Distinguishing mesorectal tumor deposits from metastatic lymph nodes by using diffusion-weighted and dynamic contrast-enhanced magnetic resonance imaging in rectal cancer.

OBJECTIVES: This study aimed to identify whether apparent diffusion coefficient (ADC) values and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters are helpful in distinguishing mesorectal tumor deposits (TD) from metastatic lymph nodes (MLN) in rectal cancer (RC). METHODS: Thirty patients (59 lesions, including 30 TD and 29 MLN) with RC who underwent pretreatment-MRI between February 2016 and August 2018 were enrolled. The morphological features, ADC values, and semi-quantitative parameters of DCE-MRI, including relative enhancement (RE), maximum enhancement (ME), maximum relative enhancement (MRE), time to peak (TTP), wash-in rates (WIR), wash-out rates (WOR), brevity of enhancement (BRE), and area under the curve (AUC) were measured on lesions (TD or MLN) and RC. The parameters were compared between TD and MLN, tumor with and without TD group by using Fisher's exact test, independent-samples t-test, and Mann-Whitney U test. The ratio (lesion-to-tumor) of the parameters was compared between TD and MLN. Receiver operating characteristic curve analysis and binary logistic regression analysis were used to assess the diagnostic ability of single and combined metrics for distinguishing TD from MLN. RESULTS: The morphological features, including size, shape, and border, were significantly different between TD and MLN. TD exhibited significantly lower RE, MRE, RE-ratio, MRE-ratio, ADCmin-ratio, and ADCmean-ratio than MLN. RE-ratio showed the highest AUC (0.749) and accuracy (77.97%) among single parameters. The combination of DCE-MRI and DWI parameters together showed higher diagnostic efficiency (AUC = 0.825). CONCLUSIONS: Morphological features, ADC values, and DCE-MRI parameters can preoperatively help distinguish TD from MLN in RC. KEY POINTS: • DWI and DCE-MRI can facilitate early detection and distinguishing mesorectal TD (tumor deposits) from MLN (metastatic lymph nodes) in rectal cancer preoperatively. • TD has some specific morphological features, including relatively larger size, lower short- to long-axis ratio, irregular shape, and ill-defined border on T2-weighted MR images in rectal cancer. • The combination of ADC values and semi-quantitative parameters of DCE-MRI (RE, MRE) can help to improve the diagnostic efficiency of TD in rectal cancer.

MRI Evaluation of Complete Response of Locally Advanced Rectal Cancer After Neoadjuvant Therapy: Current Status and Future Trends.

Complete tumor response can be achieved in a certain proportion of patients with locally advanced rectal cancer, who achieve maximal response to neoadjuvant therapy (NAT). For these patients, a watch-and-wait (WW) or nonsurgical strategy has been proposed and is becoming widely practiced in order to avoid unnecessary surgical complications. Therefore, a non-invasive, reliable diagnostic tool for accurately evaluating complete tumor response is needed. Magnetic resonance imaging (MRI) plays a crucial role in both primary staging and restaging tumor response to NAT in rectal cancer without relying on resected specimen. In recent years, numerous efforts have been made to research the value of MRI in predicting and evaluating complete response in rectal cancer. Current MRI evaluation is mainly based on morphological and functional images. Morphologic MRI yields high soft tissue resolution, multiplanar images, and provides detailed depictions of rectal cancer and its surrounding structures. Functional MRI may help to distinguish residual tumor from fibrosis, therefore improving the diagnostic performance of morphologic MRI in identifying complete tumor response. Both morphologic and functional MRI have several promising parameters that may help accurately evaluate and/or predict complete response of rectal cancer. However, these parameters still have limitations and the results remain inconsistent. Recent development of new techniques, such as textural analysis, radiomics analysis and deep learning, demonstrate great potential based on MRI-derived parameters. This article aimed to review and help better understand the strengths, limitations, and future trends of these MRI-derived methods in evaluating complete response in rectal cancer.

Characterizing MRI features of rectal cancers with different KRAS status.

BACKGROUND: To investigate whether MRI findings, including texture analysis, can differentiate KRAS mutation status in rectal cancer. METHODS: Totally, 158 patients with pathologically proved rectal cancers and preoperative pelvic MRI examinations were enrolled. Patients were stratified into two groups: KRAS wild-type group (KRASwt group) and KRAS mutation group (KRASmt group) according to genomic DNA extraction analysis. MRI findings of rectal cancers (including texture features) and relevant clinical characteristics were statistically evaluated to identify the differences between the two groups. The independent samples t test or Mann-Whitney U test were used for continuous variables. The differences of the remaining categorical polytomous variables were analyzed using the Chi-square test or Fisher exact test. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the discriminatory power of MRI features. The area under the ROC curve (AUC) and the optimal cut-off values were calculated using histopathology diagnosis as a reference; meanwhile, sensitivity and specificity were determined. RESULTS: Mean values of six texture parameters (Mean, Variance, Skewness, Entropy, gray-level nonuniformity, run-length nonuniformity) were significantly higher in KRASmt group compared to KRASwt group (p < 0.0001, respectively). The AUC values of texture features ranged from 0.703~0.813. In addition, higher T stage and lower ADC values were observed in the KRASmt group compared to KRASwt group (t = 7.086, p = 0.029; t = - 2.708, p = 0.008). CONCLUSION: The MRI findings of rectal cancer, especially texture features, showed an encouraging value for identifying KRAS status.

Laparoscopic spleen-preserving distal versus central pancreatectomy for tumors in the pancreatic neck and proximal body.

For benign and borderline tumors in the pancreatic neck and proximal body, laparoscopic spleen-preserving distal pancreatectomy (LSPDP) and laparoscopic central pancreatectomy (LCP) are alternative surgical procedures. Choosing between LSPDP and LCP is difficult. This retrospective cohort study was looking forward to provide evidence for clinical decision.A total of 59 patients undergoing LSPDP (Kimura procedure) and LCP between June 2013 and March 2017 were selected. The clinical outcomes of patients were compared by χ test or Fisher exact test and Student t test.This study included 36 patients in LSPDP group, and 23 patients in LCP group. The overall complications incidence in LCP group was significantly higher than LSPDP group (35 vs 6%, P = .004), and the postoperative pancreatic fistula (POPF) (grade B and C) rate and abdominal infection rate in LCP group were still significantly higher than LSPDP group (POPF 22 vs 3%, P = .019; abdominal infection 35 vs 3%, P = .001, respectively). The length of resected pancreas was significantly longer in LSPDP group (9.8 ±â€Š2.0 vs 5.3 ±â€Š1.1 cm, P = .007). The median follow-up was 39 months (range 12-57 months). No patient was confronted by tumor recurrence. The proportion of postoperative pancreatin and insulin treatment in LCP group were similar to LSPDP group (9 vs 17%, P = .383; 0 vs 3%, P = 1.000, respectively).For patients with poor general condition, the safety of LCP needs to be taken seriously; in some ways, LSPDP may be more secure, physiological, and easier operation for tumor located in pancreatic neck and proximal body.

Correlation Between Intravoxel Incoherent Motion and Dynamic Contrast-Enhanced Magnetic Resonance Imaging Parameters in Rectal Cancer.

RATIONALE AND OBJECTIVES: This study aimed to determine the correlation between intravoxel incoherent motion (IVIM) and multiphase dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) quantitative parameters in patients with rectal cancer. MATERIALS AND METHODS: Ninety-seven patients with rectal cancer were included in this study. All pelvic MRI examinations were performed in a 3.0 T MR unit, including diffusion-weighted imaging with 16 b values, DCE-MRI with two different flip angles (5° and 10°, respectively), and T1-fast field echo sequences as the reference. The IVIM perfusion-related parameters (f, perfusion fraction; D*, pseudo-diffusion coefficient; f·D*, the multiplication of the two parameters) were calculated by biexponential analysis. Quantitative DCE-MRI parameters were transfer constant (Ktrans) between blood plasma and extravascular extracellular space), Kep (rate between extravascular extracellular space and blood plasma), Ve (extravascular volume fraction), Vp (plasma volume fraction), and area under the gadolinium concentration curve. Interobserver agreements were evaluated using the intraclass correlation coefficient and Bland-Altman analysis. A p value <0.05 indicated a statistically significant difference. RESULTS: The study included 75 males and 22 females with a median age of 58.8 years (range, 26-85years). Interobserver reproducibility for IVIM perfusion-related parameters and DCE-MRI quantitative parameters was good to excellent (intraclass correlation coefficient = 0.8618-0.9181, intraclass correlation coefficient = 0.7826-0.9088, respectively). Moderate correlations were found between f·D* and Ktrans (r = 0.533; p < 0.001), and relatively weak correlations between D* and Ktrans (r = 0.389; p < 0.001), D* and Vp (r = 0.442; p < 0.001), f·D* and Vp (r = 0.466; p < 0.001), and f and Vp (r = -0.234; p = 0.021). CONCLUSION: IVIM perfusion-related parameters, especially f·D*, demonstrated moderate correlations with DCE-MRI quantitative parameters in rectal cancer.

Could IVIM and ADC help in predicting the KRAS status in patients with rectal cancer?

PURPOSE: To evaluate the diagnostic potential of DW-MRI relative parameters for differentiation of rectal cancers with different Kirsten rat sarcoma viral oncogene homologue (KRAS) mutation status. METHODS: Fifty-one patients with rectal cancer underwent diffusion-weighted MR imaging with eight b values. ADCs (including Max-ADC, Min-ADC and Mean-ADC) and IVIM parameters (D, pure diffusion; f, perfusion fraction; D*, pseudodiffusion coefficient) were respectively calculated by mono- and bi-exponential analysis. Patients were stratified into two groups: KRAS wild type and mutant. The DW-MRI-derived parameters between the KRAS wild-type group and KRAS mutant group were compared using the Mann-Whitney U test. Receiver-operating characteristic (ROC) analysis of discrimination between KRAS wild-type and KRAS mutant rectal cancer was performed for the DW-MRI-derived parameters. RESULTS: Max-ADC, Mean-ADC and D values were significantly lower in the KRAS mutant group than in the KRAS wild-type group, whereas a higher D* value was demonstrated in the KRAS mutant group. According to the ROC curve, Mean-ADC and D* values showed moderate diagnostic significance with the AUC values of 0.756 and 0.710, respectively. The cut-off values for Mean-ADC and D* were 1.43 × 10-3mm2/s and 26.58 × 10-3mm2/s, respectively. CONCLUSION: Rectal cancers had distinctive diffusion/perfusion characteristics in different KRAS mutation statuses. The DW-MRI-derived parameters, specifically Mean-ADC and D*, show a moderate diagnostic significance for KRAS status. KEY POINTS: • Rectal cancers with different KRAS mutation statuses demonstrated distinctive diffusion/perfusion characteristics. • Max-ADC, Mean-ADC and D values were lower in the KRAS mutant group. • A higher D* value was demonstrated in the KRAS mutant group. • IVIM-DW MRI may potentially help preoperative KRAS mutant status prediction.

Quantitative intravoxel incoherent motion parameters derived from whole-tumor volume for assessing pathological complete response to neoadjuvant chemotherapy in locally advanced rectal cancer.

BACKGROUND: Many locally advanced rectal cancer (LARC) patients can benefit from neoadjuvant chemotherapy (NACT), with some achieving a pathological complete response (pCR). However, there is limited research reporting on the value of intravoxel incoherent motion (IVIM) in monitoring pCR in patients with LARC. PURPOSE: To identify whether IVIM parameters derived from whole-tumor volume (WTV) before and after NACT could accurately assess pCR in patients with LARC. STUDY TYPE: Prospective patient control study. POPULATION: Fifty-one patients with LARC before and after NACT, prior to surgery. FIELD STRENGTH/SEQUENCE: IVIM-diffusion imaging at 3T. ASSESSMENT: Apparent diffusion coefficient (ADC), slow diffusion coefficient (D), fast diffusion coefficient (D*), and perfusion-related diffusion fraction (f) values were obtained on diffusion-weighted magnetic resonance images (DW-MRI) using WTV methods and calculated using a biexponential model before and after NACT. STATISTICAL TESTS: DWI-derived ADC and IVIM-derived parameters and their percentage changes (ΔADC%, ΔD%, ΔD*%, and Δf%) were compared using independent-samples t-test and Mann-Whitney U-test between the pCR and non-pCR groups. The diagnostic performance of IVIM parameters and their percentage changes were evaluated using receiver operating characteristic curves. RESULTS: Compared with the non-pCR group, the pCR group exhibited significantly lower pre-ADCmean (P = 0.003) and pre-D values (P = 0.024), and significantly higher post-f (P = 0.002), ΔADCmean % (P = 0.002), ΔD% (P = 0.001), and Δf% values (P = 0.017). Receiver operating characteristic curves showed that the pre-D value had the best specificity (95.12%) and accuracy (86.27%) in predicting the pCR status, and ΔD% had the highest area under the curve (0.832) in assessing the pCR response to NACT. DATA CONCLUSIONS: The IVIM-derived D value is a promising tool in predicting the pCR status before therapy. The percentage changes in D values after therapy may help assess the pCR status prior to surgery. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017.

Rectal cancer: Short-term reproducibility of intravoxel incoherent motion parameters in 3.0T magnetic resonance imaging.

The aim of this study was to evaluate the short-term test-retest reproducibility of diffusion-weighted magnetic resonance imaging (DW-MRI) parameters of rectal cancer with 3.0T MRI.Twenty-six patients with rectal cancer underwent MRI, including diffusion-weighted imaging with 8 b values. Apparent diffusion coefficient (ADC) and intravoxel incoherent motion (IVIM) parameters (D, pure diffusion; f, perfusion fraction; D*, pseudodiffusion coefficient) were, respectively, calculated. The short-term test-retest reproducibility, the intra and interobserver variation of the IVIM parameters were assessed based on the repeatability coefficient and Bland-Altman limits of agreement.There was no significant intra or interobserver difference observed in the parameters on the same DW-MRI scan. The corresponding repeatability coefficient of intra- and interobserver analysis for ADC, D, f, and D* was 5.4%, 11.1%, 55.4%, and 40.3%; 10.9%, 41.6%, 134.0%, and 177.6%, respectively. The test-retest repeatability coefficient for ADC, D, f, and D* was 19.1%, 24.5%, 126.3%, and 197.4%, respectively, greater than the intraobserver values.ADC and D have better short-term test-retest reproducibility than f and D*. Considering the poor test-retest reproducibility for f and D,* variance in these 2 parameters should be interpreted with caution in longitudinal studies on rectal cancer in which treatment response and recurrence are monitored.

HER2-targeted antibody drug conjugates for ovarian cancer therapy.

HER2 targeted delivery of ovarian cancer therapy has been beneficial for some patients, although, its efficacy is yet to be confirmed in large populations. We generated a novel anti-HER2 humanized antibody (Hertuzumab) and conjugated it to a microtubule-disrupting drug monomethyl auristatin E conjugate (MMAE) with a lysosomal protease-cleavable valine-citrulline linker. The average drug to antibody ratio (DAR) of Hertuzumab-vc-MMAE was varied by conjugating Hertuzumab antibodies with increasing linker-drugs (LDs) from D0-D8. The resulting conjugates were tested for kinetic affinity for soluble HER2-ECD, cytotoxicity, and in vivo pharmacokinetics. The kinetic binding constant values (KD) were obtained by the bio-layer interference (BLI) method. The half time (t1/2) and clearance (Cl) results of the pharmacokinetic profile in rats were DAR-dependent. Hertuzumab-vc-MMAE with DAR4 was selected for further evaluation. Both Hertuzumab and Hertuzumab conjugates could bind to HER2 antigen, and exhibited significant cytotoxicity on HER2 positive tumor cells after internalization by receptor-mediated endocytosis. Hence, Hertuzumab-vc-MMAE conjugates were significantly selective both in vitro and in vivo as compared to other ovarian cancer clinical therapies that are currently used. Cell signal transduction and cell cycle were also affected, as shown by down regulation of PI3K/AKT pathway and arrested mitosis in the G2/M phase. The pharmacokinetics and pharmacodynamics (PK-PD) of the conjugates in nude mouse xenograft model demonstrated a correlation between efficacy and drug concentration. These results show that Hertuzumab-vc-MMAE is a potential therapeutic agent for HER2 positive ovarian cancer.

Dual blockade of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) exhibits potent anti-angiogenic effects.

Both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF or FGF-2) are potent pro-angiogenic factors and play a critical role in cancer development and progression. Clinical anti-VEGF therapy trials had a major challenge due to upregulated expression of other pro-angiogenic factor, like FGF-2. This study developed a novel chimeric decoy receptor VF-Trap fusion protein to simultaneously block activity of both VEGF and FGF pathways in order to achieve an additive or synergistic anti-tumor effect. Our in vitro data showed that VF-Trap potently blocked proliferation and migration of both VEGF- and FGF-2-induced vascular endothelial cells. In animal models, treatment of xenograft tumors with VF-Trap resulted in significant inhibition of tumor growth compared to blockage of the single molecule, like VEGF or FGF blocker. In addition, VF-Trap was also more potent in inhibition of ocular angiogenesis in a mouse oxygen-induced retinopathy (OIR) model. These data demonstrated the potent anti-angiogenic effects of this novel VF-Trap fusion protein on blockage of VEGF and FGF-2 activity in vitro and in animal models. Further study will assess its effects in clinic as a therapeutic agent for angiogenesis-related disorders, such as cancer and ocular vascular diseases.

An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer.

Antibody-drug conjugate (ADC) is a novel class of therapeutics for cancer target therapy. This study assessed antitumor activity of ADC with an antimitotic agent, monomethyl auristatin E (MMAE) and a humanized monoclonal anti-HER2 antibody, hertuzumab, in gastric cancer. The efficacy of hertuzumab-MC-Val-Cit-PAB-MMAE (hertuzumab-vcMMAE) on human epidermal growth factor receptor 2 (HER2) positive human gastric cancer cells, NCI-N87, was evaluated in vitro and in vivo. The cytotoxicity of hertuzumab was significantly enhanced after conjugation with MMAE. Compared to trastuzumab, hertuzumab had a higher affinity to HER2 and had more potent antibody-dependent cell-mediated cytotoxicity (ADCC) activity in vitro. After conjugation with MMAE, the binding specificity for HER2 was not affected. Furthermore, the internalization of hertuzumab-vcMMAE in HER2 positive gastric cancer cells was verified. Although the conjugation of hertuzumab and MMAE decreased the ADCC effect, the overall cytotoxicity was dramatically increased in HER2 positive gastric cancer cells. In vitro data on this hertuzumab-vcMMAE has exerted much stronger antitumor activity compared to trastuzumab-DM1 in HER2 positive gastric cancer cells. A single administration of hertuzumab-vcMMAE at 5 or 10 mg/kg showed high potency and a sustained tumor inhibitory effect on NCI-N87 xenografts in mice. In conclusion, hertuzumab-vcMMAE conjugate is a highly effective anti-HER2 targeted therapy for HER2-positive gastric cancer.

EphB4 inhibitor overcome the acquired resistance to cisplatin in melanomas xenograft model.

The purpose of this paper is to investigate the possible mechanisms of resistance to chemotherapy in melanoma from the perspective of molecular biology and to discuss the strategies to overcome them. Cisplatin, a DNA-damaging compound that triggers apoptotic cell death, is commonly used in the treatment of malignant melanoma. However, most patients develop mechanisms of acquired resistance and about 25% of them do not achieve tumor regression at all, due to intrinsic resistance to therapy. In the current study, we reported the tumor xenografts of the human A375 melanoma, after 40-weeks' consecutive therapy with cisplatin that developed resistance as a result of EphB4 overexpression. Moreover, the expression of phospho-AKT and phospho-ERK were significantly increased in cisplatin-resistant tumors. In addition, combined of cisplatin with EphB4 selective inhibitor could abrogate this acquired mechanism of drug resistance due to an enhanced apoptotic effect in cisplatin-resistant xenografts. In summary, these results help to understand the mechanisms of acquired resistance to chemotherapy and provide important information for clinical treatment strategies.

A novel humanized anti-HER2 antibody conjugated with MMAE exerts potent anti-tumor activity.

Human epidermal growth factor receptor-2 (HER2) is a validated therapeutic target for breast cancer and trastuzumab (Herceptin), a humanized anti-HER2 antibody, has significant anti-cancer effects in the clinic. However, breast cancer patients often experience disease progression after prolonged Herceptin treatment. To develop a more effective therapy, we generated humanized monoclonal antibody hertuzumab and hertuzumab-drug conjugates as novel breast cancer therapies. The hertuzumab was conjugated with small molecule cytotoxic agents monomethylauristatin E (MMAE) or monomethylauristatin F (MMAF) with various linkers to generate antibody-drug conjugates (ADCs), which were evaluated for their in vitro and in vivo anti-cancer activities. Among these ADCs, hertuzumab-vc-MMAE can be effectively internalized and potently kill HER2 over-expressing tumor cells. In xenograft tumor models, hertuzumab-vc-MMAE showed a more potent anti-tumor activity than T-DM1, a FDA-approved ADC drug. More importantly, this novel ADC drug also showed superior anti-tumor activity than T-DM1 in trastuzumab- and lapatinib-resistant xenograft tumor models, suggesting its potential as an improved therapy for HER2-positive breast cancers. The novel ADC, hertuzumab-vc-MMAE, is an effective and selective agent for the treatment of HER2-positive breast tumors.

Anti-tumor effect of polysaccharides from Scutellaria barbata D. Don on the 95-D xenograft model via inhibition of the C-met pathway.

Polysaccharides isolated from Scutellaria barbata (PSB) have been reported to have anti-tumor effects. To investigate the underlying mechanism, a highly invasive, metastatic and phospho-c-Met overexpression lung carcinoma cell, 95-D cell line was used. The results showed that in vitro, PSB not only could inhibit the proliferation of 95-D cell line (IC(50) = 35.2 µg/mL), but also down-regulated the expression of phospho-c-Met and its downstream signaling molecules including phospho-Erk and phospho-Akt. In vivo, PSB inhibited tumor growth in the 95-D subcutaneous xenograft model in a dose-dependent manner; after once-daily intraperitoneal injection for 3 weeks, tumor growth inhibition T/C ratio for 100 and 200 mg/kg treatments was 42.72% and 13.6%, respectively. In the end of the in vivo study, tumor tissues were harvested for further evaluation of the phosphorylation level of c-Met, AKT, and ERK. Ex vivo results demonstrated that the phosphorylation of c-Met and its downstream signaling molecules were also significantly inhibited by PSB. Immunohistochemistry analysis showed dose-dependent inhibition of tumor cell proliferation (Ki67) and reduction of microvessel density (CD31). In summary, the results indicated that PSB exerted anti-tumor growth activity on human lung cancer 95-D in vitro and in vivo by directly regulating the c-Met signaling pathway and the anti-tumor effects were mainly based on its anti-proliferation and anti-angiogenesis action.

Equilibrium and kinetic studies of copper(II) removal by three species of dead fungal biomasses.

The batch experiments were conducted to study the copper(II) removal by formaldehyde inactivated Cladosporium cladosporioides, Gliomastix murorum and Bjerkandera sp., at conditions of agitation speed of 150 rpm, temperature of 25 degrees C, biosorbent dose of 2 g l(-1) and contact time of 12h. It was found that, for each biomass, the optimum pH was 6.0 and the equilibrium establishing time was about 2h. Without acid or alkali treatment for improving adsorption properties, the experimental maximum copper(II) biosorptions were relatively high: 7.74 mg g(-1) for C. cladosporioides, 9.01 mg g(-1) for G. murorum, and 12.08 mg g(-1) for Bjerkandera sp.. The biosorption data of all the dead fungal biomasses were quite fitted to Langmuir isotherm model and pseudo second-order kinetic model; first-order Lagergren kinetic model gave good adjustment to the data of Bjerkandera sp. but did not fit the data of C. cladosporioides and G. murorum very well. These fungal biomasses exhibited relatively high capacity for the removal of copper(II) from aqueous solutions.