[A Case of Glycogen-Rich Clear Cell Carcinoma of the Breast with Extensive Intraductal Components and Micrometastases to the Axillary Lymph Node].

A 48-year-old woman had a left breast mass identified during routine breast cancer screening. The mammogram showed pleomorphic-segmental microcalcifications in the mediolateral-oblique view of the left breast. Ultrasonography showed a hypoechoic mass approximately 3.7 cm in diameter with multiple calcifications. Contrast-enhanced magnetic resonance imaging of the breast showed non-mass like enhancement of approximately 4 cm in diameter in the C area of the left breast. She was diagnosed with glycogen-rich clear cell carcinoma (GRCC) by ultrasound-guided vacuum-assisted biopsy. Nipplesparing mastectomy was performed along with sentinel lymph node biopsy. The intraoperative consultation suggested sentinel lymph node metastasis and we therefore performed axillary lymph node dissection. Pathological examination reported microinvasive carcinomas, 0.4 cm in maximum diameter, and extensive intraductal components, 5 cm in size. The tumor cells were stained on PAS staining, but the stains were digested with diastase. The cells were negative for adipophilin. GRCC was first reported by Hull et al. This is a rare type of breast carcinoma. There is no standard therapy for this disease or any data on the prognosis of breast cancer patients with GRCC.

Acquired resistance to gemcitabine and cross-resistance in human pancreatic cancer clones.

The efficacy of gemcitabine (GEM), a standard treatment agent for pancreatic cancer, is insufficient because of primary or acquired resistance to this drug. Patients with tumors intrinsically sensitive to GEM gradually acquire resistance and require a shift to second agents, which are associated with the risk of cross-resistance. However, whether cross-resistance is actually present has long been disputed. Using six GEM-resistant and four highly GEM-resistant clones derived from the pancreatic cancer cell line BxPC-3, we determined the resistance of each clone and parent cell line to GEM and four anticancer agents (5-FU, CDDP, CPT-11, and DTX). The GEM-resistant clones had different resistances to GEM and other agents, and did not develop a specific pattern of cross-resistance. This result shows that tumor cells are heterogeneous. However, all highly GEM-resistant clones presented overexpression of ribonucleotide reductase subunit M1 (RRM1), a target enzyme for metabolized GEM, and showed cross-resistance with 5-FU. The expression level of RRM1 was high; therefore, resistance to GEM was high. We showed that a tumor cell acquired resistance to GEM, and cross-resistance developed in one clone. These results suggest that only cells with certain mechanisms for high-level resistance to GEM survive against selective pressure applied by highly concentrated GEM. RRM1 may be one of the few factors that can induce high resistance to GEM and a suitable therapeutic target for GEM-resistant pancreatic cancer.

Modified laparoscopic splenic vessel-preserving distal pancreatectomy: Matador assistance and peel-away technique.

BACKGROUND: Laparoscopic splenic vessel-preserving distal pancreatectomy (lap-SVPDP) is a popular procedure in pancreatic surgery. However, postoperative complications include false aneurysms of the splenic artery, splenic vein stenosis and thrombosis, pancreatic fistulas, abscess, and perigastric varices. METHODS: Eight patients (three men, five women, average age 66.1 years) with benign tumors underwent lap-SVPDP. Lap-SVPDP was performed in the lithotomy position with the head slightly elevated. The splenic vein was peeled longitudinally toward the pancreatic tail. A vessel-sealing system was used to detach the pancreatic body from the greater omentum, and the pancreas was transected using a surgical stapler. RESULTS: Mean operation time was 254 min; mean blood loss was 163 ml; and mean post-surgical hospitalization time was 13 days. No postoperative bleeding from the preserved splenic vessels occurred, and there were no splenic infarcts or splenic abscesses. CONCLUSIONS: For safe performance of lap-SVPDP, the posterior surface of the pancreas should be completely exposed. The splenic vein should be 'peeled away', starting from its central rear, enabling easy detection of its course to avoid inadvertent sealing. With improved operational techniques, lap-SVPDP can be adopted as a standard procedure in pancreatic surgery.

Effect of a combination of S-1 and gemcitabine on cell cycle regulation in pancreatic cancer cell lines.

In a previous study, we showed that a combination of an oral fluoropyrimidine anticancer agent (S-1) and gemcitabine (GEM) had synergistic effects on cell growth and cell cycle arrest in the pancreatic cancer cell line MIA PaCa-2. Therefore, we conducted further mechanistic studies using the pancreatic cancer cell lines MIA PaCa-2 and SUIT-2. The combined effect of S-1 and GEM in SUIT-2 cells was evaluated using an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the effects of S-1, GEM and S-1 plus GEM on cell cycle regulation were assessed using flow cytometry. We also examined the expression of several cell cycle regulatory proteins in both MIA PaCa-2 and SUIT-2 cells by western blotting. Classical isobolographic analysis of the MTT assay results showed that the combination of S-1 and GEM had a synergistic effect in SUIT-2 cells, and flow cytometric analysis of the cell cycle showed that the combination of S-1 plus GEM induced S-phase arrest to a greater degree than did either S-1 or GEM alone. Also, the combination of S-1 and GEM resulted in the downregulation of cyclin D1 expression and upregulation of cyclin A, p21 and p27 expression levels. Treatment of MIA PaCa-2 and SUIT-2 cells with a combination of both drugs also led to the increased phosphorylation of checkpoint kinase 1. Combined treatment with S-1 and GEM resulted in more prolonged S-phase arrest than with either treatment alone. This difference is shown to be potentially due to the higher levels of phosphorylated checkpoint kinase 1 in pancreatic cancer cell lines treated with the two agents.

Experimental study of combination therapy with S-1 against pancreatic cancer.

PURPOSE: To determine the most effective combination chemotherapy with S-1 against pancreatic cancer and to clarify the mechanism of synergy between S-1 and the partner drug. METHODS: We tested a combination of S-1 with the following antitumor drugs in an in vitro MTT assay against pancreatic cancer cell line MIA PaCa-2: gemcitabine (GEM), cisplatin (CDDP), irinotecan (CPT-11), mitomycin C, adriamycin, and paclitaxel. The efficacy of S-1, GEM, and a combination of S-1 and GEM was also tested in vivo by administering S-1 (10 mg/kg) orally to nude mice five times a week for 3 weeks, and GEM (100 mg/kg) intravenously every 2-3 days for a total of six times. A treated-to-control ratio (T/C) of relative mean tumor weight values less than 50% was determined to be effective. Furthermore, we investigated the mechanism of the synergistic effect of S-1 and GEM on the cell cycle by flow cytometry, because both S-1 and GEM are known as antimetabolic drugs. To verify cell death induced by a change in the distribution of the cell cycle phases, we investigated apoptosis by sub-G1 analysis and a TUNEL assay. RESULTS: From classical isobolography analysis of the in vitro MTT assay, the combination of S-1 plus GEM was found to be the most effective of the combinations tested. In vivo, T/C (percentage) with the combination of S-1 plus GEM was 48.2%, which was lower than that of S-1 or GEM alone, and the combination enhanced antitumor activity. Cell cycle analysis showed greater cell cycle delay with the combination treatment (S-1 plus GEM) than for each single drug treatment, and apoptotic cells were detected only in treatments including GEM. CONCLUSION: The combination chemotherapy of S-1 and GEM appears to be useful for pancreatic cancer. Both cycle delay by S-1 plus GEM and apoptosis induced by GEM are involved in this synergistic mechanism.

Pharmacokinetics and postoperative analgesia of epidural tramadol: A prospective, pilot study.

BACKGROUND: Tramadol, a centrally acting analgesic drug, can be administered via multiple routes and is generally well tolerated. OBJECTIVE: This study was designed to assess the pharmacokinetics of epidural tramadol administered preoperatively in Japanese patients undergoing upper abdominal surgery. METHOD: Japanese patients who were scheduled to undergo upper abdominal surgery in The Kitasato Institute Hospital, Tokyo, Japan, were included. Patients received tramadol 2 mg/kg with 5 mL of 1% mepivacaine epidurally 10 minutes before incision. The serum concentration of tramadol was determined by high-performance liquid chromatography for 21 hours after administration. Serum concentration was determined before tramadol administration and 10, 20, 30, and 60 minutes after tramadol administration, first postoperative night, and first postoperative day. Pain score and adverse events (AEs) were assessed at 1, 3, 6, 12, 18, 24, 36, and 48 hours after surgery by patient interview. RESULTS: Eleven patients were assessed for enrollment. Seven patients (6 men, 1 woman; mean [SD] age, 61.3 [12.6] years; mean [SD] weight, 59.9 [8.9] kg) provided consent and completed the study. The mean (SD) serum Cmax of tramadol was 1385.5 (390.8) ng/mL, Tmax was 0.33 (0.22) hour, and terminal elimination half-life (t1/2ß) was 10.5 (2.3) hours. Four patients complained of nausea; however, only 1 patient was administered an antiemetic. No other AEs were reported. CONCLUSION: This pilot study found that epidural tramadol administered before incision induced a Cmax within 30 minutes of administration. The drug was detected in serum at ∼21 hours after surgery.

[Experimental chemotherapy against human esophageal carcinoma xenografts with TS-1, cisplatin and docetaxel].

Three strains of human esophageal carcinoma xenografts established in our institution were tested against combination chemotherapy in vivo and in vitro. TS-1 plus cisplatin (CDDP) was shown to be an effective combination against two carcinoma strains of moderately-differentiated type. Determination of the thymidylate synthase (TS) demonstrated a higher inhibition of the enzyme by adding CDDP to 5-FU, suggesting biochemical modulation. The remaining strain of poorly-differentiated type was resistant to the combination and an attempt was made to add docetaxel (DTX) to show that the three-drug combination was effective against the strain. Combination chemotherapy including TS-1 and CDDP thus appears to be useful treatment choice for esophageal carcinoma.