Successful and long-term response to trastuzumab plus paclitaxel combination therapy in human epidermal growth factor receptor 2-positive extramammary Paget's disease: A case report and review of the literature.

A 58-year-old woman with a histologically confirmed diagnosis of vulvar extramammary Paget's disease (EMPD) was referred to our hospital due to locally advanced and relapsed EMPD. The patient had undergone surgical resection three times for relapsed vulvar EMPD over a period of 12 years, but developed locally advanced and unresectable EMPD. As pathological examination indicated that the lesion was positive for human epidermal growth factor receptor 2 (HER2) on immunohistochemical staining, the patient was treated with trastuzumab plus paclitaxel. The primary tumor mass and lymph node metastasis regressed successfully with combined trastuzumab and paclitaxel therapy, and the disease has been stable for >2 years after the initiation of treatment. These observations suggest that HER2 status must be determined in patients with advanced and/or metastatic extramammary Paget's disease and therapy with HER2 inhibitors should be considered as an option for the treatment of HER2-positive EMPD.

Progressive development and enhancement of palliative care services in Japan: nationwide surveys of designated cancer care hospitals for three consecutive years.

CONTEXT: Policymaking plays an important role in national palliative care services. The Japanese Cancer Control Act was implemented in 2006. OBJECTIVES: To evaluate changes in the structure and processes of palliative care services after implementation of the Cancer Control Act. METHODS: We conducted annual nationwide surveys in designated cancer care hospitals (DCCHs, n = 349) between 2008 and 2010. The 65-item questionnaire was divided into seven domains: institutional framework, information to patient and family, practice of palliative care, activities of the palliative care teams (PCTs), members of PCTs, regional medical cooperation, and education. Increasing trends were tested using generalized estimating equation models. RESULTS: The response rates were ≥ 99%. All domains showed an increasing trend (P < 0.001). There were significant increases in full-time PCT physicians (27.4%-45.7%, P(trend) < 0.001), full-time PCT nurses (38.9%-88.0%, P(trend) < 0.001), and the median number of annual referrals to PCTs (60-80 patients, P < 0.001). Essential drugs were available in most DCCHs from baseline. Although outpatient clinics increased significantly (27.0%-58.9%, P(trend) < 0.001), community outreach programs did not (9.0%-12.6%, P = 0.05). Basic education was actively introduced for in-hospital physicians and nurses (78.2% and 91.4% in 2010), but often unavailable for regional health care providers (basic education for regional physicians and nurses: 63.9% and 71.1% in 2010). CONCLUSION: The Cancer Control Act promoted the development and enhancement of palliative care services in DCCHs. Regional medical cooperation and education are the future challenges of palliative care in Japan.

In vivo monitoring of natural killer cell-dependent clearance of lung metastasis using dynamic positron emission tomography.

Immunohistological methods indicated a rapid onset of cellular defence shortly after seeding of mammary adenocarcinoma cells into the lungs of F344 rats. The purpose of the present study was to monitor natural killer (NK) cell-mediated effects on tumour cell clearance in vivo, in this model of lung metastasis using dynamic positron-emission tomography (dPET). MADB106 breast cancer cells were labelled with 2'-[(18)F]-2'-deoxy-D-glucose (FDG) then injected intravenously, after the F344 rats had been anaesthetized and placed in a PET scanner. NK cell-depleted and sham-treated control rats were investigated in parallel. The radioactivity per region of interest (ROI) over the lungs peaked at 60 s past injection and was followed by a slow decline over the observation time of 40 min in both groups. Statistical analysis using a linear mixed model revealed that release of radioactivity from tumour cells or tumour cell disintegration was significantly slower in animals after depletion of NK cells compared with controls. There was no significant tumour cell homing in organs other than the lungs. Early kinetics of tumour cells after injection were defined. PET with FDG was shown to be an adequate method to further investigate novel options for using cellular host defence mechanisms in cancer patients.

CSLEX (Sialyl Lewis X) is a useful tumor marker for monitoring of breast cancer patients.

BACKGROUND: CSLEX is a type II carbohydrate antigen that interacts with the CSLEX-1 monoclonal antibody. CSLEX in combination with carbohydrate antigen 15-3 may be more useful than Carcinoembryonic Antigen with carbohydrate antigen 15-3 as tumor markers for monitoring of breast cancer. METHODS: The serum levels of tumor markers, including CSLEX, were measured in 480 consecutive breast cancer patients with or without metastasis who visited the outpatient clinic of the Division of Breast and Endocrine Surgery, Shinshu University Hospital, between April 2007 and September 2007. RESULTS: Serum levels of each of the tumor markers correlated significantly with the status of metastasis (P < 0.01). Combinations of Carcinoembryonic Antigen and carbohydrate antigen 15-3, Carcinoembryonic Antigen and Nation Cancer Center-Stomach-439, Carcinoembryonic Antigen and CSLEX, carbohydrate antigen 15-3 and Nation Cancer Center-Stomach-439, and carbohydrate antigen 15-3 and CSLEX levels also correlated significantly with the status of metastasis (P < 0.01). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy were almost the same for CSLEX and Nation Cancer Center-Stomach-439, which are both type II carbohydrate antigens. The cutoff indexes of serum CSLEX and Nation Cancer Center-Stomach-439 for detection of breast cancer metastasis were 38.8 ± 52.7-fold and 22.1 ± 27.8-fold, respectively (P = 0.16). CONCLUSIONS: These data suggest that the diagnostic values of CSLEX and Nation Cancer Center-Stomach-439 are similar in single or combined use. However, the cutoff index of serum CSLEX tended to be higher than that of Nation Cancer Center-Stomach-439, which may make CSLEX more useful for detection of breast cancer metastasis.

Evaluation of a new method for the diagnosis of alterations of Lens culinaris agglutinin binding of thyroglobulin molecules in thyroid carcinoma.

BACKGROUND: The measurement of serum thyroglobulin (Tg) is widely used as a marker for recurrence of thyroid carcinoma following total thyroidectomy. However, this method cannot differentiate between benign and malignant disease. We focused on the sugar chain in the Tg molecule and investigated the usefulness of Lens culinaris agglutinin (LCA)-reactive Tg ratios in sera and wash fluids obtained during fine-needle aspiration (FNA) for the detection of thyroid carcinoma. METHODS: The study was performed using 203 serum samples (115 from patients with benign thyroid disease and 88 from patients with thyroid carcinomas) and 176 wash fluid samples (143 benign, 21 malignant, and 12 inconclusive). LCA-reactive Tg ratios were determined using an enzyme-linked immunosorbent assay, and a comparison was made between malignant and benign lesions. RESULTS: In serum, the ratio in patients with malignancy was 79.5+/-6.0 [mean+/-standard deviation (SD)], significantly lower than in patients with benign lesions (84.9+/-3.5). The ratios in wash fluid from malignant lesions (75.8+/-18.9) were also significantly lower than those from benign lesions (85.6+/-3.9). CONCLUSIONS: These results suggest that this method could distinguish between benign and malignant lesions and may be useful for screening serum and wash samples.

Genetically engineered Bifidobacterium longum for tumor-targeting enzyme-prodrug therapy of autochthonous mammary tumors in rats.

A fundamental obstacle in systemic therapy for cancer patients is the specific targeting of therapy directly to solid tumors. A strain of the domestic bacterium Bifidobacterium longum, which is non-pathogenic and anaerobic, showed selective localization to and proliferation within solid tumors after systemic application. Here, we propose a novel approach to cancer gene therapy in which anaerobic and non-pathogenic bacteria of the genus B. longum are used to achieve tumor-specific gene delivery and enzyme-prodrug therapy. We constructed a plasmid, pBLES100-S-eCD, which included eCD. Transfected B. longum produced CD in hypoxic tumors and achieved tumor site-specific conversion of 5-FC to 5-FU. Furthermore, we demonstrated antitumor efficacy in rat bearing autochthonous mammary tumors injected with the transfected B. longum directly or intravenously. This method was confirmed to be effective for enzyme-prodrug therapy not only by intratumoral injection but also by systemic administration. To estimate the toxicity of this bacterial vector, the systemic immunogenicity was evaluated by ASA reaction and the anaphylactic activity of IgG was evaluated by PCA reaction in guinea pigs. In the ASA reaction, no anaphylaxis symptoms were observed in any immunized guinea pigs injected with transfected B. longum. In the PCA reaction, B. longum/S-eCD specific-PCA-induced antibody was not detected. Thus, we proposed that anaerobic bacteria of the genus B. longum were an attractive and safe tumor-targeting vector and transfected B. longum was a potential anticancer agent that could effectively and specifically treat solid tumors.

Increased nuclear localization of transcription factor Y-box binding protein 1 accompanied by up-regulation of P-glycoprotein in breast cancer pretreated with paclitaxel.

PURPOSE: The Y-box binding protein 1 (YB-1) regulates expression of P-glycoprotein encoded by the MDR1 gene. There have been no previous studies regarding the involvement of YB-1 in the development of resistance to paclitaxel. The present study was done to examine how paclitaxel affects the localization and expression of YB-1 in breast cancer. EXPERIMENTAL DESIGN: We evaluated the expression and localization of YB-1 and P-glycoprotein in breast cancer tissues obtained from 27 patients before and after treatment with paclitaxel. The effect of paclitaxel on localization of cellular YB-1 was examined by using GFP-YB-1. Interaction of YB-1 with the Y-box motif of the MDR1 promoters was studied by electrophoretic mobility shift assay. The effects of paclitaxel on MDR1 promoter activity were examined by luciferase assay. RESULTS: Of 27 breast cancer tissues treated with paclitaxel, nine (33%) showed translocation of YB-1 from the cytoplasm to the nucleus together with increased expression of P-glycoprotein during the course of treatment. Twelve breast cancer tissues (44%) showed neither translocation of YB-1 nor increased expression of P-glycoprotein. Nuclear translocation of YB-1 was correlated significantly with increased expression of P-glycoprotein (P=0.0037). Confocal analysis indicated that paclitaxel induced nuclear translocation of green fluorescent fused YB-1 in MCF7 cells. Furthermore, binding of YB-1 to the Y-box of MDR1 promoter was increased in response to treatment with paclitaxel. In addition, MDR1 promoter activity was significantly up-regulated by paclitaxel in MCF7 cells (P<0.001). CONCLUSIONS: The results of the present study suggested that YB-1 may be involved in the development of resistance to paclitaxel in breast cancer.

Can cytological findings predict intraductal spread of breast cancer? Histopathological case-control study.

An important predictive factor for local recurrence after breast-conserving therapy is the state of the surgical margin. In order to obtain a negative surgical margin, the present case-control study was conducted to determine whether the extent of ductal spread can be estimated from the information obtained by fine-needle aspiration (FNA). Samples from 69 cases of extensive ductal spread (EDS) in which it was thought that cancer cells had remained in the residual breast when the lumpectomy was performed with 2 cm margins, were retrieved and compared with 62 cases having almost the same clinical and pathological tumor size. The cases of EDS included a significantly larger number of papillotubular carcinomas (37%vs 13%, P = 0.004) and displayed a high nuclear atypia (42%vs 26%, P = 0.001). We could estimate the same tendency with cytological studies. Cancer cells with cohesive papillary-like clusters suggesting papillotubular carcinoma and with a large nuclear diameter were significantly more numerous in cases of EDS (P < 0.01). In conclusion, EDS can be determined by estimating histological type via cytodiagnosis and measuring the nuclear diameter of cancer cells.

Mutation of the class I beta-tubulin gene does not predict response to paclitaxel for breast cancer.

Mutation of the class I beta-tubulin gene has been reported to be one of the mechanisms that cause resistance to paclitaxel. To assess the relationship between paclitaxel-resistance and class I beta-tubulin gene mutation in breast cancer, Japanese patients with breast cancer were screened for the class I beta-tubulin gene mutation. Total RNA was isolated from 82 breast cancer specimens and the corresponding normal tissues. Twenty-four of the 82 patients were treated with paclitaxel preoperatively and 12 of them did not respond to the treatment. Of the 82 breast cancer patients, 15 (18.3%) had silent polymorphism in exon 4, Leu217Leu (CTG/CTA). However, no mutations showing amino acid substitution of the beta-tubulin gene were detected in any of the patients, including 12 patients who did not respond to paclitaxel. Class I beta-tubulin gene mutation with amino acid substitution was not detected in 82 breast cancer specimens. Our results suggest that mutation of the class I beta-tubulin gene is unlikely to play an important role in the mechanism of resistance to paclitaxel in breast cancer.

Stromal sarcoma of the breast with leiomyosarcomatous pattern.

We report an unusual case of stromal sarcoma of the breast with leiomyosarcomatous pattern, which recurred locally and was finally treated by radical mastectomy. The tumor was composed of pleomorphic and hyperchromatic spindle-shaped cells arranged in an interdigitating fascicle. The nuclei were of moderate to severe atypia. An average of 10 mitoses per 10 high-power fields was seen. Immunohistochemically, the stromal cells were positive for vimentin and alpha-smooth muscle actin, but negative for S-100 protein, cytokeratin and desmin. The average Ki-67 (MIB1) labeling index in the stromal cells was 34%. Electron microscopic evaluation revealed further evidence of smooth muscle differentiation; stromal cells had frequently indented nuclei, well-developed rough endoplasmic reticulum, thin basal lamina and dense patch-like structures within the cytoplasm. Analysis of previous literature on 17 cases reveals mitotic activity of the tumor seemingly of little prognostic value. This case indicated difficulty in diagnosing leiomyosarcoma. The risk of local recurrence remains even if the surgical margin is free of tumor cells.