[Two Cases of Advanced Recurrent Breast Cancer with Severe Heart Failure Caused By Anthracycline].

Case 1: A 48-year-old woman, had right breast cancer with multiple liver metastases. Seven courses of paclitaxel plus bevacizumab were administered, but due to disease progression, 12 courses of FEC 75(total epirubicin 900 mg/m2)were administered. 2 months after the last FEC administration, the patient developed heart failure and died about 3 months later. Case 2: A 58-year-old woman, was on endocrine therapy after surgery for left breast cancer. Recurrence of lung and bone metastases were appeared 5 years after surgery, 10 courses of FEC 75(total epirubicin 750 mg/m2)were administered due to disease progression. Eight months after the last administration of FEC, the patient developed heart failure and died about 8 months later. Anthracycline induced cardiotoxicity is irreversible and has a severe course. Therefore, anthracycline should be administered with caution.

Amphotericin B assembles into seven-molecule ion channels: An NMR and molecular dynamics study.

Amphotericin B, an antifungal drug with a long history of use, forms fungicidal ion-permeable channels across cell membranes. Using solid-state nuclear magnetic resonance spectroscopy and molecular dynamics simulations, we experimentally elucidated the three-dimensional structure of the molecular assemblies formed by this drug in membranes in the presence of the fungal sterol ergosterol. A stable assembly consisting of seven drug molecules was observed to form an ion conductive channel. The structure is somewhat similar to the upper half of the barrel-stave model proposed in the 1970s but substantially different in the number of molecules and in their arrangement. The present structure explains many previous findings, including structure-activity relationships of the drug, which will be useful for improving drug efficacy and reducing adverse effects.

[A Case of Neuroendocrine Carcinoma Originating from the Papilla of Vater].

A woman in her late 70s with fatigue, nausea, and epigastric discomfort was found to have a tumor at the papilla of Vater through endoscopy. We performed subtotal stomach-preserving pancreaticoduodenectomy with regional lymph node dissection. The immunohistological analysis showed positive staining for chromogranin A, synaptophysin, and CD56. The definitive diagnosis was neuroendocrine carcinoma of the papilla of Vater. Although the patient declined adjuvant chemotherapy, she had to start chemotherapy with carboplatin and etoposide because multiple liver metastases, lymph node metastasis, and peritoneal dissemination occurred 6 months after surgery. We performed 6 courses of chemotherapy. However, progressive disease(PD)was assessed, and she died of cancer 13 months after the surgery. The prognosis of the disease is poor when surgery alone is performed. Adjuvant chemotherapy, in addition to surgery, may be necessary.

[Successful Experience of Negative Pressure Wound Therapy with Instillation and Dwelling(NPW Ti-d)for Patient with Wound Dehiscence Developed by Infection after Right-Hemicolectomy for Ascending Colon Cancer].

We report a case of infected and incised wound cured by negative pressure wound therapy with instillation and dwelling (NPWTi-d)after right hemicolectomy for ascending colon cancer. The patient was a 72-year-old male. An ascending colon cancer with abdominal wall invasion and enterocutaneous fistula was found. We performed the right hemicolectomy and debridement of abdominal wall for the patients. However, the leakage of ileum-transverse colon anastomosis was found on postoperative day 3. We performed the resection of anastomosis and ileostomy. Nevertheless, 2 days after second operation, the abdominal wall of debridement became open by infection, and the small intestine was exposed. As the surgical treatment and NPWT was thought to be difficult because of infection, we started NPWTi-d on day 4 after second operation. 25 day after starting NPWTi-d, benign granulation covered the small intestine. NPWTi-d may be useful for wound dehiscence after surgery in infectious conditions.

[Two Cases of Advanced and Recurrent Gastric Cancer with Long-Term Survival Due to Successful Chemotherapy].

Case 1: A 73-year-old man underwent total gastrectomy for residual gastric cancer, and final pathological diagnosis was pStage ⅠB. Adjuvant chemotherapy was not performed. CT findings showed multiple liver metastasis 16 months after procedure. S-1 and CDDP were administered for 28 months. Although chemotherapy regimen was changed to S-1, paclitaxel plus ramucirumab, nivolumab, irinotecan and S-1 plus oxaliplatin(SOX)after progression, he died 73 months after operation, and 57 months after recurrence. Case 2: A 72-year-old man was pointed out swelling of gastric lymph nodes in CT imaging. He was diagnosed as advanced gastric cancer with para-aortic lymph node metastasis by followed examination. S- 1 plus CDDP was administrated for 30 months. S-1 and SOX were administered after progressive findings, but he died 48 months after diagnosis. We report 2 cases of recurrent and advanced gastric cancer with long-term survival because of successful chemotherapy.

A Case of Hemorrhagic Cholecystitis and Hemobilia Under Anticoagulation Therapy.

BACKGROUND Hemorrhagic cholecystitis is a rare disease which can be fatal in some cases. Hemorrhagic cholecystitis can sometimes be confused with common biliary diagnoses, as its symptoms imitate other hepatobiliary diseases. We report a case of hemorrhagic cholecystitis with hemobilia caused by the administration of anticoagulant agents. CASE REPORT A 70-year-old man was admitted with abdominal distention and pain. Ultrasound (US) and computed tomography (CT) showed a distended and wall-thickened gallbladder with hyperdense materials. Based on these findings and the laboratory data, the patient was diagnosed with acute cholecystitis with cholangitis. Because the patient's hemodynamics were stable, endoscopic retrograde cholangiopancreatography (ERCP) was performed first to improve the bile flow. The results of ERCP showed blood from the common bile duct by cannulation, which was suspected to reflect hemorrhagic cholecystitis. As the abdominal symptom and CT findings worsened on the day after ERCP, emergency laparoscopic cholecystectomy was performed. An examination of the specimen revealed ulcer formation on the mucosal side of the gallbladder. The patient was discharged 6 days after the operation without any surgical complications. CONCLUSIONS ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia. Early diagnosis and treatment can lead to good outcomes in patients with hemorrhagic cholecystitis. Since the number of patients who are taking antithrombotic agents is increasing, hemorrhagic cholecystitis should be considered when any unusual imaging findings associated with cholecystitis are observed.

The Structure of the Bimolecular Complex between Amphotericin B and Ergosterol in Membranes Is Stabilized by Face-to-Face van der Waals Interaction with Their Rigid Cyclic Cores.

Amphotericin B (AmB) is a polyene macrolide antibiotic isolated from Streptomyces nodosus. The antifungal activity of AmB can be attributed to the formation of an ion-channel assembly in the presence of ergosterol (Erg), in which there are two different AmB-Erg orientations, parallel and antiparallel, as reported previously. In this study, to elucidate the structures of those AmB-Erg complexes based on solid-state nuclear magnetic resonance, a (19)F-labeled AmB derivative was newly prepared by a hybrid synthesis that utilized degradation products from the drug. Using the 2-(trimethylsilyl)ethoxymethyl (SEM) group as the protecting group for the carboxylic acid moiety of AmB, the fully deprotected labeled AmB compounds were obtained successfully. Then, these labeled AmBs were subjected to (13)C{(19)F} rotational-echo double-resonance (REDOR) experiments in hydrated lipid bilayers. The results indicated the coexistence of parallel and antiparallel orientations for AmB and Erg pairing, at a ratio of 7:3. A total of six distances between AmB and Erg were successfully obtained. Geometry analysis using the distance constraints derived from the REDOR experiments provided the plausible AmB-Erg complex structure for both the parallel and antiparallel interactions. The flat macrolide of AmB and the tetracyclic core of Erg closely contacted in a face-to-face manner, thus maximizing the van der Waals interaction between the two molecules. This interaction can be attributed to the coexistence of both the parallel and antiparallel orientations.

Axial hydrogen at C7 position and bumpy tetracyclic core markedly reduce sterol's affinity to amphotericin B in membrane.

The interaction of amphotericin B (AmB) with fungal ergosterol (Erg) is stronger than its interaction with mammalian cholesterol (Cho), and this property of AmB as an antifungal drug is thought to be responsible for its selective toxicity toward fungi. However, the mechanism by which AmB recognizes the structural differences between sterols, particularly minor difference in the sterol alicyclic portion, is largely unknown. Thus, to investigate the mode of interaction between AmB and the sterol core, we assessed the affinity of AmB to various sterols with different alicyclic structures. Ion flux assays and UV spectral measurements clearly revealed the importance of the Δ7-double bond of the sterol B-ring for interaction with the drug. AmB showed lower affinity for triene sterols, which have double bonds at the Δ5, Δ7, and Δ9 positions. Intermolecular distance measurements by (13)C{(19)F} rotational echo double resonance (REDOR) revealed that the AmB macrolide ring is in closer contact with the steroid core of Erg than it is with the Cho core in the membrane. Conformational analysis suggested that an axial hydrogen atom at C7 of Δ5-sterol (2, 6) and the protruded A-ring of Δ5,7,9-sterol (4, 8) sterically hampered face-to-face contact between the van der Waals surface of the sterol core and the macrolide of AmB. These results further suggest that the α-face of sterol alicycle interacts with the flat macrolide structure of AmB.

[Experience with levocarnitine chloride supplementation for the treatment of fatigue in cancer patients undergoing chemotherapy].

AIM: Patients undergoing chemotherapy are at risk of carnitine deficiency, and carnitine supplementation has been demonstrated to improve cancer-related fatigue. We examined the changes in fatigue when cancer patients experiencing fatigue while undergoing chemotherapy were administered levocarnitine chloride. MATERIALS AND METHODS: Ten patients with advanced and recurrent cancer experiencing fatigue during chemotherapy were administered levocarnitine chloride. We investigated changes in fatigue, and carried out nutritional assessment using the numerical rating scale(NRS)and geriatric nutritional risk index(GNRI), before and after levocarnitine chloride treatment. RESULTS: Four patients responded to levocarnitine chloride treatment, while six did not. Before treatment, the GNRI of responders was significantly lower than that of nonresponders. The difference between the two groups disappeared after treatment. CONCLUSION: A form of malnutrition may have been present in responders, which may have been improved by carnitine supplementation. It is possible that an improvement in this nutritional disorder was involved in fatigue mitigation.

Effect of sterol side chain on ion channel formation by amphotericin B in lipid bilayers.

Amphotericin B (AmB) is one of the most efficient antimycotic drugs used in clinical practice. AmB interacts with membrane sterols increasing permeability of fungal membranes; however, it is still unclear how AmB selectively recognizes the fungal sterol, ergosterol (Erg), over other sterols in cell membranes. In this study, we investigated the effect of an Erg side chain on AmB activity by testing a series of Erg analogues that shared the same alicyclic structure as Erg but varied in the side chain structure by using the K(+) influx assay. The results clearly showed that the sterol side chain is essential for AmB selectivity toward Erg and for the activity of AmB-sterol ion channels. In agreement with our previous findings showing the direct interaction between the drug and Erg, these data suggested that AmB directly recognizes the sterol side chain structure, consequently promoting the formation of ion channels by AmB. Furthermore, the C24 methyl group and Δ22 double bond in the side chain of Erg are equally important for the interaction with AmB. Conformational analysis revealed that the C24 methyl group contributes to the interaction by increasing the van der Waals (VDW) contact area of the side chain, while the Δ22 double bond restricts the side chain conformation to maximize the VDW contact with the rigid AmB aglycone. This study provides direct experimental evidence of the mechanism of AmB selectivity toward fungal Erg.

[A case of adenocarcinoma of the anal canal in which palliation was achieved by chemoradiotherapy].

An 82-year-old man who complained of constipation, anal pain, and bleeding was diagnosed with internal hemorrhoid in another hospital 6 months previously. At the time of our consultation, a tumor was observed in the anal canal. Computed tomography (CT) imaging revealed that the tumor extended to the front of the coccyx with abscess formation. Histological examination of biopsy specimens confirmed a diagnosis of adenocarcinoma. Since the patient refused to undergo surgery, we recommended chemoradiotherapy for relieving pain. A total of 60 Gy of irradiation was administered to the lesser pelvis, and chemotherapy was initiated with S-1 at a dose of 8 0mg/day for 14 consecutive days followed by 7 days of rest. Subsequently, tumor reduction was seen and the pain was controlled. The patient showed improvement in activities of daily living (ADL). Currently, the patient continues to receive S-1 therapy. We conclude that chemoradiotherapy is useful as a palliative therapy in anal mucinous carcinoma.

Tumor budding and E-cadherin expression are useful predictors of nodal involvement in T1 esophageal squamous cell carcinoma.

BACKGROUND: Endoscopic treatment has been increasingly used for T1 esophageal squamous cell carcinoma (ESCC). However, this therapy is sometimes incomplete if the depth of the T1 primary tumor reaches the muscularis mucosae or submucosal layer because these tumors have a relatively high incidence of lymph node metastasis. However, to our knowledge, no previous reports on the prediction of nodal metastasis determined by evaluating primary tumor specimens of patients with ESCC are available. PATIENTS AND METHODS: A total of 55 patients with T1 ESCC invading as deep as the submucosal layer who underwent curative esophagectomy were examined. We investigated the significance of the immunohistochemical staining of Vascular endothelial growth factor-C (VEGF-C) and E-cadherin in the primary tumor and Tumor budding for prediction of nodal metastasis. RESULTS: Metastasis to the regional lymph nodes was observed in 26 cases (47.3%) in this setting. VEGF-C expression and reduced E-Cadherin expression in the primary tumor was observed in 32 (58.1%) and 38 cases (69.1%), respectively. High-grade tumor budding was observed in 29 cases (52.7%). E-cadherin expression and tumor budding were closely correlated with nodal metastasis (p=0.04 and <0.01 respectively), whereas VEGF-C expression tended to correlate with lymph node metastasis (p=0.06). In addition, high-grade tumor budding was significantly correlated (p<0.01) with reduced E-cadherin expression. The accuracy of tumor budding and E-cadherin expression for nodal metastasis were 67.3% and 65.4% respectively, comparable with the one of lymphatic involvement (63%). Tumor budding (p<0.01), but not E-cadherin and VEGF-C expression, was significantly correlated with poor survival. CONCLUSION: After the endoscopic treatment, additional therapy, such as surgery or chemoradiotherapy, may be required if reduced E-cadherin expression and high-grade tumor budding are observed in primary tumor specimen.

Head-to-tail interaction between amphotericin B and ergosterol occurs in hydrated phospholipid membrane.

Amphotericin B (AmB) is thought to exert its antifungal activity by forming an ion-channel assembly in the presence of ergosterol. In the present study we aimed to elucidate the mode of molecular interactions between AmB and ergosterol in hydrated phospholipid bilayers using the rotational echo double resonance (REDOR) spectra. We first performed (13)C{(19)F}REDOR experiments with C14-(19)F-labeled AmB and biosynthetically (13)C-labeled ergosterol and implied that both "head-to-head" and "head-to-tail" orientations occur for AmB-ergosterol interaction in the bilayers. To further confirm the "head-to-tail" pairing, (13)C-labeled ergosterol at the dimethyl terminus (C26/C27) was synthesized and subjected to the REDOR measurements. The spectra unambiguously demonstrated the presence of a "head-to-tail" orientation for AmB-ergosterol pairing. In order to obtain information on the position of the dimethyl terminus of ergosterol in membrane, (13)C{(31)P}REDOR were carried out using the labeled ergosterol and the phosphorus atom of a POPC headgroup. Significant REDOR dephasing was observed at the C26/C27 signal of ergosterol in the presence of AmB, but not in the absence of AmB, clearly indicating that the side-chain terminus of ergosterol in the AmB complex comes close to the bilayer surface.

[A case of gastric cancer with para-aortic lymph node metastasis successfully treated with S-1/paclitaxel/lentinan combination therapy].

A 70-year-old male presented with gastric cancer with para-aortic lymph node metastasis. The patient was given combination chemotherapy of S-1, paclitaxel and Lentinan. Lymph node metastases were reduced in number at the end of one course. At the end of the eighth course, the lesions were markedly reduced but no further reduction was observed thereafter. The primary lesion was also markedly reduced, and a distal gastrectomy(D1+a)was performed because of remaining tumor tissue detected by biopsy. Pathological findings revealed pT1(SM), pN0, P0, CY0, H0, M0, and Stage IA, respectively. After surgery, this treatment was continued for 4 years and one month from the initiation of this therapy(2 years and six months from gastrectomy). During the period of treatment, there was no relapse nor serious adverse events.

[A case of unresectable sigmoid colon cancer in an elderly patient responding to S-1].

An 88-year-old man with unresectable sigmoid colon cancer due to retroperitoneal invasion and massive LN metastasis was treated with S-1 after colostomy. S-1 (80 mg/body/day) was administered for 2 weeks followed by a one week interval. Colonoscopy and abdominal CT revealed a partial response. After 5 courses, the patient underwent sigmoidectomy. S-1 was then administered for 15 courses. There was no side effect, and hospitalization was not required during the treatment. This therapy was very feasible and convenient, obtained good compliance and enhanced the quality of life of this patient. S-1 is expected to be an effective agent for the treatment of advanced colon cancer in elderly patients in days to come.

Granulation of core particles suitable for film coating by agitation fluidized bed I. Optimum formulation for core particles and development of a novel friability test method.

To prepare powdered medicines without bitter taste, film coating is required to cover the surface of core particles. In this study, effect of formulation and operating conditions of agitation fluidized bed on the core particle properties was investigated. In order to prevent breakage of the core particles during coating process, which sometimes causes variation of drug dissolution rate, addition of maltose syrup powder during the formulation process of the core particles was investigated. Also, a method for friability test in which the core particles were subjected to strong impact was proposed to evaluate strength of the core particles. The friability of the core particles determined by this test method correlated well with the actual friability of the particles during the coating process. Based on this result, we confirmed this novel friability test method could predict the core particle endurance during the coating process.