PhD Student, University of Rochester
Pancreatic ductal adenocarcinoma (PDAC) is a prevalent form of pancreatic cancer. The inherent biology of the disease makes it diﬃcult to diagnose and treat: the 5-year survival rate of patients with PDAC is less than 5% with a median survival of 4-6 months. Surgical resection is currently the best treatment plan, though less than 20% patients with PDAC qualify for surgery due to advanced stage of the disease when diagnosed and the high likelihood of an incomplete resection. Consequently, there has been a focus on reducing the size of tumor prior surgery using neoadjuvant therapies.
The standard neoadjuvant therapy agent gemcitabine increases the general quality of life for PDAC patients, but only prolongs the mean survival by a month. Possible culprits are the dense stroma surrounding the tumor and high tissue pressure at the margin of the tumor that compress and collapse functioning blood vessels. High tissue pressure not only impedes drug delivery but also prevents vascular imaging contrast agent from reaching the tumor core for effective tumor imaging. Progress must be made to develop better imaging technologies.
Most studies use the well-established, ‘wick-in-needle’ technique or pressure catheters, which are invasive and impractical for clinical studies. In my research, we've been investigating using ultrasound elastography to provide information about the tumor microenvironment. Clinicians could use this information to assess the eﬀectiveness of new therapies.
Elastography was developed in the late 1980s to early 1990s to quantitatively characterize a tissue’s mechanical properties and improve the diagnostic value of ultrasonic imaging. Change in elastic properties of soft tissues are often correlated with pathological phenomena. Our research has demonstrated that tumor stiffness was a good surrogate for total tissue pressure using quasi-static quantitative elastography. We also showed that decreased drug uptake was accompanied with increased tumor stiffness using shear wave elasticity imaging (SWEI).
Our current research focuses on using SWEI to evaluate how different therapies (immunotherapy and radiotherapy) impact murine model tumor stiffness and drug uptake. Our preliminary demonstrated that both immunotherapy and radiotherapy reduced tumor stiffness with radiotherapy being more effective in softening the tumors. The promising results can potentially facilitate the in vivo evaluation of novel therapeutic approaches.
Abstract: To estimate the validity of the point shear-wave elastography method by evaluating its reproducibility and accuracy for assessing liver stiffness.This was a single-center, cross-sectional study. Consecutive patients with chronic viral hepatitis scheduled for liver biopsy (LB) (Group 1) and healthy volunteers (Group 2) were studied. In each subject 10 consecutive point shear-wave elastography (PSWE) measurements were performed using the iU22 ultrasound system (Philips Medical Systems, Bothell, WA, United States). Patients in Group 1 underwent PSWE, transient elastography (TE) using FibroScan (Echosens, Paris, France) and ultrasound-assisted LB. For the assessment of PSWE reproducibility two expert raters (rater 1 and rater 2) independently performed the examinations. The performance of PSWE was compared to that of TE using LB as a reference standard. Fibrosis was staged according to the METAVIR scoring system. Receiver operating characteristic curve analyses were performed to calculate the area under the receiver operating characteristic curve (AUC) for F ≥ 2, F ≥ 3 and F = 4. The intraobserver and interobserver reproducibility of PSWE were assessed by calculating Lin's concordance correlation coefficient.To assess the performance of PSWE, 134 consecutive patients in Group 1 were studied. The median values of PSWE and TE (in kilopascals) were 4.7 (IQR = 3.8-5.4) and 5.5 (IQR = 4.7-6.5), respectively, in patients at the F0-F1 stage and 3.5 (IQR = 3.2-4.0) and 4.4 (IQR = 3.5-4.9), respectively, in the healthy volunteers in Group 2 (P < 10(-5)). In the univariate analysis, the PSWE and TE values showed a high correlation with the fibrosis stage; low correlations with the degree of necroinflammation, aspartate aminotransferase and gamma-glutamyl transferase (GGT); and a moderate negative correlation with the platelet count. A multiple regression analysis confirmed the correlations of both PSWE and TE with fibrosis stage and GGT but not with any other variables. The following AUC values were found: 0.80 (0.71-0.87) for PSWE and 0.82 (0.73-0.89) for TE (P = 0.42); 0.88 (0.80-0.94) for PSWE and 0.95 (0.88-0.98) for TE (P = 0.06); and 0.95 (0.89-0.99) for PSWE and 0.92 (0.85-0.97) for TE (P = 0.30) for F ≥ 2, F ≥ 3 and F = 4, respectively. To assess PSWE reproducibility, 116 subjects were studied, including 47 consecutive patients scheduled for LB (Group 1) and 69 consecutive healthy volunteers (Group 2). The intraobserver agreement ranged from 0.83 (95%CI: 0.79-0.88) to 0.96 (95%CI: 0.95-0.97) for rater 1 and from 0.84 (95%CI: 0.79-0.88) to 0.96 (95%CI: 0.95-0.97) for rater 2. The interobserver agreement yielded values from 0.83 (95%CI: 0.78-0.88) to 0.93 (95%CI: 0.91-0.95).PSWE is a reproducible method for assessing liver stiffness, and it compares with TE. Compared with patients with nonsignificant fibrosis, healthy volunteers showed significantly lower values.
Pub.: 02 May '14, Pinned: 04 Jul '17
Abstract: MR elastography (MRE) is an MRI modality that is increasingly being used to image tissue elasticity throughout the body. One MRE technique that has received a great deal of attention is based on visualizing shear waves, which reveal stiffness by virtue of their local wavelength. However, the shape of propagating shear waves can also provide valuable information about the nonlinear stress-strain behavior of tissue. Here an experiment is proposed that allows the observation of nonlinear wave propagation based on spatial-temporal phase contrast images. A theoretical description of the wave propagation was developed that reflects typical MRE excitation, which involves excitation modes both parallel and perpendicular to B0. Based on this model, it is shown that both odd and even higher harmonics are produced with their amplitudes dependent on the details of the actuator, imaging geometry, and the nonlinear tissue properties. With appropriate motion encoding, harmonic vibrations arising from nonlinear tissue response can be detected. The effect is demonstrated on an agarose gel phantom using a sinusoidal shear vibration of 150 Hz, and clearly shows the presence of harmonics at 600 and 750 Hz. Using an estimate of the strain energy of the phantom, we were able to determine the nonlinear tissue properties.
Pub.: 25 Sep '04, Pinned: 04 Jul '17
Abstract: Ultrasound elastography is able to provide a non-invasive measurement of tissue elasticity properties. Shear wave imaging (SWI) technique is a quantitative method for tissue stiffness assessment. However, traditional SWI implementations cannot acquire 2D quantitative images of tissue elasticity distribution. In this study, a new shear wave imaging system is proposed and evaluated. Detailed delineation of hardware and image processing algorithms are presented. Programmable devices are selected to support flexible control of the system and the image processing algorithms. Analytic signal based cross-correlation method and a Radon transform based shear wave speed determination method are proposed with parallel computation ability. Tissue mimicking phantom imaging, and in vitro imaging measurements are conducted to demonstrate the performance of the proposed system. The system has the ability to provide a new choice for quantitative mapping of the tissue elasticity, and has good potential to be implemented into commercial ultrasound scanner.
Pub.: 07 Jan '16, Pinned: 04 Jul '17
Abstract: Shear wave elastography is a distinctive method to access the viscoelastic characteristic of the soft tissue that is difficult to obtain by other imaging modalities. This paper proposes a novel shear wave elastography (color Doppler shear wave imaging: CD SWI) for breast tissue. Continuous shear wave is produced by a small lightweight actuator which is attached to the tissue surface. Shear wave wavefront which propagates in tissue is reconstructed as a binary pattern which consists of zero and the maximum flow velocities on color flow image (CFI). Neither any modifications of the ultrasound color flow imaging instrument nor high frame rate ultrasound imaging instrument are required to obtain the shear wave wavefront map. Although two conditions, those are shear wave displacement amplitude condition and shear wave frequency condition, are needed in order to obtain map. However, these conditions are not severe restrictions in breast imaging. It is because minimum displacement amplitude is 16 μm for the ultrasonic wave frequency of 12 MHz and the shear wave frequency is available from several frequencies suited for breast imaging. Fourier analysis along time axis suppresses clutter noise in CFI. Directional filter extracts shear wave which propagates in the forward direction. Several maps, such as shear wave phase, velocity and propagation maps, are reconstructed by CD SWI. Accuracy of shear wave velocity measurement is evaluated for homogeneous agar gel phantom by comparing with ARFI method. Experimental results for breast tissue are shown for shear wave frequency of 296.6 Hz.
Pub.: 16 Nov '16, Pinned: 04 Jul '17
Abstract: Visualization of mechanical properties of tissue can aid in noninvasive pathology diagnosis. Shear wave elastography (SWE) measures the elastic properties of soft tissues by estimation of local shear wave propagation speed. In this paper, a new robust method for estimation of shear wave speed is introduced which has the potential for simplifying continuous filtering and real-time elasticity processing. Shear waves were generated by external mechanical excitation and imaged at a high frame rate. Three homogeneous phantoms of varying elastic moduli and one inclusion phantom were imaged. Waves propagating in separate directions were filtered and shear wave speed was estimated by inversion of the 1-D first-order wave equation. Final 2-D shear wave speed maps were constructed by weighted averaging of estimates from opposite traveling directions. Shear wave speed results for phantoms with gelatin concentrations of 5%, 7%, and 9% were 1.52 ± 0.10 m/s, 1.86 ± 0.10 m/s, and 2.37 ± 0.15 m/s, respectively, which were consistent with estimates computed from three other conventional methods, as well as compression tests done with a commercial texture analyzer. The method was shown to be able to reconstruct a 2-D speed map of an inclusion phantom with good image quality and variance comparable to conventional methods. Suggestions for further work are given.
Pub.: 17 Dec '15, Pinned: 04 Jul '17
Abstract: To evaluate and compare the performance of shear-wave elastography (SWE) for breast masses using the local shear wave speed (m/sec) vs. Young modulus (kPa).A total of 130 breast lesions in 123 women who underwent SWE before ultrasound- guided core needle biopsy or surgical excision were included. With the region-of-interest placed over the stiffest areas of the lesion on SWE, the quantitative mean, maximum, and standard deviation (SD) of the elasticity values were measured in kPa and m/sec for each lesion. The SD was also measured with the region-of-interest including the whole breast lesion (wSD). The area under the receiver operating characteristic curve (AUC), sensitivity, and specificity of each elasticity value measured in kPa and m/sec were compared.Of the 130 lesions, 49 (37.7%) were malignant and 81 (62.3%) were benign. The AUCs for the mean, maximum, and SD of the elasticity values using kPa and m/sec did not differ significantly: mean, 0.974 vs. 0.974; maximum, 0.960 vs. 0.976; SD, 0.916 vs. 0.916. However, the AUC for wSD showed a significant difference: 0.964 (kPa) vs. 0.960 (m/sec) (P=0.036). There was no significant difference in the sensitivity and specificity of the mean, maximum, and wSD of the elasticity values. However, the specificity of the SD was significantly different between the two different measurements: 95.1% (kPa) vs. 87.7% (m/sec) (P=0.031).The quantitative elasticity values measured in kPa and m/sec on SWE showed good diagnostic performance. The specificity of the SD and AUC of the wSD measured in kPa were significantly higher than those measured in m/sec.
Pub.: 18 Jun '14, Pinned: 04 Jul '17
Abstract: To evaluate the interobserver agreement and the diagnostic performance of 3D shear-wave elastography (SWE) for breast lesions in comparison with 2D SWE.A total of 163 breast lesions (malignant 48, benign 115) in 146 women who underwent B-mode ultrasound and SWE before biopsy were included. Two radiologists reviewed six data sets (B-mode, SWE, and a combination of both for 2D and 3D ultrasound). B-mode and SWE features were recorded. BI-RADS category was assigned for B-mode and combined sets. Interobserver variability was assessed using the κ statistic. Diagnostic performance of each data set was evaluated using the area under the ROC curve (AUC).SWE showed substantial to almost perfect agreement, with Ehomo in 2D SWE being higher than in 3D SWE. The AUC of 2D SWE was higher than 3D SWE for all SWE features, significantly so for Ecol (0.933 vs. 0.867, P = 0.002) and Emax (0.961 vs. 0.874, P = 0.006). After adding SWE to B-mode ultrasound, the AUC in 2D ultrasound increased significantly (0.968 vs. 0.912, P = 0.008), but 3D ultrasound showed no significant difference (0.966 vs. 0.935; P = 0.07).For 3D SWE, interobserver agreement was good, but the diagnostic performance was inferior to 2D SWE even after adding to B-mode ultrasound.• Shear-wave elastography (SWE) provides further diagnostic information during breast ultrasound. • 3D SWE diagnostic performance is inferior to 2D SWE. • In 3D SWE, interobserver agreement was good. • 2D B-mode ultrasound showed significant diagnostic improvement when combined with 2D SWE. • 3D B-mode ultrasound performance was not significantly improved when combined with 3D SWE.
Pub.: 06 Dec '12, Pinned: 04 Jul '17
Abstract: To compare shear-wave speed (SWS) measured by ultrasound-based point shear-wave elastography (pSWE) and MR elastography (MRE) on phantoms with a known shear modulus, and to assess method validity and variability.5 homogeneous phantoms of different stiffnesses were made. Shear modulus was measured by a rheometer, and this value was used as the standard. 10 SWS measurements were obtained at 4 different depths with 1.0-4.5 MHz convex (4C1) and 4.0-9.0 MHz linear (9L4) transducers using pSWE. MRE was carried out once per phantom, and SWSs at 5 different depths were obtained. These SWSs were then compared with those from a rheometer using linear regression analyses.SWSs obtained with both pSWE as well as MRE had a strong correlation with those obtained by a rheometer (R(2)>0.97). The relative difference in SWS between the procedures was from -25.2% to 25.6% for all phantoms, and from -8.1% to 6.9% when the softest and hardest phantoms were excluded. Depth dependency was noted in the 9L4 transducer of pSWE and MRE.SWSs from pSWE and MRE showed a good correlation with a rheometer-determined SWS. Although based on phantom studies, SWSs obtained with these methods are not always equivalent, the measurement can be thought of as reliable and these SWSs were reasonably close to each other for the middle range of stiffness within the measurable range.
Pub.: 07 Jan '17, Pinned: 04 Jul '17
Abstract: In the past decades, the oncogenic role of fibroblast growth factor receptor 2 has been demonstrated in a number of cancer types. However, studies have reported contradictory findings concerning the correlation between fibroblast growth factor receptor 2 expression and prognosis in solid tumors. To address this discrepancy, we performed a meta-analysis with 18 published studies (2975 patients) retrieved from PubMed, EMBASE, and Web of science. Data were extracted and computed into odds ratios. The results showed that fibroblast growth factor receptor 2 overexpression was significantly associated with decreased 3-year overall survival (odds ratio = 1.93, 95% confidence interval: 1.30-2.85, p = 0.001) and 5-year overall survival (odds ratio = 1.62, 95% confidence interval: 1.07-2.44, p = 0.02) in patients with solid tumors. Subgroup analysis revealed that high fibroblast growth factor receptor 2 expression was also associated with poor prognosis of gastric cancer, hepatocellular carcinoma, and esophageal cancer, but not correlated with pancreatic cancer. In conclusion, fibroblast growth factor receptor 2 overexpression is correlated with decreased survival in most solid tumors, suggesting that the expression status of fibroblast growth factor receptor 2 is a valuable prognostic biomarker and a novel therapeutic target in human solid tumors.
Pub.: 18 Jun '17, Pinned: 04 Jul '17
Abstract: To compare the survival benefit and safety of the low power cumulative and traditional high intensity focused ultrasound (HIFU) for locally advanced pancreatic cancer.We retrospectively analyzed 38 patients with locally advanced, inoperable, stage III pancreatic patients received HIFU treatment between January 2008 and April 2014 in the Department of Surgery, the Second Affiliated Hospital, Zhejiang University, School of Medicine. 11 of them received the low power cumulative HIFU treatment, while other 27 received the traditional HIFU treatment. The HIFU device used was the FEP-BY02 (Yuande Biomedical Engineering Co. Ltd, Beijing, China). Serum biochemistry and adverse events were assessed before and after treatment. All the patients were followed up until death. The survival rate and adverse events of two groups were compared.In 38 patients, the baseline characteristics including gender, age, Karnofsky performance status (KPS) score, tumor location of two groups were generally well balanced (P > 0.05). The median overall survival (OS) for low power cumulative HIFU group was 10.3 months (95% CI, 6.3-14.3 months), which is significantly longer than traditional HIFU group with 6.0 months (95% CI, 5.2-6.8 months) (P = 0.018). In low power cumulative HIFU group, the 6-month and 12-month survival rates were higher than traditional group, 100% v.s 44.4%, 11.1% v.s 36.4%, respectively. The adverse events in both groups include abdominal pain, fever, C-reactive protein (CRP) elevated. The incidence was lower in low power cumulative HIFU group, however, without statistical significance.The low power cumulative HIFU treatment showed a statistical significance in survival benefit with better safety profile compared to the traditional HIFU treatment in patients with locally advanced pancreatic cancer.
Pub.: 18 Jun '17, Pinned: 04 Jul '17
Abstract: Although pancreatic cancer is only the twelfth most common type of cancer in the world, it features a very unfavorable prognosis. The mortality rate almost equals the incidence rate, corroborating the very poor prognosis of pancreatic cancer. The 5-year survival rate for all stages of pancreatic ductal adenocarcinoma is only 7%. Surgical resection represents the only potentially curative treatment option for pancreatic ductal adenocarcinoma patients but is often not feasible due to the advanced stage of the disease upon diagnosis. For advanced disease, palliative chemotherapy is the treatment of choice although the regimens available to date are untargeted and have extensive side-effect profiles, making them unsuitable for patients with a low performance status. For this reason, early detection of pancreatic cancer is essential in order to provide patients with an optimal therapeutic approach. Up to the present day, carbohydrate antigen 19-9 is the only diagnostic marker approved by the U.S. Food and Drug Administration but its diagnostic potential is limited due to its restricted sensitivity and specificity, supporting the urgent need for novel biomarkers. In addition, prognostic and treatment-predictive biomarkers might provide essential information regarding personalized treatment decisions for individual patients. In this article, we aim to review current and future diagnostic, prognostic, and treatment-predictive biomarkers for pancreatic cancer.
Pub.: 18 Jun '17, Pinned: 04 Jul '17
Abstract: Recent epidemiological studies indicated that metformin might improve the survival of various cancers. However, its benefit on pancreatic cancer was controversial.We performed this meta-analysis to investigate the benefit of metformin on pancreatic cancer. A comprehensive literature search was performed through PubMed, Cochrane Library and Embase. Relative risk (RR) and hazard ratio (HR) with 95% confidence interval (CI) were pooled.The meta-analysis of 2 randomized controlled trials including181 pancreatic patients, revealed that metformin use was not associated with an improved overall survival at 6 months (RR=0.90, 95% CI=0.67-1.21), overall survival (HR=1.19, 95% CI=0.86-1.63) and progression-free survival (HR=1.39, 95% CI=0.97-1.99). But the meta-analysis of 8 cohorts, involving 2805 pancreatic patients with diabetes, demonstrated a favorable result with improved overall survival (HR=0.78, 95% CI=0.66-0.92).Observations in the cohort studies supported a favorable role of metformin while the data from randomized controlled trials did not support that. Therefore, more high-quality RCTs are warranted.
Pub.: 19 Jun '17, Pinned: 04 Jul '17
Abstract: Pancreatic cancer, primarily pancreatic ductal adenocarcinoma (PDAC), accounts for 2.4% of cancer diagnoses and 5.8% of cancer death annually. Early diagnoses can improve 5-year survival in PDAC. The aim of this systematic review was to determine the sensitivity, specificity and diagnostic accuracy values for MRI, CT, PET&PET/CT, EUS and transabdominal ultrasound (TAUS) in the diagnosis of PDAC.A systematic review was undertaken to identify studies reporting sensitivity, specificity and/or diagnostic accuracy for the diagnosis of PDAC with MRI, CT, PET, EUS or TAUS. Proportional meta-analysis was performed for each modality.A total of 5399 patients, 3567 with PDAC, from 52 studies were included. The sensitivity, specificity and diagnostic accuracy were 93% (95% CI=88-96), 89% (95% CI=82-94) and 90% (95% CI=86-94) for MRI; 90% (95% CI=87-93), 87% (95% CI=79-93) and 89% (95% CI=85-93) for CT; 89% (95% CI=85-93), 70% (95% CI=54-84) and 84% (95% CI=79-89) for PET; 91% (95% CI=87-94), 86% (95% CI=81-91) and 89% (95% CI=87-92) for EUS; and 88% (95% CI=86-90), 94% (95% CI=87-98) and 91% (95% C=87-93) for TAUS.This review concludes all modalities, except for PET, are equivalent within 95% confidence intervals for the diagnosis of PDAC.
Pub.: 19 Jun '17, Pinned: 04 Jul '17
Abstract: Purpose To evaluate the diagnostic accuracy of multiparametric ultrasonography (US) consisting of gray-scale US, color Doppler US, strain elastography, and contrast agent-enhanced US in the assessment of intratesticular lesions. Materials and Methods Institutional review board approval was obtained for this retrospective study. From January 2012 to December 2015, 55 focal testicular lesions that were indeterminate on gray-scale US scans were further characterized with color Doppler US, strain elastography, and contrast-enhanced US. Strain elastography was performed to assess tissue elasticity, and hard lesions were defined as malignant. Color Doppler US and contrast-enhanced US were performed to determine the absence or presence of vascularization. Avascular lesions were defined as benign. Histopathologic results or follow-up examinations served as reference standards. Correct classification rate, sensitivity, specificity, and likelihood ratio were calculated. Results Of 55 testicular lesions, 43 (78.2%) were benign and 12 (21.8%) were malignant. Single-modality sensitivities and specificities were 66.7% and 88.4% for color Doppler US, 100% and 76.7% for contrast-enhanced US, and 100% and 72.1% for strain elastography, respectively. Among 12 malignant lesions, color Doppler US failed to demonstrate vascularization in four (33.3%) lesions, which were positive for cancer at contrast-enhanced US. By combining strain elastography and contrast-enhanced US, a sensitivity of 100% and specificity of 93.0% were achieved in differentiating benign and malignant focal testicular lesions. Positive likelihood ratio was 5.7 for color Doppler US, 4.3 for contrast-enhanced US, 3.6 for strain elastography, 14.3 for strain elastography combined with color Doppler US, and 14.3 for strain elastography combined with contrast-enhanced US. Conclusion Multiparametric US allows for a reliable differentiation of benign and malignant intratesticular lesions and can potentially be useful in deciding whether orchiectomy can be replaced with follow-up or less invasive organ-sparing strategies. (©) RSNA, 2017.
Pub.: 20 Jun '17, Pinned: 04 Jul '17
Abstract: Immunotherapy has become a new modality of cancer treatment, but has had a limited success in treating PDAC. A combination approach to immunotherapy, using both immune checkpoint inhibitors and immune activating agonists, is needed, as PDAC does not respond to single-agent checkpoint inhibitors. Studies have also supported using vaccine-based therapies to prime the tumor microenvironment of PDAC with effector T-cells. Other therapeutic strategies including epigenetic agents, stroma modulators, radiotherapy, and T-cell transfer therapies may also prime the tumor microenvironment to overcome resistance to immune checkpoint inhibitors.
Pub.: 20 Jun '17, Pinned: 04 Jul '17
Abstract: To investigate the radiological findings prognostic for the development of pancreatic adenocarcinoma in a cohort of patients with hepatocellular carcinoma, using multiphasic computed tomography (CT).A case-cohort study performed in a single university hospital. A database of patients who received hepatocellular carcinoma (HCC) treatment and trimonthly follow-up with four-phase dynamic CT was used (n = 1848). The cohort group was randomly extracted from the database (n = 103). The case group comprised nine patients from the database who developed pancreatic adenocarcinoma. The radiological findings were assessed during follow-up (average, 32 months).The incidence of pancreatic mass, inhomogeneous parenchyma, loss of fatty marbling and main pancreatic duct dilatation gradually increased from 4 to 13 months before the diagnosis of pancreatic adenocarcinoma. There was a significantly higher incidence of pancreatic mass, inhomogeneous parenchyma and loss of fatty marbling on CT at baseline (average, 34 months before diagnosis) in the case group compared with the cohort group (P values < 0.01) and those findings at baseline were revealed as prognostic factors for pancreatic carcinogenesis, respectively (log-rank test, P values < 0.001).Several radiological findings observed on multiphasic CT can assist in predicting pancreatic carcinogenesis well in advance.• Pancreatic findings in multiphasic CT help predict development of pancreatic adenocarcinoma. • Key findings are mass, inhomogeneous parenchyma and loss of fatty marbling. • Those findings were observed 34 months before confirmed diagnosis of adenocarcinoma. • Those findings were prognostic factors for pancreatic carcinogenesis.
Pub.: 21 Jun '17, Pinned: 04 Jul '17
Abstract: To investigate the feasibility of strain elastography imaging in early detecting and predicting treatment response in patients receiving concurrent chemo-radiotherapy (CCRT) for locally advanced cervical cancer.Between January 2015 and June 2016, 47 patients with locally advanced cervical cancer were enrolled in a feasibility study approved by the institutional review board. All patients underwent CCRT and received strain elastography examinations at 4 time points: pre-therapy (baseline), 1 week and 2 weeks during, as well as immediately post CCRT. Treatment response was evaluated by MRI at the time of diagnosis and immediately after CCRT. Based on the MRI findings, the treatment outcome was characterized as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Strain ratio of the normal parametrial tissue vs. cervical tumor was calculated and compared with the clinical outcome.Out of the 47 patients, 36 patients who completed all 4 examinations were included in the analyses: 25 were classified as CR, 11 as PR, and 0 in the SD/PD groups. Strain ratios were significantly different among the time points in both the CR group (F = 87.004, p < 0.001) and PR group (F = 38.317, p < 0.001). Strain ratios were significantly difference between the CR and PR groups (F = 7.203 p = 0.011). Strain ratios between the CR group and PR group were significantly different at 1 week after treatment initiation (p < 0.05). Compared to the baseline, a significant decrease in the CR group was observed at week 1, week 2 and post treatment (all p < 0.001), while a significant decrease in the PR group was shown in week 2 and post treatment (both p < 0.05), but not at week 1 during CCRT (p = 0.084).We have conducted a prospective longitudinal study to evaluate tumor response in women receiving CCRT for cervical cancers. This study has demonstrated the potential of strain elastography imaging in monitoring and early predicting tumor response induced by CCRT.
Pub.: 21 Jun '17, Pinned: 04 Jul '17
Abstract: Pancreatic cancer is the third leading cause of cancer mortality in both men and women in the United States, with poor response to current standard of care, short progression-free and overall survival. Immunotherapies that target cytotoxic T lymphocyte antigen-4, programmed cell death protein-1, and programmed death-ligand 1 checkpoints have shown remarkable activities in several cancers such as melanoma, renal cell carcinoma, and non-small cell lung cancer due to high numbers of somatic mutations, combined with cytotoxic T-cell responses. However, single checkpoint blockade was ineffective in pancreatic cancer, highlighting the challenges including the poor antigenicity, a dense desmoplastic stroma, and a largely immunosuppressive microenvironment. In this review, we will summarize available clinical results and ongoing efforts of combining immune checkpoint therapies with other treatment modalities such as chemotherapy, radiotherapy, and targeted therapy. These combination therapies hold promise in unleashing the potential of immunotherapy in pancreatic cancer to achieve better and more durable clinical responses by enhancing cytotoxic T-cell responses.
Pub.: 24 Jun '17, Pinned: 04 Jul '17
Abstract: Recent studies support the use of gemcitabine and nab-paclitaxel in adults with locally advanced unresectable or metastatic pancreatic adenocarcinoma although insufficient data are available on prognostic and predictive markers of response to treatment.The objective of this study is to identify treatment response markers in patients with locally advanced unresectable or metastatic pancreatic adenocarcinoma.This is an observational, retrospective, and multicenter study. Sociodemographic, clinical, and therapeutic data were collected. Cox regression models were applied to determine associations.In total, 39 patients were included; 23.1% presented locally advanced pancreatic cancer and 76.9% metastatic disease. They received a mean of 6 ± 3 treatment cycles; 59% required dose reduction, 59% treatment delay, and 20.5% switched to a biweekly regimen. The overall response rate was 23% and the disease control rate was 81%. Median progression-free survival was 9 months and median overall survival (OS) was 15 months. A higher neutrophil/lymphocyte ratio (NLR) was significantly associated with lower OS. We reported Grades 1-4 nonhematological and hematological toxicities.NLR is a useful prognostic factor for OS in patients with locally advanced unresectable or metastatic pancreatic adenocarcinoma treated with gemcitabine and nab-paclitaxel. Moreover, we suggest that a biweekly regimen is an option for certain groups of patients.
Pub.: 24 Jun '17, Pinned: 04 Jul '17
Abstract: The use of neoadjuvant chemotherapy or radiation for borderline resectable pancreatic adenocarcinoma (BL-PDAC) is increasing. However, the impact of neoadjuvant chemotherapy and radiation therapy on the outcome of BL-PDAC remains to be elucidated. We performed a retrospective analysis of 93 consecutive patients who were diagnosed with BL-PDAC and primarily followed at Johns Hopkins Hospital between February 2007 and December 2012. Among 93 patients, 62% received upfront neoadjuvant chemotherapy followed by chemoradiation, whereas 20% received neoadjuvant chemoradiation alone and 15% neoadjuvant chemotherapy alone. Resectability following all neoadjuvant therapy was 44%. Patients who underwent resection with a curative intent had a median overall survival (mOS) of 25.8 months, whereas those who did not undergo surgery had a mOS of 11.9 months. However, resectability and overall survival were not significantly different between the three types of neoadjuvant therapy. Nevertheless, 22% (95% CI, 0.13-0.36) of the 58 patients who received upfront chemotherapy followed by chemoradiation remained alive for a minimum of 48 months compared to none of the 19 patients who received upfront chemoradiation. Among patients who underwent curative surgical resection, 32% (95% CI, 0.19-0.55) of those who received upfront chemotherapy remained disease free at least 48 months following surgical resection, whereas none of the eight patients who received upfront chemoradiation remained disease free beyond 24 months following surgical resection. Neoadjuvant therapy with upfront chemotherapy may result in long-term survival in a subpopulation of patients with BL-PDAC.
Pub.: 24 Jun '17, Pinned: 04 Jul '17
Abstract: Treatment of pancreatic cancer is multimodal and surgery is an essential part, mandatory for curative potential. Also chemotherapy is essential, and serious postoperative complications or rapid disease progression may preclude completion of multimodal treatment. The sequence of treatment interventions has therefore become an important concern, and numerous ongoing randomized controlled trials compare clinical outcome after upfront surgery and neoadjuvant treatment with subsequent resection. In previous years, borderline resectable and locally advanced pancreatic cancer was most often considered unresectable. More effective chemotherapy together with the latest improvements in surgical expertise has resulted in extended operations, pushing the borders of resectability. Multivisceral resections with or without resection of major mesenteric vessels are now performed in numerous patients, resulting in better outcome, recorded as overall survival and/or patient reported outcome. But postoperative morbidity increases concurrently, and clinical benefit must be carefully evaluated against risk of potential harm, associated with new comprehensive multimodal treatment sequences. Even though cost/utility analyses are deficient, extended surgery has resulted in significantly longer and better life for many patients with no other treatment alternative. Improved selection of patients to surgery and/or chemotherapy will in the near future be possible, based on better tumor biology insight. Clinically available biomarkers enabling personalized treatment are forthcoming, but these options are still limited. The importance of surgical resection for each patient's prognosis is presently increasing, justifying sustained expansion of the surgical treatment modality.
Pub.: 24 Jun '17, Pinned: 04 Jul '17
Abstract: To evaluate the diagnostic accuracy of shear wave elastography (SWE) and transient elastography (TE) in the evaluation of liver fibrosis in chronic hepatitis B (CHB) and C (CHC) patients taking liver biopsy as gold standard.Ethics committee approved this prospective cross-sectional study. Between October 2012 and December 2014, consecutive CHB/CHC patients fulfilling the inclusion criteria were included-age more than 18 years, informed written consent, willing and suitable for liver biopsy. SWE, TE, and biopsy were performed the same day. Liver stiffness measurement (LSM) cut-offs for various stages of fibrosis were generated for SWE and TE. AUC, sensitivity, specificity, and positive/negative predictive values were estimated individually or in combination.CH patients (n = 240, CHB 172, CHC 68), 176 males, 64 females, mean age 32.6 ± 11.6 years were enrolled. Mean LSM of patients with no histological fibrosis (F0) was 5.0 ± 0.7 and 5.1+1.4 kPa on SWE and TE, respectively. For differentiating F2 and F3-4 fibrosis on SWE, at 7.0 kPa cut-off, the sensitivity was 81.3% and specificity 77.6%. For TE, at 8.3 kPa cut-off, sensitivity was 81.8% and specificity 83.1%. For F3 vs. F4, SWE sensitivity was 83.3% and specificity 90.7%. At 14.8 kPa cut-off, TE showed similar sensitivity (83.3%) but specificity increased to 96.5%. Significant correlation between SWE and TE was observed (r = 0.33, p < 0.001). On combining SWE and TE, a drop in sensitivity with increased specificity for all stages of liver fibrosis occured.SWE is an accurate technique for evaluating liver fibrosis. SWE compares favorably with TE especially for predicting advanced fibrosis/cirrhosis. Combining SWE and TE further improves specificity.
Pub.: 24 Jun '17, Pinned: 04 Jul '17
Abstract: This study aimed to evaluate the diagnostic value of acoustic radiation force impulse (ARFI) imaging and strain elastography in differentiating malignant from benign thyroid nodules.This study included 128 patients (104 female and 24 male; mean age ± standard deviation, 48 ± 11 years; range, 23-76 years) with 152 pathologically proven thyroid nodules. Conventional sonography, strain ratio (SR) of strain elastography, virtual touch tissue imaging (VTI) grade, and virtual touch tissue quantification (shear wave velocity [SWV]) from ARFI imaging data were generated for each nodule. The diagnostic performance of the three elastography analysis methods was analyzed and compared by multiple receiver operating characteristic curve analysis. The interobserver agreement for VTI grade was also assessed.The best cutoff values for VTI grade, mean SWV, and mean SR for predicting malignant thyroid nodules were greater than or equal to grade χ, 2.87 m/s and 2.37, respectively. The area under the receiver operating characteristic curve for VTI grade, mean SWV, and mean SR was 0.854, 0.869 and 0.849, respectively (P > .05), and the accuracy was 83.55, 81.58 and 80.26%, respectively (P > .05). The accuracy of the combined use of conventional sonography and ARFI imaging for VTI grade, mean SWV, and mean SR was 98.03, 95.39 and 96.71%, respectively, which was slightly higher than that of conventional sonography (P > .05). The interobserver agreement produced a κ-value of 0.98 (95% confidence interval, 0.959-1.000).Both strain elastography and ARFI imaging have high sensitivity and specificity for differentiating malignant from benign thyroid nodules. Combined with sonography, these techniques can improve the accuracy of thyroid nodule diagnosis.
Pub.: 25 Jun '17, Pinned: 04 Jul '17
Abstract: To investigate the use of measurements of liver stiffness (LS) by two-dimensional real-time shear wave elastography (SWE) for predicting the development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB).We retrospectively collected data on 291 enrolled patients with CHB whose LS had been measured using SWE.The mean age of the patients was 46.8 years; males predominated (67%), and 40 of the patients (14%) had clinical cirrhosis. Among the patients, 165 (56.7%) received antiviral treatment. The median LS value was 7.4 kPa, and the median follow-up period was 35.8 months (range, 3.0 to 52.8 months). During follow-up, HCC developed in 13 patients (4.5%), and the cumulative incidence rates of HCC at 1, 2, and 4 years were 1.1%, 3.6%, and 8.4%, respectively. Based on a multivariate analysis, older age (≥50 years) and higher LS value (≥10 kPa) were independently associated with the risk of developing HCC (hazard ratio [HR], 4.53, p=0.023; and HR, 4.08, p=0.022). The cumulative incidence rate of HCC was significantly higher in patients with higher LS values (≥10 kPa) than in those with lower LS values (<10 kPa) (p=0.001).Increased LS measured by SWE at any time point regardless of antiviral treatment is associated with an increased risk of HCC in patients with CHB.
Pub.: 27 Jun '17, Pinned: 04 Jul '17
Abstract: Our aim was to comparatively investigate the strain ratio and thickness of the Achilles tendon in children with cerebral palsy (CP), and to elucidate whether there is a correlation between biomechanical features of the Achilles tendon and strain ratio.A total of 155 participants (72 CP patients and 83 healthy controls) who underwent real-time elastography of both Achilles tendons were studied. A linear transducer (4.8-11.0 MHz) was used to obtain the images. Correlation analysis between age, length, and thickness of the Achilles tendon, and strain ratio (SR) was performed by means of Pearson correlation and Spearman's rho tests.Comparison of results obtained from CP patients and controls showed that the length of the Achilles tendon was shorter (p < 0.001) and SR was higher (p < 0.001) in CP patients. In CP patients, there was a positive correlation between SR and age and between SR and the thickness and length of the Achilles tendon (p < 0.001 for all). Furthermore, the length of the tendon and age were positively associated (p < 0.001). ROC analysis revealed that the cut-off value for SR was 1.89.The results of the present study demonstrated that real-time elastography can constitute a simple, practical, and noninvasive method for evaluation of the elasticity of the Achilles tendon in children with CP.
Pub.: 29 Jun '17, Pinned: 04 Jul '17
Abstract: Desmoplasia is a characteristic feature and a suspected mechanism of tumor progression in pancreatic ductal adenocarcinoma (PDAC). Main constituents of the stroma involve cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM). The aim of this study was to dissect the interaction of CAFs, ECM, and PDAC cells in both an in vitro setting and a large-scale clinical cohort study.Patients operated for PDAC were identified from our prospectively maintained clinical database. A standard pathology protocol was applied for pancreatoduodenectomy specimens also assessing CAF activation as either CAF grade 0 or CAF grade +. Interaction between a spectrum of pancreatic cancer cell lines (PCCs) and mouse embryonic fibroblasts (NIH 3T3) was assessed in a conditioned medium experimental setup.One hundred eleven patients operated for PDAC from 2001 to 2011 were identified. Univariate analysis disclosed CAF grade + (P = .030), positive M status (P < .001), and lymph node ratio (LNR) > 0.1 (P = .045) to impair overall survival. Independent prognostic factors were CAF grade (P = .050) and positive M status (P = .002). CAF grade correlated with N status (CC = 0.206, P = .030), LNR (CC = 0.187, P = .049), tumor size (CC = -0.275, P = .003), and M status (CC = 0.190, P = .045). In the in vitro setting, paracrine effects of pancreatic cancer cell resulted in morphological activation of fibroblasts and tumor cell differentiation-dependent increase of fibroblast growth. Paracrine effects of poorly differentiated PCCs led to an upregulation of Vimentin in NIH 3T3 fibroblasts. Paracrine effects of fibroblasts on their part promoted cancer cell motility in all PCCs. As the second stromal component, fibroblast-derived ECM resulted in significantly decreased proliferation depending on density and led to upregulation of ZEB1 in poorly differentiated PCCs.In PDAC patients, positive CAF grading was identified as a negative prognostic parameter correlating with positive N status, high LNR, positive M status, and smaller tumor size. Whereas bilateral interaction of PCCs and CAFs promotes tumor progression, ECM poses PCC growth restrictions. In summary, our study discloses differential effects of stromal components and may help to interpret heterogeneous results of former studies.
Pub.: 29 Jun '17, Pinned: 04 Jul '17
Abstract: Targeting the rich extracellular matrix of desmoplastic tumors has been successfully shown to normalize collagen and hyaluronan levels and re-engineer intratumoral mechanical forces, improving tumor perfusion and chemotherapy. As far as targeting the abundant cancer-associated fibroblasts (CAFs) in desmoplastic tumors is concerned, while both pharmacologic inhibition of the sonic-hedgehog pathway and genetic depletion of fibroblasts have been employed in pancreatic cancers, the results between the two methods have been contradictory. In this study, we employed vismodegib to inhibit the sonic-hedgehog pathway with the aim to i) elucidate the mechanism of how CAFs depletion improves drug delivery, ii) extent and evaluate the potential use of sonic-hedgehog inhibitors to breast cancers, and iii) investigate whether sonic-hedgehog inhibition improves not only chemotherapy, but also the efficacy of the most commonly used breast cancer nanomedicines, namely Abraxane® and Doxil®. We found that treatment with vismodegib normalizes the tumor microenvironment by reducing the proliferative CAFs and in cases the levels of collagen and hyaluronan. These modulations re-engineered the solid and fluid stresses in the tumors, improving blood vessel functionality. As a result, the delivery and efficacy of chemotherapy was improved in two models of pancreatic cancer. Additionally, vismodegib treatment significantly improved the efficacy of both Abraxane and Doxil in xenograft breast tumors. Our results suggest the use of vismodegib, and sonic hedgehog inhibitors in general, to enhance cancer chemo- and nanotherapy.
Pub.: 01 Jul '17, Pinned: 04 Jul '17