Association between Paclitaxel Clearance and Tumor Response in Patients with Esophageal Cancer.

Inter-individual variability in paclitaxel pharmacokinetics may play a role in the response to chemotherapy. Therefore, we studied the association between paclitaxel clearance and treatment response in patients with esophageal cancer. All patients who received paclitaxel (plus carboplatin) treatment for esophageal cancer between 2007 and 2013 were included. The treatment was given as neoadjuvant chemoradiotherapy (nCRT), induction chemotherapy (iCT), or palliative chemotherapy (pCT). The treatment response was assessed by the tumor regression grade (TRG) or by the RECIST1.1 criteria, respectively. The unbound paclitaxel clearance (CL) was estimated with NONMEM. The log-transformed clearance was related to response with ANOVA and independent sample t-tests. A total of 166 patients were included, of whom 113 received nCRT, 23 iCT and 30 pCT. In patients receiving nCRT, paclitaxel clearance was not associated with tumor regression grade (p-value = 0.25), nor with pathologically complete response (geometric mean 561.6 L/h) and residual disease (geometric mean 566.1 L/h, p-value = 0.90). In patients who underwent iCT or pCT, also no association between paclitaxel clearance and RECIST outcome was identified (iCT: p-value = 0.08 and pCT: p-value = 0.81, respectively). In conclusion, systemic paclitaxel exposure was not associated with response to common paclitaxel-based treatment regimens for esophageal cancer. Future studies should focus on tumor exposure in relation to systemic exposure and treatment outcome.

Unenhanced CT imaging is highly sensitive to exclude pheochromocytoma: a multicenter study.

BACKGROUND: A substantial proportion of all pheochromocytomas is currently detected during the evaluation of an adrenal incidentaloma. Recently, it has been suggested that biochemical testing to rule out pheochromocytoma is unnecessary in case of an adrenal incidentaloma with an unenhanced attenuation value ≤10 Hounsfield Units (HU) at computed tomography (CT). OBJECTIVES: We aimed to determine the sensitivity of the 10 HU threshold value to exclude a pheochromocytoma. METHODS: Retrospective multicenter study with systematic reassessment of preoperative unenhanced CT scans performed in patients in whom a histopathologically proven pheochromocytoma had been diagnosed. Unenhanced attenuation values were determined independently by two experienced radiologists. Sensitivity of the 10 HU threshold was calculated, and interobserver consistency was assessed using the intraclass correlation coefficient (ICC). RESULTS: 214 patients were identified harboring a total number of 222 pheochromocytomas. Maximum tumor diameter was 51 (39-74) mm. The mean attenuation value within the region of interest was 36 ± 10 HU. Only one pheochromocytoma demonstrated an attenuation value ≤10 HU, resulting in a sensitivity of 99.6% (95% CI: 97.5-99.9). ICC was 0.81 (95% CI: 0.75-0.86) with a standard error of measurement of 7.3 HU between observers. CONCLUSION: The likelihood of a pheochromocytoma with an unenhanced attenuation value ≤10 HU on CT is very low. The interobserver consistency in attenuation measurement is excellent. Our study supports the recommendation that in patients with an adrenal incidentaloma biochemical testing for ruling out pheochromocytoma is only indicated in adrenal tumors with an unenhanced attenuation value >10 HU.

Small-bowel Surveillance in Patients With Peutz-Jeghers Syndrome: Comparing Magnetic Resonance Enteroclysis and Double Balloon Enteroscopy.

BACKGROUND AND STUDY AIMS: Small-bowel surveillance with polypectomy of polyps ≥15 mm prevents complications in patients with Peutz-Jeghers syndrome (PJS). We aimed to compare magnetic resonance enteroclysis (MRE) and double balloon enteroscopy (DBE) for diagnostic yield of these polyps and for patient preference. MATERIALS AND METHODS: PJS patients prospectively underwent MRE followed by proximal DBE within 20 weeks. Endoscopists were blinded to the MRE results. We compared number of polyps ≥15 mm detected by MRE and DBE. Patients' perceptions of both procedures were assessed using questionnaires. RESULTS: Fifteen PJS patients (67% males, median age 47 y) underwent both MRE and DBE. Polyps ≥15 mm were identified by MRE and/or DBE in 12/15 (80%) patients. There was no significant difference in the detection of polyps ≥15 mm (38 by MRE vs. 50 by DBE, P=0.37). Sensitivity for these polyps was 62% (38/61) for MRE and 82% (50/61) for DBE. Patients' perceived shame and burden did not differ significantly between MRE and DBE. Patients reported significantly more pain during preparation for MRE than for DBE (moderate vs. no pain, P=0.02), although perceived pain during the procedures was comparable (both mild, P=0.89). For future small-bowel surveillance 10/13 (77%) patients preferred DBE over MRE (P=0.09). CONCLUSIONS: Our results suggest that MRE and DBE have a comparable diagnostic yield of polyps ≥15 mm. However, DBE allows for direct intervention and was preferred over MRE by most patients in this series. Larger cohorts of PJS patients are needed to fully evaluate the diagnostic yield of DBE compared with other modalities.

Prevalence and Progression of Pancreatic Cystic Precursor Lesions Differ Between Groups at High Risk of Developing Pancreatic Cancer.

OBJECTIVES: The aim of this study was to compare the prevalence of cystic pancreatic lesions and their natural behavior in 2 distinct high-risk groups for developing pancreatic ductal adenocarcinoma (PDAC): (1) carriers of a mutation that predisposes to PDAC and (2) individuals without a known gene mutation but with a family history of PDAC (familial pancreatic cancer [FPC]). METHODS: Pancreatic surveillance by annual magnetic resonance imaging and endoscopic ultrasound was performed in individuals with an estimated lifetime risk of developing PDAC of 10% or greater. Progression of a lesion was defined as growth 4 mm or greater or the development of worrisome features. RESULTS: We included 186 individuals: 98 mutation carriers and 88 FPC individuals (mean follow-up, 51 months). Individuals with FPC were significantly more likely than mutation carriers to have a pancreatic cyst 10 mm or greater (16% vs 5%, P = 0.045). Pancreatic cysts detected in mutation carriers, however, were significantly more likely to progress than those in FPC individuals (16% vs 2%, P = 0.050). CONCLUSIONS: This study provides evidence that the prevalence and growth characteristics of pancreatic cysts differ between distinct high-risk groups: individuals with FPC have a higher prevalence of pancreatic cysts 10 mm or greater, whereas cysts in mutation carriers are more likely to progress. These observations may help to develop more optimally tailored surveillance strategies in specific high-risk populations.

Liver Contrast-Enhanced Ultrasound Improves Detection of Liver Metastases in Patients with Pancreatic or Periampullary Cancer.

The aim of this study is to provide a diagnostic performance evaluation of contrast-enhanced ultrasonography (CEUS) in detecting liver metastases in patients with suspected of pancreatic or periampullary cancer. Computed tomography (CT) is often insufficient for detection of liver metastases, but their presence plays a crucial role in the choice of therapy. Eighty-nine patients with suspected pancreatic or periampullary cancer were included in this prospective study with retrospective analysis. Patients underwent an abdominal CT and CEUS. Fifteen patients had liver metastases. The CT sensitivity was 73.3% (11/15), the specificity 93.2% (69/74), the positive predictive value (PPV) 68.8% (11/16) and the negative predictive value (NPV) 94.6% (69/73). Based on CEUS, the sensitivity was 80% (12/15), specificity 98.6% (73/74), PPV 92.3% (12/13) and NPV 96.1% (73/76). CEUS improved characterization of liver lesions in patients with suspected pancreatic or periampullary cancer compared with CT. CEUS can better detect benign liver lesions and distinguish false-positive or indeterminate CT results.

Cytopathological Analysis of Cyst Fluid Enhances Diagnostic Accuracy of Mucinous Pancreatic Cystic Neoplasms.

Widespread use of cross-sectional imaging and increasing age of the general population has increased the number of detected pancreatic cystic lesions. However, several pathological entities with a variety in malignant potential have to be discriminated to allow clinical decision making. Discrimination between mucinous pancreatic cystic neoplasms (PCNs) and nonmucinous pancreatic lesions is the primary step in the clinical work-up, as malignant transformation is mostly associated with mucinous PCN. We performed a retrospective analysis of all resected PCN in our tertiary center from 2000 to 2014, to evaluate preoperative diagnostic performance and the results of implementation of the consensus guidelines over time. This was followed by a prospective cohort study of patients with an undefined pancreatic cyst, where the added value of cytopathological mucin evaluation to carcinoembryonic antigen (CEA) in cyst fluid for the discrimination of mucinous PCN and nonmucinous cysts was investigated. Retrospective analysis showed 115 patients operated for a PCN, with a correct preoperative classification in 96.2% of the patients. High-grade dysplasia or invasive carcinoma was observed in only 32.3% of mucinous PCN. In our prospective cohort (n = 71), 57.7% of patients were classified as having a mucinous PCN. CEA ≥ 192 ng/mL had an accuracy of 63.4%, and cytopathological mucin evaluation an accuracy of 73.0%. Combining these 2 tests further improved diagnostic accuracy of a mucinous PCN to 76.8%. CEA level and mucin evaluation were not predictive of the degree of dysplasia. These findings show that adding cytopathology to cyst fluid biochemistry improves discrimination between mucinous PCN and nonmucinous cysts.

Immunoglobulin G4-related prostatitis: a case-control study focusing on clinical and pathologic characteristics.

OBJECTIVE: To evaluate the occurrence and histopathologic characteristics of immunoglobulin G4 (IgG4)-related prostatic involvement in patients diagnosed with autoimmune pancreatitis. METHODS: Nine cases of IgG4-related prostatitis were identified among 117 men in the autoimmune pancreatitis and IgG4-associated cholangitis patient databases in 2 tertiary hospitals. Clinical information was retrieved, and available prostatic tissue samples and 18 prostatitis control samples were evaluated for characteristic IgG4-related disease (IgG4-RD) features: maximum number of IgG4-positive cells per high-power field; dense lymphoplasmacytic infiltrate; fibrosis, arranged at least focally in a storiform pattern; phlebitis with or without obliteration of the lumen; and increased number of eosinophils. RESULTS: The aspecific sign of urine retention was commonly present in IgG4-RD patients with prostatic involvement. In these patients with IgG4-related prostatitis, the median number of IgG4-positive cells in prostatic tissue was 150 (interquartile range, 20-150) per high-power field compared with a median of 3 (interquartile range, 1-11) in control patients (P = .008). Dense lymphoplasmacytic infiltrate was observed in most (86% in cases and 72% in control patients) tissue samples independent of the underlying cause of prostatitis. Fibrosis in at least a focally storiform pattern was seen rarely in both groups, and (obliterative) phlebitis was absent in all patients. Furthermore, eosinophil numbers were more often elevated in patients with IgG4-RD compared with controls (P <.001). In 2 cases, amelioration of the prostatitis symptoms on corticosteroid treatment was documented. CONCLUSION: Prostatic involvement might not be rare in patients with pancreatic or biliary IgG4-RD. Clinicians should consider this disease entity in patients with IgG4-RD and prostatic symptoms.

Pancreatic cancer risk in Peutz-Jeghers syndrome patients: a large cohort study and implications for surveillance.

BACKGROUND: Although Peutz-Jeghers syndrome (PJS) is known to be associated with pancreatic cancer (PC), estimates of this risk differ widely. This hampers counselling of patients and implementation of surveillance strategies. We therefore aimed to determine the PC risk in a large cohort of Dutch PJS patients. METHODS: PJS was defined by diagnostic criteria recommended by the WHO, a proven LKB1 mutation, or both. All patients with a presumptive diagnosis of pancreatic, ampullary or distal bile duct cancer were identified. Cases were reviewed clinically, radiologically and immunohistochemically. Cumulative PC risks were calculated by Kaplan-Meier analysis and relative risks by Poisson regression analysis. RESULTS: We included 144 PJS patients (49% male) from 61 families (5640 person years follow-up). Seven (5%) patients developed PC at a median age of 54 years. Four patients (3%) were diagnosed with distal bile duct (n=2) or ampullary cancer (n=2) at a median age of 55 years. The cumulative risk for PC was 26% (95% CI 4% to 47%) at age 70 years and relative risk was 76 (95% CI 36 to 160; p<0.001). The cumulative risk for pancreatico-biliary cancer was 32% (95% CI 11% to 52%) at age 70 years, with a relative risk of 96 (95% CI 53 to 174; p<0.001). CONCLUSIONS: PJS patients have a highly increased risk for pancreatico-biliary cancer. Therefore, patients are eligible for surveillance within well defined research programmes to establish the benefit of such surveillance.

Partial volume correction strategies for quantitative FDG PET in oncology.

PURPOSE: Quantitative accuracy of positron emission tomography (PET) is affected by partial volume effects resulting in increased underestimation of the standardized uptake value (SUV) with decreasing tumour volume. The purpose of the present study was to assess accuracy and precision of different partial volume correction (PVC) methods. METHODS: Three methods for PVC were evaluated: (1) inclusion of the point spread function (PSF) within the reconstruction, (2) iterative deconvolution of PET images and (3) calculation of spill-in and spill-out factors based on tumour masks. Simulations were based on a mathematical phantom with tumours of different sizes and shapes. Phantom experiments were performed in 2-D mode using the National Electrical Manufacturers Association (NEMA) NU2 image quality phantom containing six differently sized spheres. Clinical studies (2-D mode) included a test-retest study consisting of 10 patients with stage IIIB and IV non-small cell lung cancer and a response monitoring study consisting of 15 female breast cancer patients. In all studies tumour or sphere volumes of interest (VOI) were generated using VOI based on adaptive relative thresholds. RESULTS: Simulations and experiments provided similar results. All methods were able to accurately recover true SUV within 10% for spheres equal to and larger than 1 ml. Reconstruction-based recovery, however, provided up to twofold better precision than image-based methods. Clinical studies showed that PVC increased SUV by 5-80% depending on tumour size. Test-retest variability slightly worsened from 9.8 +/- 6.5 without to 10.8 +/- 7.9% with PVC. Finally, PVC resulted in slightly smaller SUV responses, i.e. from -30.5% without to -26.3% with PVC after the first cycle of treatment (p < 0.01). CONCLUSION: PVC improves accuracy of SUV without decreasing (clinical) test-retest variability significantly and it has a small, but significant effect on observed tumour responses. Reconstruction-based PVC outperforms image-based methods, but requires dedicated reconstruction software. Image-based methods are good alternatives because of their ease of implementation and their similar performance in clinical studies.

Blood flow and glucose metabolism in stage IV breast cancer: heterogeneity of response during chemotherapy.

OBJECTIVE: The purpose of the study was to compare early changes in blood flow (BF) and glucose metabolism (MRglu) in metastatic breast cancer lesions of patients treated with chemotherapy. METHODS: Eleven women with stage IV cancer and lesions in breast, lymph nodes, liver, and bone were scanned before treatment and after the first course of chemotherapy. BF, distribution volume of water (Vd), MRglu/BF ratio, MRglu and its corresponding rate constants K1 and k3 were compared per tumor lesion before and during therapy. RESULTS: At baseline, mean BF and MRglu varied among different tumor lesions, but mean Vd was comparable in all lesions. After one course of chemotherapy, mean MRglu decreased in all lesions. Mean BF decreased in breast and node lesions and increased in bone lesions. Vd decreased in breast and nodes, but did not change in bone lesions. The MRglu/BF ratio decreased in breast and bone lesions and increased in node lesions. In patients with multiple tumor lesions BF and MRglu response could be very heterogeneous, even within similar types of metastases. BF and MRglu increased in lesions of patients who experienced early disease progression or showed no response during clinical follow-up. CONCLUSION: BF and MRglu changes separately give unique information on different aspects of tumor response to chemotherapy. Changes in BF and MRglu parameters can be remarkably heterogeneous in patients with multiple lesions.

Effects of ROI definition and reconstruction method on quantitative outcome and applicability in a response monitoring trial.

PURPOSE: Quantitative measurement of tracer uptake in a tumour can be influenced by a number of factors, including the method of defining regions of interest (ROIs) and the reconstruction parameters used. The main purpose of this study was to determine the effects of different ROI methods on quantitative outcome, using two reconstruction methods and the standard uptake value (SUV) as a simple quantitative measure of FDG uptake. METHODS: Four commonly used methods of ROI definition (manual placement, fixed dimensions, threshold based and maximum pixel value) were used to calculate SUV (SUV([MAN]), SUV15 mm, SUV50, SUV75 and SUVmax, respectively) and to generate "metabolic" tumour volumes. Test-retest reproducibility of SUVs and of "metabolic" tumour volumes and the applicability of ROI methods during chemotherapy were assessed. In addition, SUVs calculated on ordered subsets expectation maximisation (OSEM) and filtered back-projection (FBP) images were compared. RESULTS: ROI definition had a direct effect on quantitative outcome. On average, SUV[MAN), SUV15 mm, SUV50 and SUV75, were respectively 48%, 27%, 34% and 15% lower than SUVmax when calculated on OSEM images. No statistically significant differences were found between SUVs calculated on OSEM and FBP reconstructed images. Highest reproducibility was found for SUV15 mm and SUV[MAN] (ICC 0.95 and 0.94, respectively) and for "metabolic" volumes measured with the manual and 50% threshold ROIs (ICC 0.99 for both). Manual, 75% threshold and maximum pixel ROIs could be used throughout therapy, regardless of changes in tumour uptake or geometry. SUVs showed the same trend in relative change in FDG uptake after chemotherapy, irrespective of the ROI method used. CONCLUSION: The method of ROI definition has a direct influence on quantitative outcome. In terms of simplicity, user-independence, reproducibility and general applicability the threshold-based and fixed dimension methods are the best ROI methods. Threshold methods are in addition relatively independent of changes in size and geometry, however, and may therefore be more suitable for response monitoring purposes.

Effects of noise, image resolution, and ROI definition on the accuracy of standard uptake values: a simulation study.

UNLABELLED: Semiquantitative standard uptake values (SUVs) are used for tumor diagnosis and response monitoring. However, the accuracy of the SUV and the accuracy of relative change during treatment are not well documented. Therefore, an experimental and simulation study was performed to determine the effects of noise, image resolution, and region-of-interest (ROI) definition on the accuracy of SUVs. METHODS: Experiments and simulations are based on thorax phantoms with tumors of 10-, 15-, 20-, and 30-mm diameter and background ratios (TBRs) of 2, 4, and 8. For the simulation study, sinograms were generated by forward projection of the phantoms. For each phantom, 50 sinograms were generated at 3 noise levels. All sinograms were reconstructed using ordered-subset expectation maximization (OSEM) with 2 iterations and 16 subsets, with or without a 6-mm gaussian filter. For each tumor, the maximum pixel value and the average of a 50%, a 70%, and an adaptive isocontour threshold ROI were derived as well as with an ROI of 15 x 15 mm. The accuracy of SUVs was assessed using the average of 50 ROI values. Treatment response was simulated by varying the tumor size or the TBR. RESULTS: For all situations, a strong correlation was found between maximum and isocontour-based ROI values resulting in similar dependencies on image resolution and noise of all studied SUV measures. A strong variation with tumor size of > or =50% was found for all SUV values. For nonsmoothed data with high noise levels this variation was primarily due to noise, whereas for smoothed data with low noise levels partial-volume effects were most important. In general, SUVs showed under- and overestimations of > or =50% and depended on all parameters studied. However, SUV ratios, used for response monitoring, were only slightly dependent of ROI definition but were still affected by noise and resolution. CONCLUSION: The poor accuracy of the SUV under various conditions may hamper its use for diagnosis, especially in multicenter trials. SUV ratios used to measure response to treatment, however, are less dependent on noise, image resolution, and ROI definition. Therefore, the SUV might be more suitable for response-monitoring purposes.

Measuring response to chemotherapy in locally advanced breast cancer: methodological considerations.

In this review the findings of response monitoring studies in breast cancer, using [(18)F]2-fluoro-2-deoxy-D-glucose (FDG) and positron emission tomography (PET), are summarised. These studies indicate that there is a strong relationship between response and decrease in FDG signal even at an early stage of therapy. The review concentrates on methodological aspects of monitoring response with FDG: timing of serial scans, approach to region of interest definition, method of quantification and pitfalls of FDG. It is argued that, for clinical applications, there is now a need to standardise methodology. This would be necessary to establish firm cut-off values for discriminating responders from non-responders, which in turn would provide a means for providing optimal treatment for as many patients as possible.

18F-2-fluoro-2-deoxy-d-glucose positron emission tomography in staging of locally advanced breast cancer.

PURPOSE: To prospectively evaluate the effect of adding whole-body (18)F-2-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) to conventional screening for distant metastases in patients with locally advanced breast cancer (LABC). PATIENTS AND METHODS: All women with LABC referred for participation in the LABC Spinoza trial were considered eligible for this study. Patients were included if chest x-ray, bone scan, liver ultrasound, or computed tomography scan performed by the referring physician failed to reveal distant metastases. They underwent whole-body FDG PET scanning before therapy. Patients with subsequently proven distant metastases were switched to alternative forms of chemotherapy, hormonal therapy, or both. RESULTS: Among the 48 patients evaluated with PET, 14 had abnormal FDG uptake, and metastases were suspected in 12. After simple clinical evaluation (plain x-ray, history), 10 sites that were suggestive of abnormality remained. Further work-up revealed that four sites were metastases. Proven false positivity occurred in one patient with sarcoidosis. In the other five patients, the reason for abnormal FDG uptake (liver, lung, bone) remained unclear, and patients were treated as planned. Eleven months later, distant metastases were found in one patient at sites unrelated to the previous FDG uptake. CONCLUSION: The addition of FDG PET to the standard work-up of patients with LABC may lead to the detection of unexpected distant metastases. This may contribute to a more realistic stratification between patients with true stage III breast cancer and those who are in fact suffering from stage IV disease. Abnormal PET findings should be confirmed to prevent patients from being denied appropriate treatment.

Measuring [(18)F]FDG uptake in breast cancer during chemotherapy: comparison of analytical methods.

Over the years several analytical methods have been proposed for the measurement of glucose metabolism using fluorine-18 fluorodeoxyglucose ([(18)F]FDG) and positron emission tomography (PET). The purpose of this study was to evaluate which of these (often simplified) methods could potentially be used for clinical response monitoring studies in breast cancer. Prior to chemotherapy, dynamic [(18)F]FDG scans were performed in 20 women with locally advanced ( n=10) or metastasised ( n=10) breast cancer. Additional PET scans were acquired after 8 days ( n=8), and after one, three and six courses of chemotherapy ( n=18, 10 and 6, respectively). Non-linear regression (NLR) with the standard two tissue compartment model was used as the gold standard for measurement of [(18)F]FDG uptake and was compared with the following methods: Patlak graphical analysis, simplified kinetic method (SKM), SUV-based net influx constant ("Sadato" method), standard uptake value [normalised for weight, lean body mass (LBM) and body surface area (BSA), with and without corrections for glucose (g)], tumour to non-tumour ratio (TNT), 6P model and total lesion evaluation (TLE). Correlation coefficients between each analytical method and NLR were calculated using multilevel analysis. In addition, for the most promising methods (Patlak, SKM, SUV(LBMg) and SUV(BSAg)) it was explored whether correlation with NLR changed with different time points after the start of therapy. Three methods showed excellent correlation ( r>0.95) with NLR for the baseline scan: Patlak10-60 and Patlak10-45 ( r=0.98 and 0.97, respectively), SKM40-60 ( r=0.96) and SUV(LBMg) ( r=0.96). Good correlation was found between NLR and SUV-based net influx constant, TLE and SUV(BSAg) (0.90< r<0.95). The 6P model and TNT had the lowest correlation ( r