Evidence-Based Practice Guideline for the Management of Lymphedema Proposed by the Japanese Lymphedema Society.

Background: Secondary lymphedema mostly occurs as an aftereffect of cancer treatment, and it is estimated that 100,000-150,000 patients are affected in Japan. An estimated 3500 patients, develop lymphedema of the lower and upper extremities each year secondary to uterine and breast cancer treatment. Medical reimbursement was first instituted in April 2008 by the Ministry of Health, Labour and Welfare in Japan. Since 2008, we have developed guidelines regarding treatment options for patients with lymphedema based on scientific evidence. This is the third edition of the guidelines established by the Japanese Lymphedema Society (JLES), published in 2018. The JLES Practice Guideline-Making Committee (PGMC) developed 21 clinical questions (CQs). Methods and Results: A review of these 15 CQs was performed in accordance with the methodology for establishing clinical guidelines. The 15 recommendations for each of these CQs were developed and discussed until consensus by the PGMC was reached. Moreover, outside members who had no involvement in these guidelines evaluated the contents using the Appraisal of Guidelines for Research and Evaluation (AGREE) II reporting checklist. Conclusion: These guidelines have been produced for the adequate management of lymphedema by doctors and other medical staff on the lymphedema management team of medical institutes, including nurses, physical technicians, and occupational therapists.

Japanese translation and linguistic validation of the US National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).

BACKGROUND: The US National Cancer Institute (NCI) has developed the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) to capture patients' self-reported symptomatic adverse events in cancer clinical trials. The aim of this study was to develop and linguistically validate a Japanese translation of PRO-CTCAE. Forward- and back-translations were produced, and an independent review was performed by the Japan Clinical Oncology Group (JCOG) Executive Committee and the US NCI. We then conducted cognitive interviews with 21 patients undergoing cancer treatment. Participants were asked to complete the PRO-CTCAE and were interviewed using semi-structured scripts and predetermined probes to investigate whether any items were difficult to understand or answer. The interviews were recorded and transcribed, and a thematic analysis was performed. The data were split into two categories: 1) remarks on the items and 2) remarks on the questionnaire in general. RESULTS: Twenty-one cancer patients undergoing chemotherapy or hormone therapy were interviewed at the University of Tokyo Hospital and the Kansai Medical University Hirakata Hospital during 2011 and 2012. Thirty-three PRO-CTCAE items were evaluated as "difficult to understand," and 65 items were evaluated as "difficult to answer" by at least one respondent. However, on further investigation, only 24 remarks were categorized as "comprehension difficulties" or "clarity" issues. Most of these remarks concerned patients' difficulties with rating their experience of individual symptomatic events. CONCLUSIONS: The study provides preliminary evidence supporting the linguistic validity of the Japanese version of PRO-CTCAE. Further cognitive interviewing is warranted for PRO-CTCAE items relating to sexuality and anxiety and for response options on severity attribute items.

Efficacy and safety of an amino acid jelly containing coenzyme Q10 and L-carnitine in controlling fatigue in breast cancer patients receiving chemotherapy: a multi-institutional, randomized, exploratory trial (JORTC-CAM01).

PURPOSE: Cancer-related fatigue (CRF) is one of the most common symptoms reported by cancer patients. This randomized trial investigated the efficacy of the amino acid jelly Inner Power(®) (IP), a semi-solid, orally administrable dietary supplement containing coenzyme Q10 and L-carnitine, in controlling CRF in breast cancer patients in Japan. METHODS: Breast cancer patients with CRF undergoing chemotherapy were randomly assigned to receive IP once daily or regular care for 21 days. The primary endpoint was the change in the worst level of fatigue during the past 24 h (Brief Fatigue Inventory [BFI] item 3 score) from day 1 (baseline) to day 22. Secondary endpoints were change in global fatigue score (GFS; the average of all BFI items), anxiety and depression assessed by the Hospital Anxiety and Depression Scale (HADS), quality of life assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC Breast Cancer-Specific QLQ (EORTC QLQ-BR23), and adverse events. RESULTS: Fifty-nine patients were enrolled in the study, of whom 57 were included in the efficacy analysis. Median patient age was 50 years. Changes in the worst level of fatigue, GFS, and current feeling of fatigue were significantly different between the intervention and control groups, whereas the change in the average feeling of fatigue was not significantly different between groups. HADS, EORTC QLQ-C30, and EORTC QLQ-BR23 scores were not significantly different between the two groups. No severe adverse events were observed. CONCLUSION: IP may control moderate-severe CRF in breast cancer patients. TRIAL REGISTRATION: The registration number of this study in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) is UMIN000008646.

Bevacizumab in the treatment of five patients with breast cancer and brain metastases: Japan Breast Cancer Research Network-07 trial.

BACKGROUND: Brain metastases from breast cancer occur in 20%-40% of patients, and the frequency has increased over time. New radiosensitizers and cytotoxic or cytostatic agents, and innovative techniques of drug delivery are still under investigation. METHODS: Five patients with brain metastases who did not respond to whole-brain radiotherapy and then received bevacizumab combined with paclitaxel were identified using our database of records between 2011 and 2012. The clinicopathological data and outcomes for these patients were then reviewed. RESULTS: The median time to disease progression was 86 days. Of five patients, two (40%) achieved a partial response, two had stable disease, and one had progressive disease. In addition, one patient with brain metastases had ptosis and diplopia due to metastases of the right extraocular muscles. However, not only the brain metastases, but also the ptosis and diplopia began to disappear after 1 month of treatment. The most common treatment-related adverse events (all grades) were hypertension (60%), neuropathy (40%), and proteinuria (20%). No grade 3 toxicity was seen. No intracranial hemorrhage was observed. CONCLUSION: We present five patients with breast cancer and brain metastases, with benefits from systemic chemotherapy when combined with bevacizumab.

Efficacy of meloxicam in combination with preoperative chemotherapy for breast cancer - Japan Breast Cancer Research Network (JBCRN) 02-1 trial.

BACKGROUND: We reported that doxorubicin and cyclophosphamide (DC) followed by weekly paclitaxel is an active and manageable preoperative regimen for breast cancer patients. However, as one of the side effects of paclitaxel, neuropathy was noted in up to 30% of patients. Cyclooxygenase-2 (COX-2) and its derived prostaglandins play a role in stimulating angiogenesis, inhibiting apoptosis, and suppressing the immune response. Some recent studies showed that COX-2 inhibitors, such as meloxicam, have the potential to enhance tumor suppression and reduce the severity of paclitaxel-induced neuropathy. PATIENTS AND METHODS: Four cycles of DC (doxorubicin: 60 mg/m(2) and cyclophosphamide: 600 mg/m(2)) administered intravenously (i.v.) on day 1 every 21 days were followed by 12 cycles of paclitaxel i.v. (80 mg/m(2)) every 7 days, prior to surgery. During paclitaxel therapy, breast cancer patients were administered meloxicam (10 mg per day) daily, when experiencing symptoms of grade 2 neuropathy (motor or sensory). The primary endpoint was the pCR rate achieved with the treatment. RESULTS: Forty-three patients received preoperative chemotherapy between April 2004 and March 2007 at six centers. The patient population was identified from a database of the Japan Breast Cancer Research Network. Clinical responses were rated as clinically complete response (cCR) in 9 patients (22%), clinically partial response (cPR) in 25 patients (59%), and clinically stable disease (cSD) in 9 patients (19%). pCR was seen in 25.6%. In addition, we identified 15 patients, who developed grade 2 neuropathy during paclitaxel therapy and subsequently received meloxicam. Meloxicam application had a marked effect within 28 days of initiation. The sensory neuropathy of the patients was reduced gradually, but their motor neuropathy did not improve. Five out of the 15 patients with neuropathy experienced symptom improvement after meloxicam treatment (p<0.05; before versus after 2 months of meloxicam administration). Furthermore, among the 15 patients, who received meloxicam, clinical responses were rated as cCR in 2 patients, cPR in 4 patients, and cSD in 9 patients. The pCR was seen in 4 patients (26.7%). CONCLUSION: Although meloxicam in combination with DC and weekly paclitaxel chemotherapy did not show promising therapeutic activity, it may provide some relief for neuropathy.

Anti-apoptotic effect of claudin-1 in tamoxifen-treated human breast cancer MCF-7 cells.

BACKGROUND: Claudin-1 is a membrane protein of tight junctions, and is associated with the development of various cancers. However, the significance of claudin-1 expression in cancer cells is not well understood. Here, we showed for the first time the anti-apoptotic effect of claudin-1 in human breast cancer MCF-7 cells. METHODS: Human breast cancer MCF-7 and T47 D cells were treated with or without tamoxifen, siRNA against claudin-1, or tamoxifen and claudin-1 siRNA. The samples were analyzed by RT-PCR, Western blotting or immunofluorescent staining. RESULTS: The expression of claudin-1 was upregulated in tamoxifen-treated MCF-7 cells, whereas the expression of claudin-1 was not altered in tamoxifen-treated T47 D cells. Knockdown of claudin-1 by siRNA increased the amount of poly (ADP-ribose) polymerase (PARP) regardless of tamoxifen treatment in MCF-7 cells, but not T47 D cells. In the cell membranes of the MCF-7 cells, tamoxifen treatment increased the amount of claudin-1, but decreased the amount of ß-catenin. Claudin-1 siRNA increased the amount of E-cadherin in the cytoplasm of the MCF-7 cells as well as the amount of ß-catenin in their cell membranes. CONCLUSION: These results indicate that claudin-1 has anti-apoptotic effects, and is involved in the regulation of the expression and subcellular localization of ß-catenin and E-cadherin in MCF-7, but not T47 D cells.

[A case of recurrent breast cancer with liver metastasis responding to exemestane].

We report a woman in her 30s who developed a right breast tumor 10 years after undergoing mastectomy for invasive ductal carcinoma of the left breast. She underwent modified radical mastectomy for the right breast cancer, which was diagnosed histologically as invasive ductal carcinoma with metastasis to the axillary lymph nodes. Because of the risk of recurrence, she received postoperative systemic adjunctive chemotherapy using CMF, but this had to be withdrawn because of liver toxicity. The patient therefore received hormonal therapy with goserelin and tamoxifen for 24 months. During this period, however, she became menopausal, necessitating withdrawal of the goserelin. After a disease-free interval of 34 months, liver metastasis appeared, and so tamoxifen was changed to exemestane. After 3 months, the metastasis showed a marked response, and this has been subsequently maintained for 48 months. Because the patient's menstrual cycle then returned, goserelin was restarted after consultation with a gynecologist. This case illustrates that exemestane and goserelin combination therapy is effective for recurrent breast cancer.

A phase II study of trastuzumab and capecitabine for patients with HER2-overexpressing metastatic breast cancer: Japan Breast Cancer Research Network (JBCRN) 00 Trial.

PURPOSE: To determine the response rate and toxicity profile of trastuzumab and capecitabine in women with HER2-overexpressing advanced breast cancer. PATIENTS AND METHODS: A total of 59 patients from 6 participating centers in Japan entered onto the study of trastuzumab and capecitabine. Eighty six percent of women had received prior chemotherapy as part of adjuvant (21.4%) or metastatic treatment (48.2%), or both (16.1%), including substantial portions of patients who had previously received either CMF (7.1%), anthracyclines (28.6%), taxanes (25.0%), or both types (25.0%) of chemotherapy. RESULTS: Responses were observed in 28 of 56 patients (overall response rate, 50%). The response rate was 65.0% in patients treated with trastuzumab and capecitabine as first-line therapy for metastatic disease, and 62.5% among HER2 +3 positive patients, while high response rates were also seen in women treated with second- or third-line therapy. Patients receiving trastuzumab and capecitabine as first-line therapy had a longer TTP than did patients receiving this treatment as second- or third-line therapy (median TTP, 280 vs. 130 days, P < 0.05). Further, patients receiving trastuzumab and capecitabine as first-line therapy had longer OS than did patients receiving this treatment as second- or third-line therapy (median OS, 780 days vs. 480 weeks, P < 0.05). The treatment-related adverse events were hand-foot syndrome (30.4%), nausea (25%), diarrhea (10.7%), stomatitis (10.7%), fatigue (7.1%), and vomiting (5.4%). However, the majority were Grade 1-2 adverse events and only six patients experienced Grade 3 adverse events. Further Grade 1 cardiac toxicity was observed in one patient, while there were no cases of alopecia and treatment-related death. CONCLUSION: Trastuzumab in combination with capecitabine is highly active in women with HER2-overexpressing metastatic breast cancer and is well tolerated.

Complete remission of recurrent breast cancer with multiple liver metastases after oral capecitabine and injected trastuzumab.

A 32-year-old woman underwent modified radical mastectomy for right breast cancer (invasive ductal carcinoma, f, INF beta, v0, ly1, pT2, pN1, M0, Stage II B ER (+/-), PR (-), Her2 (3+)) in June 2003, and received postoperative systemic adjunctive chemotherapy using epirubicin combined with cyclophosphamide, followed by paclitaxel. In August 2004, after a disease-free interval of 14 months, liver metastasis appeared, and therefore from September 2004, combination chemotherapy with oral capecitabine (2,400 mg/day) and injected trastuzumab (120 mg/week) was started. After 3 cycles, all the metastases responded and this marked response has been maintained for 16 months. This therapy is currently being continued (19 cycles), and no serious side effects have been encountered. Capesitabine and trastuzumab combination therapy is effective for recurrent breast cancer showing overexpression of HER2 and resistance to taxane, and can be considered as a first-line therapy for this purpose. It is anticipated that many cases treated with this regimen will be reported and discussed in the near future.

Decreased expression of claudin-1 correlates with recurrence status in breast cancer.

Claudins (CLDNs) constitute the major transmembrane proteins of tight junctions. It may be hypothesized that changes in or loss of expression of tight junctional proteins such as CLDNs can lead to cellular disorientation and detachment, which is commonly seen in neoplasia. Recent studies have suggested that claudin-1 (CLDN1) plays an important role in invasion and metastasis and claudin-4 (CLDN4) has a particular role in mammary glandular cell differentiation and carcinogenesis. In this study, we examined 83 breast cancer cases and demonstrated immunohistochemical expression patterns of CLDN1/CLDN4 in recurrent and non-recurrent groups. We found significant results between the recurrent and non-recurrent group for expression of CLDN1/CLDN4. The recurrent group (26 cases) showed decreased expression patterns of CLDN1 (p<0.001), compared to the non-recurrent group (57 cases). Decreased expression of CLDN1 (p<0.0001) correlated with short disease-free interval. The lymph node metastasis-positive group showed decreased expression patterns of CLDN1 (p=0.001). However, there was no significance between the recurrent group and non-recurrent group in CLDN4 expression. There was no significance between histological factors and CLDN4 expression. The results indicated that CLDN1 expression correlated with the recurrence status and malignant potential of breast cancer.

Clinicopathological features of gastric cancer cases and aberrantly expressed recoverin.

Cancer-associated retinopathy (CAR) is an ocular manifestation of a paraneoplastic syndrome whereby immunological reactions toward recoverin, a retina-specific calcium binding protein, and other retinal antigens aberrantly expressed in tumor cells lead to the degeneration of retinal photoreceptor cells. Recently we reported that aberrant expression of recoverin was identified in more than 50% of tumor cells and their cell lines from several kinds of cancers, including gastric cancer, lung carcinoma, and other cancers. To elucidate the clinicopathological significance of aberrantly expressed recoverin in cancer cells, we performed immunocytochemical analysis using a monoclonal antibody against human recoverin. Within 18 patients with different clinical stages (I-IV) of gastric cancer, the aberrant expression of recoverin in tumor cells was recognized in 6 out of 18 patients (2 out of 2 stage IA, 1 out of 1 stage IB, 2 out of 3 stage II, 0 out of 7 stage IIIA, 0 out of 1 stage IIIB, and 1 out 4 stage IV). The present data are consistent in part with the previous observations that recoverin-expressing cancer cells induced tumor immunity and provide a favorable prognosis for primary cancer in CAR patients.

Chemosensitivity of human pancreatic carcinoma cells is enhanced by IkappaBalpha super-repressor.

Pancreatic cancer has an unfavorable prognosis; surgery and chemotherapy at present have only limited value. To improve the prognosis of pancreatic cancer, effective non-surgical therapy is necessary. NF-kappaB is reported to be related to resistance to apoptosis, but its role in chemosensitivity remains controversial. We examined the effects on chemosensitivity of inhibition by induction of the super-repressor IkappaBalpha in pancreatic cancer cell lines, BxPC-3, Capan-1 and Panc-1. IkappaBalpha protein was transduced by infection of adenovirus vector AxCAhIkBDeltaN. Sensitivity to VP-16 and doxorubicin was increased significantly by IkappaBalpha induction in all three pancreatic cell lines. To investigate molecular events during IkappaBalpha induction, we examined the changes in expression of drug-resistance-related genes by real-time RT-PCR and those in apoptosis-related genes by cDNA microarray. There was no common change of gene expression before and after IkappaBalpha induction among the three pancreatic cancer cell lines, except for mdm2. Further examination of other genes is necessary for a better understanding of the molecular mechanisms of enhancement of chemosensitivity through IkappaBalpha induction. However, we have confirmed that IkappaBalpha induction leads to an increase of chemosensitivity of pancreatic cancer. Many problems remain before clinical application of this adenoviral system will be feasible, but our results may ultimately lead to an improved therapy of pancreatic cancer.

Aberrantly expressed recoverin is functionally associated with G-protein-coupled receptor kinases in cancer cell lines.

Cancer-associated retinopathy (CAR) is an ocular manifestation of a paraneoplastic syndrome whereby immunological reactions toward recoverin (Rec), a retina-specific Ca(2+) binding protein, and its aberrant expression in tumor cells lead to the retinal degeneration. To elucidate functional roles of the aberrantly expression in cancer cells, we performed immunoprecipitation using anti-human Rec mAb. We observed co-precipitation of G-protein-coupled receptor kinases (GRKs) and caveolin-1 with Rec from cell lysates of 293 or SSTW cells. Immunocytochemistry revealed that immunoreactivities toward Rec within the cancer cells were almost identical to those toward GRKs and caveolin-1. The present data strongly suggest that aberrantly expressed Rec should be involved in the GRK-dependent cellular regulation in cancer cells.

Upregulation of alpha-synuclein by lipopolysaccharide and interleukin-1 in human macrophages.

Alpha-synuclein was originally identified as the presynaptic nerve terminal protein. Recently, we reported that alpha-synuclein is also expressed in cultured human astrocytes and that its levels are increased by stimulation with interleukin-1beta, suggesting that it may be involved in inflammatory processes. We therefore investigated the effect of inflammatory stimuli on alpha-synuclein expression in human macrophages. Alpha-synuclein mRNA and protein were detected in cultured human macrophages and levels of alpha-synuclein protein were increased by stimulation with lipopolysaccharide and interleukin-1beta in a time- and concentration-dependent manner. Immunofluorescent staining showed that alpha-synuclein protein was expressed within the cytoplasm and nucleus. Furthermore, alpha-synuclein immunoreactivity was present in alveolar macrophages from human lung tissues. These findings suggest that the function of alpha-synuclein is not exclusive to the nervous system and that alpha-synuclein may play a role in inflammatory processes and immune responses.