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.

In vitro evaluation of dose-response curve for paclitaxel in breast cancer.

BACKGROUND: The dose-response curve for anticancer agents cannot be evaluated by studying patients directly. To investigate individual differences in the dose-response curve for paclitaxel in breast cancer, we utilized the histoculture drug response assay (HDRA) technique. MATERIALS AND METHODS: Twenty specimens obtained from breast cancer patients who underwent surgical resection were used in this study. The inhibition rates of paclitaxel at several concentrations were measured and fitted to a sigmoid dose-response curve, using non-linear least squares analysis with the fitting equation y=A(1-1/(1+exp(B(x-log(C))))), where A denotes maximal response; B, slope factor; and C, ED50. RESULTS: A dose-response curve was obtained in all tumors. The mean value (+/-SD) of maximum response, slope factor, and ED50 were 90.2+/-5.5%, 9.4+/-4.3, and 36.8+/-17.2 microg/ml, respectively. The slope factor was higher in nuclear grade 3 tumors compared with nuclear grade 1 and 2 tumors. CONCLUSION: An individual dose-response curve for paclitaxel in breast cancer can be obtained using the HDRA technique. Nuclear grade 3 tumors appeared to have more uniform chemosensitivity to paclitaxel compared with nuclear grade 1 and 2 tumors.

Data acquisition for the histoculture drug response assay in lung cancer.

OBJECTIVE: Application of the histoculture drug response assay for lung cancer was investigated by using data acquired from lung cancer specimens. METHODS: From May 1994 through February 2005, histoculture drug response assay data were obtained from 359 lung cancer specimens held in our institute. We examined chemosensitivities of the tissues to cisplatin, doxorubicin, mitomycin C, 5-fluorouracil, docetaxel, paclitaxel, etoposide, irinotecan, and gemcitabine. Cutoff inhibition rates were determined with each drug for non-small cell lung cancer and were used to calculate predictabilities for chemotherapy responses. RESULTS: The evaluability of the histoculture drug response assay was high at 97.4%. Good predictability, including true-positive and true-negative rates of 73.2% and 100%, respectively, with an accuracy of 83.0%, was observed. CONCLUSION: The histoculture drug response assay appears to be applicable to non-small cell lung cancer for the prediction of responses to chemotherapy.

Limited mediastinal lymph node dissection for non-small cell lung cancer according to intraoperative histologic examinations.

BACKGROUND: Although radioisotopic procedures are commonly used to detect sentinel lymph nodes in breast cancer surgery, these procedures are often problematic and not necessarily suitable for lung cancer surgery. METHODS: Our previous study revealed that the mediastinal sentinel lymph node, defined as the regional mediastinal lymph node, consisted of nodes 2, 3, or 4 in right upper lobe cancers; 3, 7, or 8 in right lower lobe cancers; 4, 5, or 7 in left upper lobe cancers; and 4, 7, or 8 in left lower lobe cancers. On the basis of these findings, we pathologically investigated one representative lymph node at each of the 3 levels dissected during surgical intervention in 69 patients with non-small cell lung cancer from September 1993 through December 2002. Fifty-eight patients with lung cancer underwent lobectomies with limited mediastinal lymph node dissection according to this strategy. RESULTS: Mediastinal lymph node recurrence was observed in only one patient during 41 +/- 25 months (maximum, 98 months) of follow-up. The cancer-specific 5-year survivals were 96.6% in patients with pathologic stage IA disease (n = 31) and 67.4% in patients with stage IB disease (n = 16). CONCLUSION: These results suggested that limited mediastinal lymph node dissection is applicable to patients with non-small cell lung cancer whose regional mediastinal lymph nodes are not metastatic.

[Cut-off level of docetaxel, paclitaxel and gemcitabine in histoculture drug response assay for non-small cell lung cancer].

Cut-off levels of docetaxel (DOC), paclitaxel (PAC), and gemcitabine (GEM) in histoculture drug response assay are determined by data acquisition of non-small cell lung cancer. Inhibition rates were 47.5 +/- 22.2% in DOC (n=181), 66.6 +/- 25.1% in PAC (n=57), and 25.4 +/- 18.4% in GEM (n=63), respectively. Cut-off levels were determined as 50% in DOC, 60% in PAC, and 30% in GEM. The positive rates such as 47.5% in DOC, 68.4% in PAC, and 33.3% in GEM were obtained.

[Dose response curve of paclitaxel measured by histoculture drug response assay].

Dose response curves of paclitaxel were measured by histoculture drug response assay (HDRA) in 11 lung cancer patients. Inhibition rates of paclitaxel at several concentrations were measured and fitted to the sigmoid dose response curve, using non-linear least square analysis, with fitting equation y=A (1-1/(1+exp (b (x-log (ED50)). Parameters A, b, and ED50 were 88.3+/-6.0 (80.0-100.0) %, 9.57+/-4.32 (2.25-15.0), and 26.8+/-8.1 (15.0-41.0) microg/ml, respectively. The parameter b was lower in well-differentiated tumors compared with moderately and poorly-differentiated tumors. Dose response curves of paclitaxel could be measured by HDRA in lung cancer. This method provides us more information for drug sensitivity than the usual HDRA method. This may lead to the improved accuracy of HDRA.

[Anastrozole-resistant breast cancer responsive to exemestane--a case report].

We describe a postmenopausal woman suffering from advanced breast cancer with pleural effusion. She had prior anastrozole therapy, and was referred to our hospital with dyspnea. The use of exemestane, a highly selective steroidal aromatase inhibitor (25 mg daily), successfully induced remission of pleural effusion. Exemestane is a useful treatment for postmenopausal woman with advanced breast cancer, which is refractory to anastrozole.

A case of serum CEA disappearance curve after resection of breast carcinoma.

Carcinoembryonic antigen (CEA) elimination kinetics after tumor resection were measured in a case of breast cancer. A 45-year-old woman with a left breast carcinoma underwent surgery after neoadjuvant chemotherapy. The serum CEA level before surgery was 34.3 ng/ml. After sequential monitoring of serum CEA levels, postoperative serum CEA elimination kinetics were calculated using non-linear least square analysis with the fitting equation C(t)=(C0-Cp)exp(-kt)+Cp, where C(t) was the postoperative CEA level, t was the number days after surgery, C0 was the CEA level at postoperative time zero, Cp was the CEA at plateau, and k was the rate constant of elimination. Cp was calculated as 6.9 ng/ml, which was above the cut-off level and indicated residual malignancy. After adjuvant chemotherapy, CEA normalized to 1.8 ng/ml. In breast cancer patients with high preoperative serum CEA levels, our analytical method for CEA elimination might be useful for the detection of residual malignancies.

[Histoculture drug response assay for solitary fibrous tumor--a case report].

A 49-year-old male was referred to our hospital because of an abnormal shadow in his left lower lung field on chest X-ray. Magnetic resonance imaging scans revealed a large mass on the left diaphragm. The tumor was surgically extirpated. The tumor, encapsulated and growing from the center of the left diaphragm, measured 18 x 8 x 4 cm and weighed 440 g. Microscopic examination revealed a solitary fibrous tumor with mitotic activity of 7/ 50 hpf. Immunohistochemically, the tumor was negative for cytokeratin, s-100 protein, desmin, and alpha-smooth muscle actin, while positive for vimentin and CD34. On a histoculture drug response assay using the resected tissue, the tumor was sensitive to 5-FU, adriamycin, mitomycin C and docetaxel, and resistant to cisplatin, irinotecan, and gemcitabine.

[Histoculture drug response assay guided concurrent chemoradiotherapy for lung metastasis from adrenocortical carcinoma--a case report].

A 50-year-old woman underwent surgical resection of a left adrenocortical carcinoma in April 2000. Bilateral pulmonary metastases and abdominal lymph node metastasis were detected in June 2001. After radiation therapy for the abdominal lymph node metastasis, a pulmonary metastatic lesion was thoracoscopically resected. The specimen was subjected to histoculture drug response assay (HDRA), and results revealed that this tumor was sensitive for cisplatin. We therefore performed concurrent chemoradiotherapy including cisplatin for the residual pulmonary metastatic lesion; a complete response was then obtained. Standard protocols of chemotherapy are often absent for malignant tumors, such as in this case, with low incidences. HDRA seems useful for chemotherapy agent selection in cases of rare malignant tumors.

Increased expression of integrin alpha3beta1 in highly brain metastatic subclone of a human non-small cell lung cancer cell line.

To clarify the roles of integrin and extracellular matrix (ECM) in the process of non-small cell lung cancer (NSCLC) brain metastasis, we established an in vivo model of brain metastasis of human NSCLC cell line EBC-1/original in athymic mice, and established highly brain metastatic subclone EBC-1/brain and highly bone metastatic subclone EBC-1/bone. Integrin expression of these subclones was evaluated by flow cytometry. In vitro cell attachment, migration and proliferation assays with ECMs were performed using these subclones. Expression of integrin alpha3 subunit was higher in EBC-1/brain than in both EBC-1/original and EBC-1/bone. In vitro cell attachment, migration, and proliferation assays revealed that EBC-1/brain had higher affinity and higher reactivity to laminin than EBC-1/original and EBC-1/bone. Blocking of integrin alpha3beta1 significantly (P < 0.05) decreased brain metastasis by EBC-1/brain. Interaction of integrin alpha3beta1 and laminin plays important roles in the process of brain metastasis of non-small cell lung cancer.

[Successful management of malignant pericardial effusion with weekly paclitaxel therapy in a lung adenocarcinoma patient].

A 67-year-old woman had undergone lobectomy and mediastinal lymphadenectomy on December 17, 1999, for lung adenocarcinoma. On June 29, 2001, the patient was readmitted because of acute deterioration of diabetic chronic renal failure due to cardiac dysfunction. Serum CEA level was high at 724 ng/ml. Chest X-ray and ultrasound suggested the presence of pericardial effusion, which was managed with pericardial drainage. Cytological examination revealed malignant cells (class V) in the effusion. Therefore, the patient was suffering from carcinomatous pericarditis. After the introduction of hemodialysis, the patient was treated with weekly paclitaxel therapy. Each cycle consisted of 3 weeks of therapy followed by a 1-week treatment break. Weekly paclitaxel therapy (11 infusions) brought about a normalization of the elevated CEA levels and a good control of the pericardial effusion. The patient has developed neither tumor progression nor reelevation of serum CEA levels for 12 month with no further therapy.

Time course of carcinoembryonic antigen after resection of lung cancer: a predictor of recurrence.

UNLABELLED: We investigated whether the early postoperative time course of carcinoembryonic antigen (CEA) level after resection of lung cancer could be used to predict patients' prognosis. Fifty-three lung cancer patients were included in this study. Postoperative serum CEA levels were calculated by means of non-linear least-squares fitting to the equation C(t) = (C(0)-C(p))exp(-kt) + C(p), where C(t) is postoperative CEA level, t is days after surgery, C(0) is CEA level at postoperative time 0, C(p) is CEA level at plateau, and k is the rate constant of elimination. Postoperative CEA production (P(p)) was calculated as C(p) multiplied by k. C(p) and P(p) represent the numbers of residual tumor cells after surgery. More residual tumor cells yield higher values of C(p) and P(p), and result in earlier recurrence. RESULTS: Kinetic parameters could be obtained for 30 patients whose preoperative CEA levels were sufficiently elevated. Cutoff levels as predictors for recurrence were 1.1 ng/ml for C(p) and 0.9 ng/ml/day for P(p). The accuracy of prediction of recurrence using these cutoff levels was 79% with C(p) and 89% with P(p). A very poor prognosis was observed for patients with P(p) over 0.9 ng/ml/day. CONCLUSION: Analysis of the time course of changes in CEA levels after resection of lung cancer appears to be useful for predicting patient prognosis. C(p) and P(p) are very precise predictors of recurrence.

[Histoculture drug response assay (HDRA) guided induction concurrent chemoradiotherapy for mediastinal node-positive non-small cell lung cancer].

To improve the response to chemotherapy for non-small cell lung cancer (NSCLC), effective drugs should be selected for each patient. In 1994 we introduced histoculture drug response assay (HDRA) for NSCLC patients. For clinical N2 patients, biopsy of mediastinal lymph node is performed both for histological diagnosis and for HDRA. Induction concurrent chemoradiotherapy is then performed using HDRA positive chemotherapy agents. We have treated three patients with this strategy. HDRA could be performed using mediastinal lymph node biopsy specimens. Tumor reduction rates of these patients were 80.4%, 85.3%, and 57.1%. Their histological responses were Ef.3, Ef.2, and Ef.1b, respectively. Complete resection was done in all patients. This strategy appeared to be useful in NSCLC patients with mediastinal lymph node metastasis.

Clinical efficacy of bisphosphonate therapy for bone metastasis from breast cancer.

Bisphosphonates inhibit osteoclastic bone resorption and are being used as treatment for bone metastases from breast cancer. Intravenous bisphosphonate therapy can significantly reduce skeletal related events (SREs) when administered concurrently with chemotherapy or endocrine therapy. In addition, intravenous bisphosphonate monotherapy is also able to alleviate cancer induced bone pain, and to improve bone metastases in some patients. Oral bisphosphonates are not routinely used for the treatment of bone metastases due to their low bioavailability. However, minodronate, a bisphosphonate 100-fold more potent than pamidronate, is now in phase II clinical studies in Japan, and may alter the role of oral bisphosphonates in the treatment of bone metastasis from breast cancer. The ASCO guidelines recommend that patients with osteolytic bone metastases be treated not with bisphosphonate monotherapy, but with concurrent bisphosphonate and systemic therapy. In addition, it is also recommended that current standards of care for cancer pain, analgesics and radiotherapy, should not be replaced with bisphosphonate therapy.

A case of granulomatous mastitis mimicking breast carcinoma.

A 58-year-old woman presenting with idiopathic granulomatous mastitis mimicking breast carcinoma is described. The mass was elastic, hard and painless, and located in the upper outer quadrant of the right breast. Fine needle aspiration cytology did not provide any diagnostic information. Mammography, ultrasonography and magnetic resonance imaging (MRI) strongly suggested malignancy. Excisional biopsy was performed for definitive diagnosis, and idiopathic granulomatous mastitis was demonstrated histopathologically. Neither wound complication nor recurrence has been identified in the patient, although corticosteroids were not used post operatively. We reviewed the literature, and found that our present case is rare in older patients, and that mammography, ultrasonography and MRI provide little information for differentiating between granulomatous mastitis and carcinoma.

[Weekly administration of gemcitabine in outpatient clinic for non-small cell lung cancer].

We treated inoperable or recurrent non-small cell lung cancer (NSCLC) patients with weekly outpatient administration of gemcitabine. The aim of this therapy was to improve or to maintain the patients' performance status. From November 1999 to December 2001, 15 NSCLC patients were treated with gemcitabine. The patients were 12 males and 3 females, 14 with adenocarcinoma and 1 with squamous cell carcinoma, aged 57 to 81 years old. A dose of 1,000 mg/m2 of gemcitabine was administered on days 1 and 8 every 3 weeks. Patients were treated for 1 to 17 (median 3) months. Performance status was maintained in 12 of 15 patients during this treatment. Average tumor marker doubling time was 289 days. Median survival time was 8.1 months. Weekly administration of gemcitabine in an outpatient setting is a useful treatment for inoperable or recurrent non-small cell lung cancer.