Multidisciplinary Treatment for Locally Advanced Mucinous Breast Cancer.

Background: Due to its indolent biology and high estrogen receptor positivity of mucinous breast cancer, vast majority of locally advanced mucinous breast cancer (LABC) are treated with first-line endocrine therapy. Case Presentation: A 50-year-old woman was referred to our hospital for the treatment of her huge breast tumor. Computed tomography showed an oval solid tumor, 17 cm in size, and lymph node swelling in both the axilla and parasternum. Pathological study of the core needle biopsy specimen showed the tumor to be luminal mucinous carcinoma. After the failure of endocrine therapy aiming for tumor regression, the patient received sequential chemotherapy to get favorable local control, leading to marked tumor shrinkage. Axillar and parasternal lymph nodes, however, remained unchanged in size. The patient further underwent mastectomy and regional lymph node dissection including removal of the still enlarged parasternal lymph nodes followed by covering of the large skin defect with the latissimus dorsi musculocutaneous (LDMC) flap using a spindle skin island, 15 × 8 cm in size. Postoperative pathological study showed sparse cancer cell remnants with abundant mucus in both the primary tumor and the dissected lymph nodes. The patient has been well without any recurrences on endocrine therapy for 21 months. Conclusion: Breast oncologists should note that multidisciplinary treatment including preoperative chemotherapy and skin defect covering using LDMC flap can give favorable local control even to breast cancer patients with LABC.

A case of bilateral methotrexate-associated diffuse large B-cell lymphomas of the breasts with unique clinical presentation and outcome.

A 54-year-old woman on methotrexate (MTX) treatment developed reddish skin change in her right breast. Mammography and ultrasound showed no masses in the breasts but bilateral mammary glands presented diffuse lower-level echoes. Only 19 days later, the patient developed bilateral breast masses. Histological examination showed that diffuse large B-cell lymphoma cells spread widely and sparsely in the bilateral breasts in addition to the tumor cell conglomerate, leading to the diagnosis of MTX-associated lympho-proliferative disorders (MTX-LPDs). Withdrawal of MTX resulted in complete disappearance of the left MTX-LPD in 2 months but no regression of the right MTX-LPD. Chemotherapy led to a partial response followed by re-growth of the right MTX-LPD. Re-biopsy of the right MTX-LPD revealed double/triple hit lymphoma. Second-line and later-line chemotherapies caused no regression of the right MTX-LPD. The patient died in a year after the diagnosis of MTX-LPDs. Breast oncologists should note the presence, biology, and diagnostic images of MTX-LPD.

Risk factors for breast cancer-related lymphedema: correlation with docetaxel administration.

BACKGROUND: Upper-limb lymphedema is a well-known complication of breast cancer and its treatment. This retrospective cohort study aims to determine what risk factors affect breast cancer-related lymphedema in patients with breast cancer. METHODS: This retrospective study comprised patients diagnosed with breast cancer and who underwent surgery at Wakayama Medical University Hospital between January 1, 2012 and December 31, 2018. Assessed factors using univariate and multivariate analyses were patient-related factors (age, gender, and BMI), breast cancer-related factors (tumor size, nodal status, histology, tumor location, and intrinsic subtype), and treatment-related factors (type of surgery, application, timing and regimen of chemotherapy, and application of radiotherapy). RESULTS: This study included 1041 patients. BMI did not affect the onset of breast cancer-related lymphedema. There were only six sentinel lymph node biopsy cases in the breast cancer-related lymphedema group (6.6%). In cases of axillary lymph node dissection, adjuvant chemotherapy was marginally associated with increased risk of breast cancer-related lymphedema compared to no chemotherapy (HR 2.566; 95% CI 0.955-6.892; p = 0.0616). Among anti-cancer agents, docetaxel (HR 3.790; 95% CI 1.413-10.167; p = 0.0081) and anti-HER2 therapy (HR 2.507; 95% CI 1.083-5.803; p = 0.0318) were associated with increased risk of lymphedema according to multivariate analysis. Neo-adjuvant chemotherapy did not affect the onset of breast cancer-related lymphedema. Radiotherapy (HR 2.525; 95% CI 1.364-4.676; p = 0.0032) was an important risk factor for breast cancer-related lymphedema. CONCLUSIONS: Axillary lymph node dissection, radiotherapy and adjuvant chemotherapy, especially docetaxel, were risk factors for breast cancer-related lymphedema, but BMI and neo-adjuvant chemotherapy were not.

A Case of Diffuse Large B Cell Lymphoma of the Breast with Predominantly High-Level Internal Echoes.

A 70-year-old woman had a large mass in her right breast. Mammography displayed focal asymmetrical density in the scattered areas of fibroglandular density. Ultrasonography showed the tumor to have predominantly high-level internal echoes. Histological examination showed that the tumor was composed of CD20-positive atypical cells with a large nucleus, scant cytoplasm, and abundant mitoses accompanied by a lot of fat cell interspersion and the diagnosis of diffuse large B cell lymphoma was made. We considered that the massive back scattering generated by the heterogeneity of acoustic impedance between fat cells and tumor cells brought about the high-level internal echoes. The patient had undergone chemotherapy followed by radiotherapy to the breast and regional nodes and has been well without lymphoma recurrence for more than 6 years. Although breast malignant lymphoma generally shows very low-level internal echoes, it could have high-level internal echoes especially in case of a non-dense breast.

[Application of Bevacizumab beyond Progressive Disease in Patients with Lung Cancer Recurrence after Surgery].

BACKGROUND: The benefits of continuing bevacizumab (BEV) beyond progressive disease (PD) in patients with non-small cell lung cancer (NSCLC) remain unclear. We present our experience of continuing chemotherapy with BEV in patients with recurrent NSCLC after surgery. PATIENTS: From January 2010 to December 2016, chemotherapy with BEV was continued beyond PD in 20 patients. These patients included 10 men and 10 women, and their mean age at surgery was 71±10 years. Recurrence was observed at 630±460 days after surgery. RESULTS: The average number of protocols with BEV was 3±1 (1-6). The presented side effects were acceptable. Eight patients died of cancer. The 5-year survival rates after surgery, recurrence, and initiation of BEV were 78.8%, 50.1%, and 34.3%, respectively, and the median survival times were 2,465, 2,017, and 1,120 days, respectively. CONCLUSION: The majority of patients with operable NSCLC had a good performance status. We could detect recurrence early on, before the symptoms appeared, by regular examination. Therefore, these patients had an advantage in that more chemotherapeutic regimens could be administered to them and their prognosis could be improved by the continuation of BEV beyond over PD.

A Theoretical Model for the Hormetic Dose-response Curve for Anticancer Agents.

In the present article, we quantitatively evaluated the dose-response relationship of hormetic reactions of anticancer agents in vitro. Serial dilutions of gemcitabine, cisplatin, 5-fluorouracil, vinorelbine, and paclitaxel were administered to the A549 non-small-cell lung cancer cell line. The bi-phasic sigmoidal curve with hormetic and cytotoxic effects is given by the formula y=(a-b/(1+exp(c(*)log(x)-d)))/(1+exp(e(*)log(x)-f)), that was used to perform a non-linear least square regression. The dose-responses of the five anticancer agents were fitted to this equation. Gemcitabine and 5-fluorouracil, which had the lowest ED50 for their hormetic reaction, had the most pronounced promotive effects out of the five anticancer agents tested. The hormetic reaction progressed exponentially with culturing time. Our theoretical model will be useful in predicting how hormetic reactions affect patients with malignant tumors.

Class III Beta-tubulin Expression in Non-small Cell Lung Cancer: A Predictive Factor for Paclitaxel Response.

AIM: In order to clarify whether class III beta-tubulin (TUBB3) is a predictive marker for paclitaxel (PTX) chemotherapy, chemosensitivity was examined using an in vitro drug sensitivity assay. PATIENTS AND METHODS: Twelve specimens from non-small cell lung cancer (NSCLC) patients were obtained for dose-response curve analysis and measurement of the half-maximal effective dose (ED50) of PTX using the histoculture drug response assay (HDRA). Forty-one specimens were evaluated using the HDRA and the inhibition ratio (IR) at a concentration of 25 µg/ml PTX (IR25) was measured. TUBB3 expression was evaluated by H-score in immunohistochemical staining. RESULTS: The ED50 of PTX was 24.5 ± 8.06 µg/ml. The median H-score was significantly higher (p=0.0076) in the high effective dose (HE)-group (ED50 >25 µg/ml) than in the low effective (LE)-group (ED50 ≤ 25 µg/ml). The mean IR25 was 53.8 ± 26.6%. The median H-score for the high-inhibition ratio (HI)-group (IR25 >50%) was significantly higher (p=0.0337) than the low-inhibition ratio (LI)-group (IR25 ≤ 50%). CONCLUSION: High TUBB3 expression in NSCLC appeared to correlate with lower PTX sensitivity.

[The importance of p53 and ras mutation as predictive markers for adjuvant chemotherapy in non-small-cell lung cancer].

OBJECTIVE: A previous large, randomized, control trial(JBR.10)revealed that adjuvant chemotherapy with cisplatin(CDDP) and vinorelbine(VNR)was effective for non-small-cell lung cancer(NSCLC). It was also reported that adjuvant chemotherapy was not effective for p53-negative or K-ras mutation-positive patients. To clarify whether p53 and ras statuses are true predictive markers for chemotherapy with cisplatin, chemosensitivity was examined using an in vitro drug sensitivity assay. MATERIALS AND METHODS: Surgically resected fresh tumor specimens obtained from 27 patients at our institute with NSCLC were used for this study. Histoculture Drug Response Assay(HDRA)was applied to evaluate the chemosensitivity of CDDP and VNR in these specimens. p53 expression was evaluated by immunohistochemistry, and K-ras mutation by direct sequencing. RESULT: Four of the 27 patients were positive for K-ras mutation. The inhibition rate of CDDP was 54±5% for K-ras mutation positive-patients, and 50±13% for negative-patients. There was no significant difference between these two groups. p53 overexpression was observed in 14 patients, but not in 13 patients. The inhibition rate of CDDP was 50±12% for p53- overexpressed patients, and 50±12% for patients not overexpressed. The inhibition rate of VNR was 36±17% for p53- overexpressed patients, and 33±14%for patients not overexpressed. As for 8 adenocarcinoma patients, the inhibition rate of CDDP of p53-overexpressed patients(59±8%)was significantly(p=0. 018)higher than that of patients not overexpressed (45±9%). p53 overexpression may be a predictive marker for chemotherapy using CDDP in lung adenocarcinoma. CONCLUSION: p53 overexpression may be a possible predictive marker for adjuvant chemotherapy using CDDP in NSCLC.

Epidermal growth factor receptor mutations are associated with docetaxel sensitivity in lung cancer.

INTRODUCTION: A recent large randomized controlled trial revealed that patients with lung cancer with epidermal growth factor receptor (EGFR) mutations had better prognoses when treated with the EGFR-tyrosine kinase inhibitor, gefitinib, than with cytotoxic chemotherapeutic agents. Lung cancer with EGFR mutations is highly sensitive to EGFR-tyrosine kinase inhibitors. The previous trial implied that EGFR mutations might be predictive of the response to cytotoxic chemotherapy. METHODS: Forty-six tumor tissue specimens (32 adenocarcinomas and 14 nonadenocarcinomas) were obtained from patients with lung cancer who underwent surgical resection. EGFR mutations were detected using polymerase chain reaction-invader assay. A histoculture drug response assay was used as an in vitro drug sensitivity test. The inhibition rates of cisplatin, docetaxel (DOC), vinorelbine, and gemcitabine were measured. RESULTS: Sensitizing EGFR mutations were detected in samples from 14 patients, all with adenocarcinomas. The inhibition rate of cisplatin in tumors with EGFR mutations (group M) was 34.8 ± 15.5%, which was significantly lower (p = 0.0153) than in wild-type tumors (group W; 46.6 ± 14.0%). The inhibition rate of DOC in group M (18.8 ± 13.4%) was also significantly lower (p = 0.0051) than in group W (35.4 ± 19.1%). There were no significant differences in inhibition rates of gemcitabine and vinorelbine between groups M and W. Inhibition rates of DOC were significantly lower in group M (p = 0.0256) than in group W (32.6 ± 18.4) in samples from patients with adenocarcinoma. CONCLUSION: The histoculture drug response assay indicated that lung cancers with EGFR mutations were less sensitive to DOC than EGFR wild-type tumors.

Is class III beta-tubulin a true predictive marker of sensitivity to vinorelbine in non-small cell lung cancer? Chemosensitivity data evidence.

AIM: To clarify whether class III ß-tubulin (TUBB3) is a true predictive marker for chemotherapy with vinorelbine, chemosensitivity was examined using an in vitro drug sensitivity assay. PATIENTS AND METHODS: Initially, 9 specimens were obtained to analyze the dose-response curve and to measure the median effective dose 50 (ED(50)) in the histoculture drug response assay (HDRA). Subsequently, 68 surgically resected non-small cell lung cancer (NSCLC) specimens were applied to the HDRA and H-scores were calculated by immunohistochemical staining. RESULTS: The mean (±SD) slope factor, ED(50) and maximal response was 8.7±5.4, 39.0±17.9 µg/ml and 85.5±5.1% respectively. The mean inhibition rate was 26.4±16.2% and the mean H-score was 1.09±1.07. The inhibition rate was significantly correlated with TUBB3 expression (r=0.27, p=0.03), and was significantly higher in TUBB3-positive specimens than in TUBB3-negative specimens (p=0.003). CONCLUSION: Tumors with high TUBB3 levels exhibited greater chemosensitivity to vinorelbine than tumors with low TUBB3 levels. This finding provides support for the results of the JBR.10 trial.