Inhibitory effects of rapamycin on the different stages of hepatic fibrosis.

AIM: To investigate and compare the inhibitory effects of rapamycin in the different stages of liver fibrosis. METHODS: We performed bile duct ligation (BDL) in male Wistar rats (n = 24). The experimental rats were classified into four groups: the BDL(+)/Rapa(-) group (un-treated control, n = 4), the BDL(+)/Rapa(+) group (treated 14 d after BDL, n = 8), the BDL(+)/Rapa(++) group (treated on the day after BDL, n = 8), and the BDL(-)/Rapa(-) group (un-treated, sham -operated control, n = 4). The BDL(+)/Rapa(+) and BDL(+)/Rapa(++) groups were administered rapamycin (2 mg/kg) for 28 d. The liver tissues were tested by immunohistochemical staining for α-smooth muscle actin (α-SMA) and cytokeratin. RESULTS: The liver mRNA levels of transforming growth factor (TGF)-ß1 and platelet-derived growth factor (PDGF) were measured using the polymerase chain reaction. The protein levels of liver p70s6K and p-p70s6k were determined using Western blotting. α-SMA expression was lowest in the BDL(+)/Rapa(++)group. TGF-ß1 and PDGF expression levels in the rapamycin-treated group were lower than those in the un-treated group and higher than those in the control groups (TGF-ß1: 0.23 ± 0.00 vs 0.34 ± 0.01, 0.23 ± 0.0 vs 0.09 ± 0.00, P < 0.0001; PDGF: 0.21 ± 0.00 vs 0.34 ± 0.01, 0.21 ± 0.0 vs 0.09 ± 0.00, P < 0.0001). The p70s6k and p-p70s6k levels decreased in the treated groups and were lowest in the BDL(+)/Rapa(++)group (p70s6k: 1.05 ± 0.17 vs 1.30 ± 0.56, 0.40 ± 0.01 vs 1.30 ± 0.56, P < 0.0001; p-p70s6k: 1.40 ± 0.5 vs 1.67 ± 0.12, 0.70 ± 0.01 vs 1.67 ± 0.12, P < 0.0001). CONCLUSION: The results of our study indicate that rapamycin has inhibitory effects on liver fibrosis, and the treatment is most effective in the early stages of fibrosis.

[A case of mantle cell lymphoma with meningioma].

Mantle cell lymphoma (MCL) is an uncommon type of gastrointestinal lymphoma. MCL is a distinct subtype of B-cell non-Hodgkin lymphomas. The major subtype of MCL is characterized by the presence of multiple lymphomatous polyposis (MLP), in which multiple polyps are observed along the gastrointestinal tract. The malignant cells express pan B-cell marker and the T-cell marker cluster of differentiation 5. The chromosomal translocation t(11;14)(q13;q32) that causes cyclin D1 overexpression is commonly observed on the cytogenetic analysis of MCL. Survival improvement has recently been achieved for patient with MCL by the successful introduction of monoclonal antibodies and dose-intensified approaches for treatment, including autologous stem cell transplantation strategies. Some reports suggest that there is an increased incidence of second malignancies in patients with MCL or lymphoma. We report a case of MCL involving the colon; the patient was a 60-year-old man who complained of low abdominal discomfort during defecation. During the workup, a meningioma was unexpectedly discovered. On analysis, the tumor was found to be a t(11;14)-negative and non-MLP-type MCL.

Reactivation of tuberculosis in hepatocellular carcinoma treated with transcatheter arterial chemoembolization: A report of 3 cases.

Pulmonary tuberculosis is an opportunistic infection that can be reactivated in immunocompromised conditions, for example, in malignancy or after liver transplantation. Hepatocellular carcinoma (HCC) has a high mortality rate because it is frequently diagnosed at an advanced stage. Although surgical resection is the established curative measure for HCC, it is only feasible for early-stage HCC. Transcatheter arterial chemoembolization (TACE) is the most common treatment modality for patients with unresectable HCC. However, repeated TACE sessions and, occasionally, the tumor itself can further impair the reserve hepatic function and immunity. We report 3 recent cases of HCC with reactivation of pulmonary tuberculosis after TACE.

[Comparison of the toxicities and efficacies of the combination chemotherapy regimens in advanced gastric cancer patients who achieved complete response after chemotherapy].

BACKGROUND/AIMS: We retrospectively analyzed comparative toxicities and efficacies of chemotherapy regimens in advanced gastric cancer (AGC) patients who achieved complete response (CR) after chemotherapy. METHODS: We reviewed the medical records of 1,203 patients, who were pathologically diagnosed as AGC in a single center between January 2001 and October 2007. On the basis of the Response Evaluation Criteria in Solid Tumors, CR was evaluated with abdominal computed tomography. Toxicities were evaluated using the National Cancer Institute's common toxicity criteria before each chemotherapy cycle. RESULTS: Among the 1,203 AGC patients enrolled in this study, 568 received chemotherapy and 635 received best supportive care. The major chemotherapy regimens were 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX), docetaxel, cisplatin and 5-fluorouracil (DCF) and 5-fluorouracil, leucovorin and irinotecan (FOLFIRI). Among the 568 patients, 51 (9.0%) achieved CR (49 [8.6%] with FOLFOX [n=12], DCF [n=26], or FOLFIRI [n=11] and 2 [0.3%] with etoposide, leucovorin and 5-fluorouracil). For patients administered FOLFOX, DCF, and FOLFIRI, the median time to disease progression was 4 months (range, 1.8-59.5), 15 months (range, 2.9-31.2) and 10 months (range, 2.0-39.5), and the median survival times were 48 months (range, 5.9-74.0), 37 months (range, 14.0-86.0), and 30 months (range, 6.0-50.0), respectively. Grades 3-4 mucositis occurred mostly in patients administered DCF (n=8, 30.8%). Grades 3-4 leucopenia were observed in 1 (8.3%), 11 (42.3%), and 4 (36.4%) patients administered FOLFOX, DCF and FOLFIRI, respectively. No statistically significant differences were observed in the 3 regimens. CONCLUSIONS: All 3 regimens (FOLFOX, DCF and FOLFIRI) were active and tolerable. Their efficacies and toxicities were not significantly different.

Recurrent renal leiomyosarcoma mimicking a colonic submucosal tumor: a case report.

A primary leiomyosarcoma of the kidney is a rare, but highly aggressive, neoplasm, accounting for only 0.1% of all invasive renal tumors. Local or systemic recurrence is common, but a leiomyosarcoma is difficult to diagnose preoperatively. We recently encountered an interesting case of an unusual recurrence of a renal leiomyosarcoma. A 57-year-old woman visited our hospital complaining of lower abdominal pain. Four years previously, she had undergone a left nephrectomy. She had a primary leiomyosarcoma of the kidney that had been misdiagnosed as a renal cell carcinoma. Colonoscopy revealed the presence of a lesion similar to a submucosal tumor in the descending colon. Postoperative pathologic examination confirmed that the mass was a recurrent leiomyosarcoma. We report this unusual case and present a review of the literature.

[A case of gastric lymphoepithelioma-like carcinoma presenting as panperitonitis by perforation of stomach].

Gastric lymphoepithelioma-like carcinoma is a rare carcinoma among gastric malignant tumor but has a good prognosis. The carcinoma has histologic feature characterized by small nest of cancer cells mixed with lymphoid stroma. We report a case with lymphoepithelioma-like carcinoma of stomach initially presenting as panperitonitis because of spontaneous tumor perforation. A 56-year-old man visited our emergency room because of epigastric pain. A preoperative abdominal CT scan showed a massive pneumoperitoneum in the upper abdomen, and the presence of gastric cancer in the lesser curvature of the stomach. An emergent laparotomy was performed followed by radical subtotal gastrectomy. Pathologic examination revealed that the tumor was a lymphoepithelioma-like gastric carcinoma.

[Importance of medication adherence to peginterferon-ribavirin combination therapy in patients with chronic hepatitis C].

BACKGROUND/AIMS: The combination therapy with peginterferon and ribavirin is a standard treatment for patients with chronic hepatitis C. However, because of the long duration of the treatment and many complications, the reduction of adherence frequently occur. This study aimed to assess influences of reduced medication adherence in the combination therapy of chronic hepatitis C patients. METHODS: We retrospectively reviewed the medical records of 82 patients with chronic hepatitis C who received a combination therapy with peginterferon and ribavirin. The patients were categorized into 3 subgroups on the basis of medication adherence. Group 1 comprised patients who received ≥80% of the recommended dosage of both peginterferon and ribavirin. Group 2 comprised those patients who received ≥80% of the recommended dosage of only 1 drug. The patients of Group 3 received <80% of the recommended dosage of both the drugs. RESULTS: Sustained virologic response (SVR)s of patients in Group 1, 2 and 3 were 85.4% (41/48), 85.7% (18/21), and 38.5% (5/13), respectively (p=0.002). SVRs of genotype 1 patients in Group 1, 2 and 3 were 84.2% (16/19), 75% (9/12), and 14.3% (1/7) , respectively (p=0.003). SVRs of genotype non-1 patients in Group 1, 2 and 3 were 86.2% (25/29), 100% (9/9), and 66.7% (4/6), respectively (p=0.196). Furthermore are SVRs significantly differed with the degree of medication adherence to either peginterferon or ribavirin (p=0.003 and 0.021, respectively). In multivariate analysis, the peginterferon dose was a significant independent factor associated with SVR. CONCLUSIONS: Medication adherence of chronic hepatitis C patients to the combination therapy with peginterferon and ribavirin is very important for achieving SVR. In particular, we think that genotype 1 patients should maintain higher adherence than genotype non-1 patients.

[A case of a retroperitoneal schwannoma presenting as hypermetabolic mass in PET-CT].

Schwannoma is a benign neoplasm of the Schwann cells of the neural sheath. Most schwannomas occur in the head and neck, and extremities and rarely in the retroperitoneal space. The differentiation of a schwannoma from other malignant tumor or benign tumor is very difficult on a preoperative examination with ultrasonography, computed tomography or magnetic resonance imaging. Furthermore, the lesion with increased fluorodeoxyglucose uptake in PET-CT cannot exclude malignant tumor. Therefore, this lesion needs surgical excision and a histological examination with immunohistochemical staining. We report a case of schwannoma occuring in the retroperitoneal space that incidentally discovered by PET-CT for health-check up. Pathologic confirmation by laparoscopic excision was done.

Clinical outcomes of endoscopic submucosal dissection for undifferentiated or submucosal invasive early gastric cancer.

BACKGROUND/AIMS: Early gastric cancer (EGC) that is undifferentiated or shows submucosal invasion has not been generally accepted as an indication for endoscopic treatment. But recently, experiences with endoscopic submucosal dissection (ESD) for undifferentiated EGC or submucosal invasive (SM) EGC have increased. The aim of this study was to evaluate clinical outcomes of ESD for EGC with undifferentiation or submucosal invasion. METHODS: Between August 2005 and August 2009, among 210 EGCs treated using ESD at our hospital, 18 lesions were diagnosed as undifferentiated gastric cancer and 41 as SM gastric cancer. A retrospective analysis was done on the medical records of these patients. RESULTS: Mean follow-up periods were 19.39±11.2 months. During the follow-up period, local recurrence was noted in 4 lesions. Local recurrence rates of the EGC groups (group 1, mucosal cancer with undifferentiation; group 2, SM cancer with differentiation; group 3, SM cancer with undifferentiation) were 10%, 4.5%, and 50%, respectively. Groups 1 and 2 were not significantly different in local recurrence rates compared to the mucosal cancer with differentiation group (p=0.061, p=0.125, respectively). The undifferentiated EGC group was significantly lower in curability using ESD than the differentiated EGC group (55.6% vs. 89.6%, p=0.000). The curability of the SM EGC group was lower than the mucosal EGC group (36.6% vs. 98.9%). CONCLUSIONS: Complete resection using ESD is difficult in undifferentiated and SM gastric cancers. SM cancer with undifferentiation should be treated immediately by salvage operation. For mucosal cancer with undifferentiation or SM cancer with differentiation, one should consider careful short-term follow-up.

Diagnostic value of pyrosequencing for the BRAF V600E mutation in ultrasound-guided fine-needle aspiration biopsy samples of thyroid incidentalomas.

CONTEXT: Dideoxy sequencing is the most commonly used method for detecting the BRAF(V600E) mutation in thyroid cancer and melanoma. However, this gold standard method often makes less definite results in detecting the BRAF(V600E) mutation when there are relatively low amounts of the mutant template in biopsy specimens, which are invariably contaminated with normal tissues. Pyrosequencing, which measures the incorporation of each of the four nucleotides at each template position and indicates the amounts of mutant template present, may be more useful in such situations. OBJECTIVE: To investigate the diagnostic efficiency of pyrosequencing for the mutant BRAF allele in ultrasound (US)-guided fine needle aspiration biopsies (FNABs) of thyroid incidentalomas. DESIGN, SETTING AND SUBJECTS: A total of 101 thyroid incidentaloma cases were included prospectively. Cytological diagnoses of the FNAB samples were made according to the American Thyroid Association (ATA) guidelines, 2006. The presence of the BRAF(V600E) mutation was investigated by pyrosequencing and dideoxy sequencing. RESULTS: On the basis of cytological analysis, the thyroid incidentalomas were classified into benign (n = 43), malignant (n = 30), indeterminate or suspicious neoplasm (n = 24), and nondiagnostic (n = 4) categories. Pyrosequencing detected the BRAF(V600E) mutation in 30 cases: 22 malignant cases, 7 indeterminate cases, and 1 nondiagnostic case. Dideoxy sequencing also detected the BRAF(V600E) mutation in 28 of the same cases but failed to clearly distinguish the mutant allele from the wild-type allele in one indeterminate case and one nondiagnostic case. Histopathological analysis ascertained that all BRAF(V600E)-positive cases were papillary thyroid carcinomas. CONCLUSIONS: Pyrosequencing may be suitable for detecting the BRAF(V600E) mutation in thyroid incidentaloma and may be superior to dideoxy sequencing when low amounts of the mutant template are present in the biopsy.

Regulation of inhibitors of differentiation family proteins by thyroid-stimulating hormone in FRTL-5 thyroid cells.

Members of the inhibitors of differentiation (Id) family of helix-loop-helix (HLH) proteins are known to play important roles in the proliferation and differentiation of many cell types. Thyroid-stimulating hormone (TSH) regulates proliferation and differentiation by activating TSH receptor (TSHR) in thyrocytes. In this study, we found that Id2, one of the Id family proteins, is a major target for regulation by TSH in FRTL-5 thyroid cells. TSH rapidly increases the Id2 mRNA level in FRTL-5 thyroid cells but the Id2 protein showed biphasic regulatory patterns, being transiently reduced and subsequently induced by TSH treatment. Transient reduction of Id2 protein was noted within 2 hr of TSH treatment and was mediated by proteasomal degradation. Moreover, reduced Id2 expression correlated with the activity of the phosphatidylinositol 3 kinase pathway, which is activated by TSH. Although TSH increases the activity of the Id2 promoter, TSH-induced activation of this promoter was independent of c-Myc. Id2 did not alter TTF-1- and Pax-8-mediated effects on the regulation of the Tg promoter. Thus, in summary, we found that TSH regulates Id2 expression, but that Id2 does not alter the expression of thyroid-specific genes, such as Tg, in FRTL-5 thyroid cells.

Significance of the expression of major histocompatibility complex class II antigen, HLA-DR and -DQ, with recurrence of papillary thyroid cancer.

Normal thyroid epithelial cells lack major histocompatibility complex (MHC) Class II antigen. Oncogenic kinases involved in papillary thyroid carcinoma (PTC) trigger the expression of Class II transactivator and MHC Class II complex. However, the relationship between MHC Class II antigen expression and clinical outcome in PTC is unknown. To investigate the frequency of MHC Class II antigen expression in PTC and to identify the effects of MHC Class II antigen expression on clinical outcomes in PTC patients, the expression of HLA-DR/-DQ antigen was analyzed in surgical specimens from 77 PTCs and 44 benign nodules (23 nodular hyperplasias, 21 follicular adenomas). Of the 77 PTC cases, 36 (46.8%) cases expressed HLA-DR and 41 (53.2%) cases expressed HLA-DQ. Next, we investigated clinicopathological characteristics and found that HLA-DR(+) and/or HLA-DQ(+) PTC tended to present without nodal metastasis. Multivariate analyses clearly showed that HLA-DR(+) or HLA-DQ(+) PTC has a low risk of recurrence (HLA-DR OR = 0.22, CI, 0.06-0.9; p = 0.03, HLA-DQ OR = 0.25, CI, 0.07-0.9, p = 0.03). The Kaplan-Meier estimate revealed a significantly lower recurrence-free probability in patients with HLA-DR(-) PTC and HLA-DQ(-) PTC (Log-rank test; chi(2) = 4.59 and 6.07, p = 0.03 and 0.01, respectively). In conclusion, PTC frequently expresses MHC Class II antigen, and the expression of MHC Class II antigen correlated inversely with the risk of recurrence of PTC.