Effect of mistletoe extract on tumor response in neoadjuvant chemoradiotherapy for rectal cancer: a cohort study.

BACKGROUND: Mistletoe extract, used as a complementary chemotherapeutic agent for cancer patients, has anticancer effects against various malignancies. The aim of the present study was to evaluate the effect of mistletoe extract (Abnoba Viscum Q®) on tumor responses to neoadjuvant chemoradiotherapy (NCRT) for locally advanced rectal cancer. METHODS: This study included patients with rectal cancer who underwent NCRT between January 2018 and July 2020. In the mistletoe group (MG), the patients were administered Abnoba Viscum Q® subcutaneously during chemoradiotherapy-maintained just before surgery. Patient demographics, clinical outcomes, histopathological outcomes, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) assay results were compared between the MG and non-mistletoe group (NMG). Two rectal cancer cell lines (SNU-503 and SNU-503R80Gy) were treated with Abnoba Viscum Q® to assess its mechanistic effects in vivo. RESULTS: Overall, the study included 52 patients (MG: n = 15; NMG: n = 37). Baseline demographics between the two groups were similar, except carbohydrate antigen 19-9 levels and tumor location from the anal verge. There was no difference in the clinical stage between the two groups. A better tumor response in the MG, relative to the NMG, was observed with respect to tumor regression grade (TRG), T stage, and overall tumor-node-metastasis stage. Tumor response was significantly better in the MG than in the NMG in terms of pathologic complete response rate (53.3% vs. 21.6%, P = 0.044), good TRG response (66.7% vs. 32.4%, P = 0.024), T downstaging (86.7% vs. 43.2%, P = 0.004), and overall downstaging (86.7% vs. 56.8%, P = 0.040). The toxicities during NCRT were minimal in both groups. More apoptotic cells were noted in MG samples than in the NMG samples on TUNEL staining. Cleaved caspase-3 level following treatment with Abnoba Viscum Q® was higher in SNU-503R80Gy cells than in SNU-503 cells. CONCLUSION: Patients treated with chemoradiation combined with mistletoe extract showed better outcomes than patients not treated with mistletoe extract in terms of tumor responses. This diversity in treatment may improve the efficacy of NCRT, leading to better oncologic outcomes. Prospective and randomized studies with long-term follow-up are warranted to confirm and extend these results.

Clinical Impact of PD-L1 Expression for Survival in Curatively Resected Colon Cancer.

BACKGROUND: Programmed death 1 (PD-1) and its ligand PD-L1 play a key dysfunction of T lymphocytes. The purpose of this study was to assess and compare the prognostic role of tumor- TILs and its relationship with PD-L1 expression in stage II and III colon cancer. METHODS: Immunohistochemisty was used to assess the densities of CD8+, CD4+, and FOXP3+ cells, and PD-L1 expression in intraepithelial tumor site from 58 stage II and III colon cancers. These were evaluated for association with histopathologic features and overall survival. RESULTS: PD-L1-positive tumors contained a higher number of CD8+ TILs with statistical significance (p = 0.001). CD4+ TILs showed positive correlation with PD-L1 expression (p = 0.034). There were no associations between PD-L1 expression and FOXP3+ TILs. Microsatellite instability (MSI)-high status (p = 0.001; Odd ration 18.0; 95% CI = 4.3-74.8) was the strongest prognostic factor along with mucinous/poor cell differentiation, CD8 and right tumor location was associated with PD-L1 expression (p = 0.024, 0.035 and 0.033, respectively). CONCLUSION: This study demonstrated that PD-L1 expression was associated with MSI-high, increased CD8+ TILs, mucinous and poor cell differentiation, and right-sided tumor location.

Peritumoral decreased uptake area of gadoxetic acid enhanced magnetic resonance imaging and tumor recurrence after surgical resection in hepatocellular carcinoma: A STROBE-compliant article.

Recently, it has been suggested that peritumoral decreased uptake area (PDUA) in the hepatobiliary phase (HBP) of gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) was associated with vascular invasion in hepatocellular carcinoma (HCC). We aimed to investigate correlations between microvascular invasion and PDUA, and elucidate the predictability of PDUA for tumor recurrence after resection.We retrospectively analyzed clinicopathological and radiological data from 126 consecutive patients with single HCC ≤5 cm without macrovascular invasion who underwent preoperative Gd-EOB-DTPA-enhanced MRI and surgical resection. The presence of a faint and hypointense area around the tumor in the HBP was defined as PDUA.Among 126 patients with HCCs, microvascular invasion was observed in 29 (23.0%) patients and PDUA was observed in 15 (11.9%) patients. PDUA [odds ratio (OR) 20.06, confidence interval (CI) 4.74-84.96, P < .001] was an independent risk factor for microvascular invasion. In multivariate survival analysis using Cox regression, PDUA [hazard ratio (HR) 4.51, CI 2.17-9.38, P < .001], pathologically confirmed satellite nodules (HR 5.18, CI 1.50-17.88, P = .009), and AFP (≥100 ng/mL, HR 2.28, CI 1.04-5.01, P = .040) were independent risk factors for recurrence after resection. Recurrence-free survival in the group with PDUA was significantly lower than that in the group without PDUA according to analysis using the Kaplan-Meier method with the log-rank test (P < .001).PDUA in the HBP of Gd-EOB-DTPA-enhanced MRI could be a useful preoperative predictor of microvascular invasion and independent prognostic factor after surgical resection in patients with single HCC ≤5 cm without macrovascular invasion.

Characterization of small (≤3 cm) hepatic lesions with atypical enhancement feature and hypointensity in hepatobiliary phase of gadoxetic acid-enhanced MRI in cirrhosis: A STARD-compliant article.

It is difficult to characterize the nodular lesions in cirrhotic liver if typical enhancement pattern is not present on dynamic contrast-enhanced imagings. Although the signal intensity of the hepatobiliary phase in gadoxetic acid-enhanced magnetic resonance imaging (MRI) is helpful for characterization of the lesions, some dysplastic nodules may also exhibit low signal intensity in the hepatobiliary phase. We aimed to assess the usefulness of gadoxetic acid (Gd-EOB-DTPA)-enhanced MRI including diffusion-weighted imaging (DWI) for differentiation between atypical small hepatocellular carcinomas (HCCs) and dysplastic nodules showing low signal intensity (SI) in the hepatobiliary phase, and to evaluate the MRI findings in determining the histological grade of atypical HCCs in patients with cirrhosis.A total of 43 cirrhotic patients with a small (≤3 cm) liver nodule (n = 25, HCC; n = 18, dysplastic nodule) who underwent Gd-EOB-DTPA-enhanced MRI and pathologic confirmation were retrospectively reviewed. Atypical HCC was defined as not showing arterial hyperenhancement and delayed washout on dynamic MRI.High SI on both T2WI and DWI (sensitivity 80.0%, specificity 100%, positive predictive value 100%, negative predictive value 78.3%) was the most specific feature to differentiate atypical HCCs from dysplastic nodules. High SI on both T2WI and DWI (100% vs 61.5%, P = .039) or low SI on pre-enhanced T1WI (83.3% vs 30.8%, P = .021) was more frequent observed in Edmonson grade II-III HCCs compared with those in grade I HCCs.The combination of DWI and T2WI is most useful for the differentiation of atypical small HCCs from dysplastic nodules showing low SI in the hepatobiliary phase. Combination of DWI and T2WI or pre-enhanced T1WI seems to be useful for predicting the histological grade of atypical HCCs.

Contrast-enhanced ultrasound for the differentiation of small atypical hepatocellular carcinomas from dysplastic nodules in cirrhosis.

BACKGROUND: Contrast-enhanced ultrasound is highly accurate in depicting the vascularity of liver nodules. The aim of this study was to evaluate the usefulness of contrast-enhanced ultrasound for the differentiation of hepatocellular carcinomas from dysplastic nodules in cirrhotic patients with small liver nodules showing atypical or not coincidental typical vascular pattern on two dynamic imaging techniques (computed tomography and magnetic resonance imaging). METHODS: A total of 46 patients with cirrhosis and a liver nodule smaller than 3cm showing an atypical or non-coincident typical vascular pattern on two dynamic imaging techniques, who underwent liver contrast-enhanced ultrasound and ultrasound-guided liver biopsy, were retrospectively reviewed. Contrast-enhanced ultrasound findings were compared with histopathological and clinical data, and with the two dynamic imaging findings. RESULTS: Significantly different contrast-enhanced ultrasound enhancement patterns were observed among dysplastic nodules, Edmondson grade I and grade II-III hepatocellular carcinomas. Ten out of 11 (90.9%) non-hypervascular hepatocellular carcinomas on two dynamic imaging techniques showed a hypervascular pattern on contrast-enhanced ultrasound, and these made it possible to distinguish hepatocellular carcinomas from dysplastic nodules. CONCLUSION: Contrast-enhanced ultrasound is useful for the differentiation of hepatocellular carcinomas from dysplastic nodules in cirrhotic patients with small liver nodules.

Neoadjuvant treatment of mid-to-lower rectal cancer with oxaliplatin plus 5-fluorouracil and leucovorin in combination with radiotherapy: a Korean single center phase II study.

PURPOSE: To evaluate the safety and efficacy of neoadjuvant chemoradiation with oxaliplatin and 5-fluorouracil (5-FU) in advanced mid-to-lower rectal cancer. METHODS: This was a single-arm, open-label phase II study conducted between August 2008 and August 2010. Thirty-one patients (n = 31) with clinical stage T3/T4 or lymph node positive rectal adenocarcinoma located in the middle or lower rectum without metastasis were enrolled onto the study. Data were analyzed according to the intention-to-treat principle. RESULTS: Thirty-one patients were enrolled into the study. Six patients (19.4%) experienced grade 3 diarrhea. Grade 2 nausea and vomiting occurred in 5 and 2 patients, respectively. Severe neurotoxicity was not observed. Grade 1 sensory neuropathy occurred in 10 patients (32.3%). Sphincter-saving surgery was performed in 29 patients (93.5%). The mean distance of the tumor from the anal verge was 4.9 cm. Anastomotic leakage occurred in 4 of 29 (13.8%) patients. The circumferential resection margin was involved in 2 patients (6.5%). Overall, 23 patients (77.4%) responded to treatment. The complete pathologic response (ypCR) rate was 12.9%. There was no death secondary to toxicity, and the mean follow-up time was 12.3 months. CONCLUSION: The overall toxicity of oxaliplatin and continuous 5-FU/leucovorin infusion in combination with radiation was well tolerated. Neoadjuvant chemoradiation for patients with locally advanced rectal cancer was associated with higher rates of sphincter preservation and downstaging, but did not significantly increase ypCR. The impact of this neoadjuvant chemoradiation regimen on survival will be determined by longer follow-up studies.

[A case of primary hepatic epithelioid hemangioendothelioma with spontaneous rupture].

Primary hepatic epithelioid hemangioendothelioma is a rare neoplasm of endothelial origin. The clinical manifestations are nonspecific, ranging from complete absence of symptoms to hepatic failure and death. Spontaneous rupture of a hepatic epithelioid hemangioendothelioma is an extremely rare presentation. We present a case of primary hepatic epithelioid hemangioendothelioma in a 65-year-old male patient with alcoholic liver cirrhosis. He was hospitalized due to epigastric pain and multiple liver masses on abdominal ultrasound. Dynamic liver CT imaging revealed multiple peripheral nodular enhanced mass lesions with delayed centripetal enhancement, and the adjacent collection of high-attenuation fluid along the liver capsule. Abdominal tapping revealed blood in the peritoneal cavity. Primary hepatic epithelioid hemangioendothelioma with spontaneous rupture was finally diagnosed based on a histopathologic examination revealing positive immunohistochemical staining for CD34.

Perivascular epithelioid cell tumor (PEComa) in the transverse colon of an adolescent: a case report.

Perivascular epithelioid cell tumor (PEComa) is defined as a very rare mesenchymal tumor of histologically and immuno-histochemically distinctive perivascular epithelioid cells. PEComa in the colon is very rare, with only a few reported cases so far. Because of its rarity, the clinical features and biological behavior of PEComa in the colon have yet to be established. A 16-year-old female patient with PEComa in the transverse colon was referred to our hospital for rectal bleeding. Laboratory data showed a hemoglobin level of 6.6 g/dL, WBC of 8,800/mm(3), and platelet count of 191,000/mm(3). Colonoscopy, barium enema, and abdominal computed tomography revealed a 2-cm, smooth-surfaced, round tumor with focal ulceration in the proximal transverse colon. The patient complained of abdominal pain one day after endoscopic polypectomy. She underwent a segmental resection for a perforated transverse colon. Immunohistochemically, the tumor cells showed strong diffuse positivity for HMB-45 while they were negative for c-kit, smooth muscle actin, cytokeratin, S-100, vimentin, desmin, chromogranin, synaptophysin, EMA, and CD-34. The diagnosis of PEComa was based on histological and immunohistochemical staining. The patient did not receive any adjuvant therapy and was discharged on postoperative day 11 without complications. Whole-body fluorine-18 fluorodeoxyglucose fusion positron emission tomography performed 2 months after surgery showed no signs of recurrence or metastasis. There was also no recurrence or metastasis at 24 months' follow-up.

64 multidetector-row computed tomography for preoperative evaluation of gastric cancer: histological correlation.

OBJECTIVE: To assess the accuracy of 64 multidetector-row computed tomography (MDCT) in the diagnosis and staging of gastric cancer. METHODS: This study was approved by the institutional review board, and the patients involved gave informed consent. Forty-four patients (34 men and 10 women; mean age, 57 years) with gastric carcinoma underwent preoperative 64 MDCT (SOMATOM Sensation 64; Siemens Medical System, Forchheim, Germany; slice collimation, 0.6 mm; slice width, 5 mm; feed/rotation, 23 mm; pitch factor, 1.2; kernel, B30f; and gantry speed, 0.5 second per rotation). Gastric distension was achieved by ingestion of 8 g of effervescent granules. Scanning was performed during arterial and portal phases, as determined with bolus tracking and automated triggering technique after intravenous administration of 100 mL of contrast materials (4 mL/s). All computed tomography scans were retrospectively reviewed by 2 radiologists. Each tumor was staged according to the TNM classification system. All patients underwent surgery. Computed tomography results were compared with histological staging of tumor invasion depth and regional lymph node metastasis. RESULTS: The accuracy of 64 MDCT for detection of gastric cancer was 90% (18/20) and 100% (24/24) in early and advanced gastric cancer, respectively, with an overall detection rate of 95% (42/44). Its accuracy for determination of tumor penetration depth was 89% (16/18) and 88% (21/24) in early and advanced gastric cancer, respectively, with an overall accuracy of 88% (37/42). Its accuracy for determination of lymph node metastasis was 90% (18/20) and 71% (17/24) in early and advanced gastric cancer, respectively, with an overall accuracy of 80% (35/44). CONCLUSIONS: The 64 MDCT is a promising technique for the detection and preoperative staging of gastric cancer.

Tailgut cyst: MRI evaluation.

OBJECTIVE: The purpose of our study was to evaluate the MRI features of tailgut cysts in five patients. CONCLUSION: Our results suggest that MRI may be useful in the diagnosis of tailgut cyst. A multilocular cystic mass in the presacral space is a characteristic MRI finding of tailgut cyst, which may also be revealed as a cystic mass consisting of a large cyst accompanied by a small peripheral cyst. However, further studies are necessary to establish the usefulness of MRI for evaluating tailgut cysts.

Retroperitoneal cystic masses: CT, clinical, and pathologic findings and literature review.

Cystic lesions of the retroperitoneum can be classified as either neoplastic or nonneoplastic. Neoplastic lesions include cystic lymphangioma, mucinous cystadenoma, cystic teratoma, cystic mesothelioma, müllerian cyst, epidermoid cyst, tailgut cyst, bronchogenic cyst, cystic change in solid neoplasms, pseudomyxoma retroperitonei, and perianal mucinous carcinoma. Nonneoplastic lesions include pancreatic pseudocyst, nonpancreatic pseudocyst, lymphocele, urinoma, and hematoma. Because the clinical implications of and therapeutic strategies for retroperitoneal cystic masses vary depending on the cause, the ability to noninvasively differentiate between masses is important. Although there is substantial overlap of computed tomographic (CT) findings in various retroperitoneal cysts, some CT features, along with clinical characteristics, may suggest a specific diagnosis. CT may provide important information regarding lesion location, size, and shape; the presence and thickness of a wall; the presence of septa, calcifications, or fat; and involvement of adjacent structures. The most important clinical parameters include patient gender, age, symptoms, and clinical history. Familiarity with the CT and clinical features of various retroperitoneal cystic masses facilitates accurate diagnosis and treatment.

Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes.

OBJECTIVE: The purpose of the present study was to elucidate the cytochrome P450 (P450) isoform(s) involved in the metabolism of loperamide (LOP) to N-demethylated LOP (DLOP) in human liver microsomes. METHODS: Three established approaches were used to identify the P450 isoforms responsible for LOP N-demethylation using human liver microsomes and cDNA-expressed P450 isoforms: (1) correlation of LOP N-demethylation activity with marker P450 activities in a panel of human liver microsomes, (2) inhibition of enzyme activity by P450-selective inhibitors, and (3) measurement of DLOP formation by cDNA-expressed P450 isoforms. The relative contribution of P450 isoforms involved in LOP N-demethylation in human liver microsomes were estimated by applying relative activity factor (RAF) values. RESULTS: The formation rate of DLOP showed biphasic kinetics, suggesting the involvement of multiple P450 isoforms. Apparent Km and Vmax values were 21.1 microM and 122.3 pmol/min per milligram of protein for the high-affinity component and 83.9 microM and 412.0 pmol/min per milligram of protein for the low-affinity component, respectively. Of the cDNA-expressed P450 s tested, CYP2B6, CYP2C8, CYP2D6, and CYP3A4 catalyzed LOP N-demethylation. LOP N-demethylation was significantly inhibited when coincubated with quercetin (a CYP2C8 inhibitor) and ketoconazole (a CYP3A4 inhibitor) by 40 and 90%, respectively, but other chemical inhibitors tested showed weak or no significant inhibition. DLOP formation was highly correlated with CYP3A4-catalyzed midazolam 1-hydroxylation (rs=0.829; P<0.01), CYP2B6-catalzyed 7-ethoxy-4-trifluoromethylcoumarin O-deethylation (rs=0.691; P<0.05), and CYP2C8-catalyzed paclitaxel 6alpha-hydroxylation (rs=0.797; P<0.05). CONCLUSION: CYP2B6, CYP2C8, CYP2D6, and CYP3A4 catalyze LOP N-demethylation in human liver microsomes, and among them, CYP2C8 and CYP3A4 may play a crucial role in LOP metabolism at the therapeutic concentrations of LOP. Coadministration of these P450 inhibitors may cause drug interactions with LOP. However, the clinical significance of potential interaction of LOP metabolism by CYP2C8 and CYP3A4 inhibitors should be studied further.

Diffuse multinodular infarction of regenerative nodules after massive bleeding from esophageal varices: computed tomography findings.

We report the computed tomography findings in a case of diffuse multinodular infarcted regenerative nodules, which mimicked an infiltrative hepatocellular carcinoma. Computed tomography revealed multiple hypodense lesions in the right hepatic lobe on the arterial phase and progressive enhancement of the peripheral and central portions of the lesions on the portal venous and delayed phases. A pathologic examination indicated that these regenerative nodules were necrotic and surrounded by fibrous tissue.