RC of 1.3% HTGC (ICC 0.998). The CV in fatty livers was 4.1%, with a RC of 1.3% HTGC (ICC 0.997). Within day CV was 4.5%, with a RC of 0.4% HTGC (ICC 0.999). CV for within liver variability was 14.5%. CONCLUSION: Reproducibility of (1)H-MRS to measure HTGC for "between-weeks" measurements and in fatty livers is high, which is important for follow-up studies. Within liver variability displays a larger variation, meaning that liver fat is not equally distributed and during consecutive measurements the same voxel position should be used.

Psychological factors and preferences for communicating prognosis in esophageal cancer patients.

OBJECTIVE: Discussing prognosis is often confronting and complex for cancer patients. This study investigates how patients' psychological characteristics relate to their preferences concerning the disclosure of prognosis. METHODS: One hundred and seventy-six esophageal cancer patients participated in the study. They had undergone esophagectomy within the past 28 months and did not have evidence of cancer recurrence. Patients completed a questionnaire eliciting their preferences for prognostic information. Sociodemographic characteristics, involvement preferences, anxiety, depression, fear of recurrence, striving for quality of life (QOL) or quantity of life and trust in physicians were explored as predictors for (a) wanting to be informed about prognosis and (b) the initiation of discussion about prognosis. RESULTS: Patients wanting all prognostic information had more fear for the disease to recur (p<0.05) and were inclined to be more actively involved during consultation (p<0.001). Post hoc analyses showed that patients with worse QOL scores reported more fear of recurrence. Anxiety, depression, trust and tendency to strive for QOL or quantity of life were not related to preferences concerning prognostic information. CONCLUSIONS: The more fear patients have for esophageal cancer to recur, the more information they want about prognosis. Thus, patient's fear for recurrent disease is not a reason for withholding prognostic information. Results also suggest that there is no harm in asking patients what information they want.

Patient preferences for the disclosure of prognosis after esophagectomy for cancer with curative intent.

INTRODUCTION: The aim of this study was to determine the preferences for content, style, and format of prognostic information of patients after potentially curative esophagectomy for cancer and to explore predictors of these preferences. PATIENTS AND METHODS: This multicenter study included a consecutive series of patients who underwent surgical resection for cancer in the past 2 years and who did not have evidence of cancer recurrence. A questionnaire was used to elicit patient preferences for the content, style, and format of prognostic information. Sociodemographic characteristics, clinicopathological factors, and quality of life (EORTC QLQ-30 and OES18) were explored as predictors for certain preferences. RESULTS: Of the 204 eligible patients, 176 patients (86%) returned the questionnaire. The majority of patients desired prognostic information. Information preferences declined when information became more specific and more negative. Married patients and higher-educated patients were more likely to want all prognostic information. The majority of patients wanted their specialist to start the discussion about prognosis. However, a significant proportion of these patients wanted their specialist to first ask if they want to have prognostic information. The percentage of patients wanted a realistic and individualistic approach was 97%. Words and numbers were preferred over visual presentations. CONCLUSION: After potentially curative esophagectomy for cancer, the majority of patients want detailed prognostic information and want their specialist to begin the prognostic discussion. Patients prefer their doctor to be realistic; words and numbers are preferred over figures and graphs.