Safety and effectiveness of oral blonanserin for schizophrenia: A review of Japanese post-marketing surveillances.

Schizophrenia significantly limits social functioning with positive and negative symptoms and cognitive dysfunction. Blonanserin (LONASEN®), a novel second-generation antipsychotic approved for treating schizophrenia in Japan in 2008, reportedly shows beneficial effects on cognitive function as well as positive and negative symptoms, with potential for improving social functioning. To understand the safety and effectiveness of blonanserin in the real clinical practice, five Japanese post-marketing surveillances have been conducted and published to date. In this article, we reviewed all the Japanese post-marketing surveillances and discussed the clinical usefulness of blonanserin in patients with schizophrenia having diverse clinical characteristics. Adverse drug reactions, such as akathisia and extrapyramidal symptoms, were common in all surveillances. However, those specific to second-generation antipsychotics, such as weight gain and abnormalities in glycometabolism or lipid metabolism, were rarely observed. In addition, no adverse drug reactions apart from clinical trial results were found. Brief Psychiatric Rating Scale total scores in all surveillances significantly lowered at the last evaluation than at baseline. These results were consistent through 1-year of treatment, suggesting that effectiveness is maintained even after long-term use. In conclusion, blonanserin is considered a beneficial drug in real clinical practice for patients with schizophrenia having diverse characteristics.

Long-term oral blonanserin treatment for schizophrenia: a review of Japanese long-term studies.

In general, the course of schizophrenia is chronic accompanied not only by positive and negative symptoms but also by cognitive dysfunction associated with psychosocial disability, and thus treatment combining antipsychotics and psychological therapy is considered promising. This review focused on two prospective, open-label, multicenter, phase 3 long-term studies for approval of oral blonanserin for the treatment of schizophrenia. These two studies included both inpatients and outpatients with variable disease duration or symptom prominence according to the Positive and Negative Syndrome Scale (PANSS). The selected two studies consisted of almost the same study schedule and eligibility criteria but different protocols regarding prior medications and concomitant antipsychotics. The proportion of patients who had a baseline PANSS negative score higher than the positive score was 82.2 and 67.2% in the two studies. In both studies, patients with an illness duration of ≥ 10 years were the most common. Based on the clinical symptoms at baseline, the physician determined the treatment: blonanserin monotherapy, blonanserin in combination with the existing antipsychotic medication, or therapy simplified to haloperidol together with blonanserin. The 28-week completion rate for long-term blonanserin treatment was high in both studies (82.2 and 78.7%). The types of adverse events in both studies were similar to those in the preceding 8-week randomized, active-controlled studies in Japan, which were included in the application package for the approval of oral blonanserin for patients with schizophrenia. Long-term blonanserin use did not increase the risk of extrapyramidal symptoms but reduced the dose of antiparkinsonian drugs, minimally affecting functioning. In both studies, the PANSS total score, positive score, and negative score were improved at the last observation carried forward compared with those at baseline. In conclusion, blonanserin is useful for long-term treatment of chronic schizophrenic patients when the appropriate management of clinical symptoms and adverse drug reactions are applied. Blonanserin might represent a promising treatment option that partially or completely relieves patients with chronic schizophrenia of polypharmacy. Blonanserin may possibly fit both the current real-world clinical setting and the currently recommended approach to antipsychotic medication.

Identification of 2-(2'-fluoro-[1,1'-biphenyl]-2-yl)acetamide as a Sodium Valproate-like broad spectrum anti-epileptic drug candidate.

By further optimizing compound A [2'-fluoro-N-methyl-[1,1'-biphenyl]-2-sulfonamide], we identified DSP-0565 [2-(2'-fluoro-[1,1'-biphenyl]-2-yl)acetamide, 17a] as a strong, broad-spectrum anti-epileptic drug (AED) candidate. Our efforts mainly focused on finding an alternative polar group for the sulfonamide in order to improve ADME profile of compound A including good metabolic stability and no reactive metabolic production. This led to the identification of biphenyl acetamide as a new scaffold for development of broad-spectrum AED candidates. DSP-0565 showed anti-convulsant activity in various models (scPTZ, MES, 6 Hz and amygdala kindling) with good safety margin, and was therefore selected as a clinical candidate.

Synthesis and biological evaluation of novel orally available 1-phenyl-6-aminouracils containing dimethyldihydrobenzofuranol structure for the treatment of allergic skin diseases.

We have designed and efficiently synthesized novel 1-phenyl-6-aminouracils by replacing the chroman moiety in CX-659S, a nonsteroidal dermatologic candidate, with dimethyldihydrobenzofuranol to cancel CX-659S asymmetric center. Medicinal chemistry effort culminated in the discovery of 13d bearing a 3-methyl group at the 1-phenyl group as a promising compound. Compound 13d, having good in vitro ADME profile and moderate oral bioavailability in mice, showed potent anti-inflammatory activity against hapten-induced contact hypersensitivity reaction in mice following topical and oral administration. The effects of 13d were equipotent to that of tacrolimus or prednisolone. In addition, compound 13d, having potent hydroxyl radical-scavenging activity, showed more potent suppressive effect on substance P-induced pruritus in mice than oxatomide.

Influence of nutritional status on the therapeutic effect of infliximab in patients with Crohn's disease.

PURPOSE: Crohn's disease (CD) is a refractory inflammatory bowel disease of unknown etiology, frequently complicated by malnutrition. It is thought that the delayed wound healing associated with this malnutrition in CD patients might adversely affect the therapeutic benefits of infliximab (IFX). Therefore, we investigated the effects of nutritional status on IFX treatment. METHODS: We assessed nutritional status and CD activity when IFX therapy was initiated and following the third dose, 6 weeks later. Nutritional status was assessed using the body mass index (BMI) and nutritional risk index (NRI), whereas CD activity was assessed using the CD activity index (CDAI). RESULTS: All patients with a BMI ≥ 18.5 kg/m(2) at the time of IFX therapy met the effective criteria for the CDAI, and IFX treatment was considered responsive in these patients. Furthermore, IFX treatment was responsive, with a high level of effectiveness, in all five subjects (31.3 %) with NRI scores of 97.5 and above with no risk of malnutrition (p = 0.037). CONCLUSIONS: Our results suggest that nutritional status does influence the therapeutic effect of IFX in CD patients. The response rate to IFX treatment thus could be improved by optimizing the nutritional status. We recommend comprehensive nutritional assessment and intervention prior to IFX treatment schedules.

[Dietary reference intakes of trace elements for Japanese and problems in clinical fields].

In the dietary reference intakes, EAR(estimated average requirement), RDA(recommended dietary allowance), AL(adequate intake), DG(tentative dietary goal for preventing life style related diseases) and UL(tolerable upper intake level) of eight types of trace elements (iron: Fe, zinc: Zn, copper: Cu, manganese: Mn, iodine: I, selenium: Se, chromium: Cr, molybdenum: Mo) have been set. However, in the meals of hospitals, only iron of which has been taken into account. The content of these trace elements in the enteral nutrient released after 2000 was determined by considering the content of dietary reference intakes of trace elements for Japanese and considered so not fall into deficiency. However, enteral nutrient must be used considering the content of Zn, Cu and the Zn/Cu ratio, the selenium content, and the route of administration, in order to avoid falling into deficiency.

Effects of lipid emulsion and multivitamins on the growth of microorganisms in peripheral parenteral nutrition solutions.

BACKGROUND: Blood stream infections caused by Bacillus cereus or Serratia marcescens in patients receiving peripheral parenteral nutrition (PPN) have occasionally been reported in Japan, but these microorganisms are not major causes of blood stream infections in patients receiving total parenteral nutrition via a central venous catheter. In Japan, commercially available PPN solutions contain amino acids, glucose, and electrolytes, but not contain lipid emulsion (LE) and multivitamins (MV). In this study, the effects of LE and MV on the growth of microorganisms such as Bacillus cereus, Serratia marcescens, Staphylococcus aureus, and Candida albicans in PPN solutions were investigated. METHODS: A commercial 3% amino acid and 7.5% glucose solution with electrolytes (AF) was used as the base solution to prepare test solutions (LAF, AFV, and LAFV) containing LE, MV, or both. Specifically, 20% LE was added to AF in a ratio of 1:9 to prepare LAF. MV was added to AF and LAF to prepare AFV and LAFV, respectively. A specified number of each microorganism was added to each 100 mL of AF, LAF, AFV, and LAFV in sterile plastic flasks, and all flasks were allowed to stand at room temperature. The number of colony forming units per mL of each microorganism was counted at 0, 24, and 48 hours after the addition of each microorganism. RESULTS: Both Bacillus cereus and Serratia marcescens increased rapidly in AF as well as in LAF, AFV, and LAFV. Staphylococcus aureus did not increased in AF, but increased slightly in LAF and increased rapidly in AFV and LAFV. Candida albicans increased slightly in AF and increased rapidly in LAF, AFV, and LAFV. CONCLUSIONS: The results suggest the followings: if microbial contamination occurs, 1) Bacillus cereus and Serratia marcescens can grow rapidly in PPN solutions consisting of amino acids, glucose and electrolytes; 2) Staphylococcus aureus cannot grow without LE and MV, but can grow rapidly with MV; 3) Candida albicans can grow slowly without LE and MV, and the addition of LE or MV accelerates its growth.

Parathyroid hormone-responsive Smad3-related factor, Tmem119, promotes osteoblast differentiation and interacts with the bone morphogenetic protein-Runx2 pathway.

The mechanisms whereby the parathyroid hormone (PTH) exerts its anabolic action on bone are incompletely understood. We previously showed that inhibition of ERK1/2 enhanced Smad3-induced bone anabolic action in osteoblasts. These findings suggested the hypothesis that changes in gene expression associated with the altered Smad3-induced signaling brought about by an ERK1/2 inhibitor would identify novel bone anabolic factors in osteoblasts. We therefore performed a comparative DNA microarray analysis between empty vector-transfected mouse osteoblastic MC3T3-E1 cells and PD98059-treated stable Smad3-overexpressing MC3T3-E1 cells. Among the novel factors, Tmem119 was selected on the basis of its rapid induction by PTH independent of later increases in endogenous TGF-ß. The levels of Tmem119 increased with time in cultures of MC3T3-E1 cells and mouse mesenchymal ST-2 cells committed to the osteoblast lineage by BMP-2. PTH stimulated Tmem119 levels within 1 h as determined by Western blot analysis and immunocytochemistry in MC3T3-E1 cells. MC3T3-E1 cells stably overexpressing Tmem119 exhibited elevated levels of Runx2, osteocalcin, alkaline phosphatase, and ß-catenin, whereas Tmem119 augmented BMP-2-induced Runx2 levels in mesenchymal cells. Tmem119 interacted with Runx2, Smad1, and Smad5 in C2C12 cells. In conclusion, we identified a Smad3-related factor, Tmem119, that is induced by PTH and promotes differentiation in mouse osteoblastic cells. Tmem119 is an important molecule in the pathway downstream of PTH and Smad3 signaling in osteoblasts.

Synthesis and SAR study of imidazoquinolines as a novel structural class of microsomal prostaglandin E2 synthase-1 inhibitors.

The imidazoquinoline derivative 1 was found as a novel mPGES-1 inhibitor. Optimization of 1 led to the identification of the 2-chlorophenyl group at the C(2)-position and the quinolone structure at the C(4)-position. Compound 33, the most potent synthesized compound, showed excellent mPGES-1 inhibition (IC(50)=9.1nM) with high selectivity (>1000-fold) over both COX-1 and COX-2.

Smad7 inhibits differentiation and mineralization of mouse osteoblastic cells.

The transforming growth factor (TGF)-ß family members, bone morphogenetic protein (BMP)-2 and TGF-ß that signal via the receptor-regulated Smads (R-Smads) induce bone formation in vivo. The inhibitory Smads (I-Smads), Smad6 and Smad7, negatively regulate TGF-ß family ligand signaling by competing with R-Smads for binding to activated type I receptors, and preventing R-Smad activation, Hence, the I-Smads potentially act as suppressors of bone formation although their effects on phenotypic changes in mature osteoblasts are unclear. While Smad7 inhibits both BMP and TGF-ß signaling, Smad6 is less effective in inhibiting TGF-ß signaling. The present study was performed to examine the role of Smad7 on the phenotype of mouse osteoblastic MC3T3-E1 cells. We employed stable Smad7-transfected MC3T3-E1 cells to examine the role of Smad7 in osteoblast proliferation, differentiation and mineralization. Stable Smad7 overexpression significantly inhibited the absorbance in the MTT-dye assay and inhibited the levels of PCNA compared with those in empty vector-transfected cells. Smad7 overexpression suppressed the type 1 collagen mRNA and protein levels. Moreover, Smad7 inhibited ALP activity and mineralization of osteoblastic cells. The effects of stable overexpression of Smad6 were similar to those of Smad7 suggesting the changes mediated by either I-Smad occurred by inhibition of BMP rather than TGF-ß signaling. In addition, PTH-(1-34) elevated the levels of Smad7 in parental MC3T3-E1 cells. In conclusion, the present study demonstrated that Smad7, as well as Smad6, inhibits proliferation, differentiation and mineralization of mouse osteoblastic cells. Therefore, I-Smads are important molecular targets for the negative control of bone formation.

Effectiveness and safety of blonanserin for improving social and cognitive functions in patients with first-episode schizophrenia: a study protocol for a prospective, multicentre, single-arm clinical trial.

INTRODUCTION: Both the pharmacological characteristics of blonanserin and its related small sample size studies suggest that blonanserin could alleviate social and cognitive dysfunctions in patients with schizophrenia. However, no large sample size studies have been performed so far. This study aimed to investigate the effectiveness and safety of blonanserin in improving social and cognitive functions in patients with first-episode schizophrenia. METHODS AND ANALYSIS: This is a prospective, multicentre, single-arm clinical trial. A total of 188 patients with first-episode schizophrenia will be enrolled and will undergo a 0-7 day washout period before blonanserin administration. Doses of blonanserin will first be set to 4 mg P.O. twice per day after meals and gradually increased to 8-16 mg/d P.O., depending on patient's age and symptoms, for 26 weeks. Maximum dose of blonanserin will not be exceeding 24 mg/day. The primary endpoint of the study is the changes of Personal and Social Performance (PSP) score in patients from baseline to week 26. Secondary endpoints include changes in MATRICS consensus cognitive battery (MCCB), Paced Auditory Serial Addition Test (PASAT), grooved pegboard test (GPT), Positive and Negative Syndrome Scale (PANSS) total score and PANSS 5-factor subscale scores. Other endpoints include changes of serum brain-derived neurotrophic factor (BDNF) at corresponding visits and MRI results. Moreover, incidence of adverse events, changes in endocrine and metabolic profiles, renal, hepatic and sexual functions and extrapyramidal symptoms will be strictly monitored and recorded. ETHICS AND DISSEMINATION: The study was approved by the ethics committee of the leading site Peking University Sixth Hospital (No. 2018-18), and all included patients are requested to provide written informed consent before enrolment. The study will be conducted according to the principles of the Declaration of Helsinki and follow the principles for clinical research. TRIAL REGISTRATION NUMBER: NCT03784222.

Growth of microorganisms in total parenteral nutrition solutions without lipid.

BACKGROUND: To identify the microorganisms that can grow rapidly in total parenteral nutrition (TPN) solutions, we investigated the growth of the major causes of catheter-related blood stream infection (Staphylococcus aureus, Serratia marcescens, Bacillus cereus, and Candida albicans) in TPN solutions without lipid. METHODS: Experiment 1: A commercial TPN solution without lipid containing multivitamins (pH5.6) was used. A specific number of each test microorganism was added to each 10 mL of the TPN solution and incubated at room temperature. An aliquot of test solution was sampled and inoculated to SCD agar plates at 0, 24, and 48 hrs after the addition of the microorganisms. The number of microorganisms was counted as colony forming units. Experiment 2: The other 2 commercial TPN solutions without lipid (pH5.5) were supplemented with multivitamins. The pH values of the solutions were adjusted to about 6.0, 6.5, or 7.0 using 0.5 mol/L NaOH. The addition of microorganisms, incubation, and counting were performed in the same manner. RESULTS: Experiment 1: S. aureus, S. marcescens, and B. cereus did not increase in the TPN solution without lipid containing multivitamins (pH5.6), but C. albicans increased rapidly. Experiment 2: The 3 bacterial species did not increase even at pH6.0, but increased at pH6.5 and increased rapidly at pH7.0 in both TPN solutions. C. albicans increased similarly at any pH. CONCLUSION: These results suggest that bacterial species cannot grow in TPN solutions without lipid due to the acidity (pH5.6 or lower), but Candida species can grow regardless of the acidity.

Efficacy and safety of blonanserin transdermal patch in patients with schizophrenia: A 6-week randomized, double-blind, placebo-controlled, multicenter study.

BACKGROUND: Blonanserin is a second-generation antipsychotic used for the treatment of schizophrenia. This study determined the efficacy, safety and pharmacokinetics of a blonanserin transdermal patch in patients with acutely exacerbated schizophrenia. METHODS: This double-blind, multicenter, phase 3 study consisted of a 1-week observation period during which patients were treated with two patches of placebo, followed by a 6-week double-blind period where patients were randomized (1:1:1) to receive once-daily blonanserin 40 mg, blonanserin 80 mg, or placebo patches. The primary endpoint was the change from baseline in the total Positive and Negative Symptom Scale (PANSS) score. Safety assessments included treatment-emergent adverse events (TEAEs). RESULTS: Between December 2014 and October 2018, patients were recruited and randomly assigned to blonanserin 40 mg (n = 196), blonanserin 80 mg (n = 194), or placebo (n = 190); of these, 77.2% completed the study. Compared with placebo, blonanserin significantly improved PANSS total scores at 6 weeks (least square mean [LSM] difference vs placebo: -5.6 with blonanserin 40 mg; 95% confidence interval [CI] -9.6, -1.6; adjusted p = 0.007, and - 10.4 with blonanserin 80 mg; 95% CI -14.4, -6.4; adjusted p < 0.001). Blonanserin was well tolerated; the most common TEAEs reported were application-site erythema and pruritus, akathisia, tremor, and insomnia. CONCLUSIONS: Blonanserin transdermal patch improved the symptoms of acute schizophrenia with acceptable tolerability.

Role of Smad3, acting independently of transforming growth factor-beta, in the early induction of Wnt-beta-catenin signaling by parathyroid hormone in mouse osteoblastic cells.

Parathyroid hormone (PTH) exerts an anabolic action on bone but the mechanisms are incompletely understood. We showed previously that PTH interacts with the canonical Wnt-beta-catenin signaling pathway via the transforming growth factor (TGF)-beta signaling molecule, Smad3, to modulate osteoblast differentiation and apoptosis. Here, we examined which actions of Smad3 are TGF-beta-independent in stimulating the osteoblast phenotype and PTH-induced Wnt-beta-catenin signaling. For this, the TGF-beta receptor type 1 [activin receptor-like kinase (ALK5)] inhibitor (SB431542), and a Smad3 mutant in which the site normally phosphorylated by ALK5 is mutated from SSVS to AAVA, was used. PTH induced total beta-catenin and reduced phosphorylated beta-catenin levels at 1, 6, and 24 h in mouse osteoblastic MC3T3-E1 cells. Transient transfection of Smad3AAVA inhibited the PTH induction of total beta-catenin and reduction of phosphorylated beta-catenin levels at 6 and 24 h, but not at 1 h, indicating that the early effects occur independently of TGF-beta receptor signaling. On the other hand, MC3T3-E1 cell clones in which Smad3AAVA was stably expressed demonstrated elevated beta-catenin levels, although alkaline phosphatase (ALP) activity and mineralization were unaltered. In contrast, MC3T3-E1 cell clones in which wild-type Smad3 was stably expressed exhibited increased ALP activity and mineralization that were decreased by the ALK5 inhibitor, SB431542, although the beta-catenin levels induced in these cells were not modulated. In conclusion, the present study indicates that PTH induces osteoblast beta-catenin levels via Smad3 independently of, and dependently on, TGF-beta in the early and later induction phases, respectively.

Vitamin D status affects osteopenia in postmenopausal patients with primary hyperparathyroidism.

Controversy still exists about whether vitamin D status is related to the severity of primary hyperparathyroidism (pHPT), although vitamin D insufficiency is frequent in pHPT. The present study was therefore performed to examine the relationships between vitamin D status and various parameters in 30 postmenopausal pHPT patients. BMD values were measured by dual-energy x-ray absorptiometry at the lumbar spine (L(2-4)), femoral neck (FN) and distal one third of the radius (Rad 1/3). Serum levels of 25 hydroxy-vitamin D(3) [25(OH)D] and 1,25-dihydroxy vitamin D(3) [1,25(OH) (2)D(3)] were 15.8 +/- 3.5 microg/l and 69.3 +/- 33.3 ng/l in pHPT patients, respectively. Serum levels of calcium and PTH seemed to be negatively correlated to serum 25(OH)D levels, although the differences were not significant. However, when subjects with the highest serum PTH levels (PTH>1000 pg/ml) were excluded from the analysis, the correlation was significant between serum 25(OH)D levels and PTH, indicating that vitamin D status affects the severity of pHPT when severe cases were excluded. In addition, serum levels of 1,25(OH)(2)D(3) were significantly and negatively correlated to serum 25(OH)D levels. On the other hand, serum levels of 25(OH)D were significantly and positively correlated to BMD (Z-score) at the lumbar spine, but not at the radius and femoral neck; however, serum 25(OH)D levels were not correlated to the levels of any bone metabolic indices measured. Moreover, serum levels of 25(OH)D were not related to urinary calcium and the tubular reabsorption rate of phosphorus, and they were similar in groups with and without renal stones. In conclusion, vitamin D status seemed to be related to the severity of disease in postmenopausal patients with pHPT. In particular, the relationship between serum 25(OH)D level and BMD at the lumbar spine was predominant.

[Nutritional support in cooperation with home medical care clinic and home visiting nursing].

There is a tendency that home care has been promoted as an alternative way to shorten the duration of hospital stay and to reduce a medical cost. But the Japanese reimbursement system has not been established enough to cover home medical care. The system and technique to carry out home nutritional care has almost established, but has not been spread yet. Hospitals have several choices to carry out home nutritional care: a patient cares his nutritional support by himself, a help provided by a home visiting nurse and a request from hospital to home medical care clinic. In order to carry out home medical care safely and successfully, it is important to communicate with a home visiting nurse as well as home medical care clinic before a patient leaves the hospital.

A case of noninvasive ductal carcinoma arising in malignant phyllodes tumor.

We report on an exceedingly rare case of noninvasive ductal carcinoma arising in malignant phyllodes tumor of the breast. The patient was a 75-year-old woman who presented with a chief complaint of an indolent tumor mass of the left breast. Papillotubular carcinoma was diagnosed by aspiration cytology, and mastectomy with preservation of the pectoral muscle was subsequently performed (Bt+Ax+Ic, R2). Histopathological examination showed proliferation of monotonous, uniform tumor cells in a cribriform pattern amid atypical and spindle-shaped cells. Neither stromal invasion of the epithelial tumor cells nor clear transition between epithelial tumor cells and non-epithelial tumor cells was seen. Immunohistochemical staining revealed that the epithelial component was positive for antibodies such as CEA, EMA and keratin, while the non-epithelial component was negative for the same antibodies. Malignant phyllodes tumor with a noninvasive ductal carcinoma was diagnosed rather than true carcinosarcoma of the breast. No metastasis was detected in the axillary lymph nodes, and the patient was classified as stage II A (T2N0M0). Although neither chemoendocrine therapy nor irradiation was employed postoperatively, no recurrence was observed two years and two months after the surgery. There is little consensus on the treatment or prognosis of the disease. Careful observation of the present case is therefore important.

[A case of gastric adenosquamous carcinoma with abdominal paraaortic lymph node metastases successfully treated by TS-1 plus CDDP neoadjuvant chemotherapy].

A 62-year-old woman was admitted for anemia. An endoscopic examination revealed type 2 cancer from the upper body of the stomach to the antrum, and abdominal CT scan demonstrated enlarged abdominal paraaortic lymph nodes. The preoperative diagnosis was cStage IV gastric cancer (cT 3, cN 3, cH 0, cP 0, cM 0). Since a curative operation was deemed impossible, we conducted neoadjuvant chemotherapy using TS-1 plus cisplatin (CDDP) for downstaging. TS-1( 100 mg/day) was orally administered for 3 weeks,and CDDP (60 mg/m2) was given intravenously on day 8. Appetite loss of grade 3 and erythropenia of grade 1 were observed. After two courses of chemotherapy the primary lesion and the paraaortic lymph nodes were significantly reduced in size. She was judged as clinical PR, followed by distal gastrectomy and lymph node dissection, resulting in curability A. Histopathologically, the tumor was diagnosed as adenosquamous carcinoma of the stomach with lymph node metastasis at only No.3. This case suggests that neoadjuvant chemotherapy using TS-1 plus CDDP is effective for advanced gastric adenosquamous carcinoma with massive lymph node metastases.

[A case of drug-induced interstitial pneumonitis after gemcitabine treatment for advanced pancreatic cancer].

A 54-year-old woman with advanced pancreatic cancer with peritoneal dissemination was given gemcitabine on days 1,8 and 15, and this was repeated on day 29 at a dose of 1,000-1, 150 mg/m2. After 5 courses,the total infusion was 20,900 mg. Thirteen days after the last infusion, she suffered from sudden dyspnea, and soon went into respiratory failure of WHO grade 4 with severe hypoxemia. Chest radiograph and CT showed interstitial infiltrates of bilateral lower lung. She was diagnosed with drug-induced interstitial pneumonitis due to gemcitabine. Corticosteroid therapy consisting of methylprednisolone (1 g/day) for three days followed by prednisolone(50 mg/day) was significantly effective in treatment of respiratory failure. Her symptoms were improved clinically within one week after the onset,and the interstitial shadows in the lungs had almost disappeared radiographically within three weeks after the onset. Respiratory symptoms did not appear again,but the patient died of progression of peritoneal dissemination of pancreatic cancer 73 days after the onset of the interstitial pneumonitis. Gemcitabine- induced interstitial pneumonitis is very rare, but could become a serious complication in long-term gemcitabine treatment.

Pathological complete response to trastuzumab and paclitaxel in a patient with inflammatory local recurrence following breast conserving surgery.

We encountered a case of inflammatory local recurrence of breast cancer after breast conserving surgery which attained pathological CR after combination therapy with trastuzumab and paclitaxel. The patient was a 49-year-old premenopausal woman whose left breast cancer(T2N0M0)was treated by breast conserving surgery (Bp+Ax). The pathological diagnosis was scirrhous carcinoma, g, ly1, v0, t2, n0, ER (-), PgR (+) and stage I A. Postoperatively, the residual breast was treated by 50 Gy irradiation followed by hormone therapy(Tamoxifen citrate+LH-RH analog). At 26 months after the surgery, local recurrence developed as inflammatory breast cancer. As the recurrent tumor was confirmed to be HER2-positve (3+ by IHC), combination therapy with trastuzumab and paclitaxel was started. After the 6 courses of pharmacotherapy were completed, she was judged to have clinical CR, and subsequently underwent total breast excision(Bt)and skin grafting. No visible cancer cell was observed in the resected specimens, pathological CR was diagnosed. Postoperatively, the patient is receiving trastuzumab alone every other week, and at present 10 months after the second operation, the patient is in CR status and is visiting the outpatient clinic. No severe side effects (over grade 3) from this therapy have been observed. It is suggested that combination therapy with trastuzumab and paclitaxel for inflammatory local recurrence after breast conserving surgery is a treatment of choice.