Outcomes of fulvestrant therapy among japanese women with advanced breast cancer: a retrospective multicenter cohort study (JBCRG-C06; Safari).

PURPOSE: This retrospective study evaluated the effect of clinical background and treatment line on time to treatment failure (TTF) in advanced/metastatic breast cancer (AMBC) patients receiving F500 in Japan (UMIN 000015168). METHODS: Patients who commenced F500 treatment were registered at 16 sites in Japan. Correlations between baseline clinicopathological factors, treatment line, and TTF were investigated by Kaplan-Meier analysis. TTF data were analyzed using univariate analysis and multivariate analysis with a Cox proportional hazards model. RESULTS: Data for 1072 patients were available; 1031 patients (96.2%) were evaluable for efficacy. F500 was administered as first-line treatment in 2.0%, second-line in 22.7%, third-line in 26.7%, and ≥fourth-line in 48.6% patients. Median TTF was 5.4 months. Multivariate analysis found that earlier F500 use (first and second vs. third vs. ≥fourth line; hazard ratio (HR) = 0.80, 95% confidence interval (CI) 0.74-0.86; P < 0.001), longer period from AMBC diagnosis to F500 use (≥3 vs. <3 years; HR 0.60, 95% CI 0.51-0.70; P < 0.001), and no prior palliative chemotherapy administered for unresectable or metastatic breast cancer (no vs. yes; HR 0.69, 95% CI 0.60-0.80; P < 0.001) were associated with significantly longer TTF. Among 691 patients, where information on histologic/nuclear grade was available, a low grade was also associated with a longer TTF, but this finding was not maintained among patients with recurrent breast cancer (N = 558). Among women with recurrent breast cancer, a longer DFI between a patient's initial breast cancer diagnosis and their recurrence was associated with a longer TTF on F500 therapy. CONCLUSIONS: Our study showed that treatment period of F500 was longer when used in earlier-line treatment. For patients on F500, TTF was also longer for patients who had not received prior palliative chemotherapy and for those who had a longer period from their AMBC diagnosis to F500 use.

Changes in tumor expression of HER2 and hormone receptors status after neoadjuvant chemotherapy in 21,755 patients from the Japanese breast cancer registry.

BACKGROUND: We investigate rates of pathologic complete response (pCR) and tumor expression of ER, PgR, HER2 discordance after neoadjuvant chemotherapy using Japanese breast cancer registry data. PATIENTS AND METHODS: Records of more than 300,000 breast cancer cases treated at 800 hospitals from 2004 to 2013 were retrieved from the breast cancer registry. After data cleanup, we included 21,755 patients who received neoadjuvant chemotherapy and had no distant metastases. pCR was defined as no invasive tumor in the breast detected during surgery after neoadjuvant chemotherapy. HER2 overexpression was determined immunohistochemically and/or using fluorescence in situ hybridization. RESULTS: pCR was achieved in 5.7% of luminal tumors (n = 8730), 24.6% of HER2-positive tumors (n = 4403), and 18.9% of triple-negative tumors (n = 3660). Among HER2-positive tumors, pCR was achieved in 31.6% of ER-negative tumors (n = 2252), 17.0% of ER-positive ones (n = 2132), 31.4% of patients who received trastuzumab as neoadjuvant chemotherapy (n = 2437), and 16.2% of patients who did not receive trastuzumab (n = 1966). Of the 2811 patients who were HER2-positive before treatment, 601 (21.4%) had HER2-negative tumors after neoadjuvant chemotherapy, whereas 340 (3.4%) of the 9947 patients with HER2-negative tumors before treatment had HER2-positive tumors afterward. Of the 10,973 patients with ER-positive tumors before treatment, 499 (4.6%) had ER-negative tumors after neoadjuvant chemotherapy, whereas 519 (9.3%) of the 5607 patients who were ER-negative before treatment had ER-positive tumors afterward. CONCLUSION: We confirmed that loss of HER2-positive status can occur after neoadjuvant treatment in patients with primary HER2-positive breast cancer. We also confirmed that in practice, differences in pCR rates between breast cancer subtypes are the same as in clinical trials. Our data strongly support the need for retest ER, PgR, HER2 of surgical sample after neoadjuvant therapy in order to accurately determine appropriate use of targeted therapy.

Randomized trial of preoperative docetaxel with or without capecitabine after 4 cycles of 5-fluorouracil­ epirubicin­cyclophosphamide (FEC) in early-stage breast cancer: exploratory analyses identify Ki67 as a predictive biomarker for response to neoadjuvant chemotherapy.

This randomized, multicenter study compared the efficacy of docetaxel with or without capecitabine following fluorouracil/epirubicin/cyclophosphamide (FEC) therapy in operable breast cancer and investigated the role of Ki67 as a predictive biomarker. Patients were randomized to 4 cycles of docetaxel/capecitabine (docetaxel: 75 mg/m2 on day 1; capecitabine: 1,650 mg/m2 on days 1­14 every 3 weeks) or docetaxel alone (75 mg/m2 on day 1 every 3 weeks) after completion of 4 cycles of FEC (5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 every 3 weeks). The primary endpoint was the pathological complete response (pCR) rate. Predictive factor analysis was conducted using clinicopathological markers, including hormone receptors and Ki67 labeling index (Ki67LI). A total of 477 patients were randomized; the overall response in the docetaxel/capecitabine and docetaxel groups was 88.3 and 87.4 %, respectively. There were no significant differences in the pCR rate (docetaxel/capecitabine: 23 %; docetaxel: 24 %; p = 0.748), disease-free survival, or overall survival. However, patients with mid-range Ki67LI (10­20 %) showed a trend towards improved pCR rate with docetaxel/capecitabine compared to docetaxel alone. Furthermore, multivariate logistic regression analysis showed pre-treatment Ki67LI (odds ratio 1.031; 95 % CI 1.014­1.048; p = 0.0004) to be a significant predictor of pCR in this neoadjuvant treatment setting. Docetaxel/capecitabine (after 4 cycles of FEC) did not generate significant improvement in pCR compared to docetaxel alone. However, exploratory analyses suggested that assessment of pre-treatment Ki67LI may be a useful tool in the identification of responders to preoperative docetaxel/capecitabine in early-stage breast cancer.

A phase II study of eribulin in Japanese patients with heavily pretreated metastatic breast cancer.

BACKGROUND: Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that recently gained Food and Drug Administration approval for late-line metastatic breast cancer (MBC). PATIENTS AND METHODS: In this single-arm, multicentre open-label phase II trial Japanese patients pretreated with an anthracycline and a taxane received 1.4 mg/m(2) eribulin mesylate (2- to 5-min i.v. infusion on days 1 and 8 of a 21-day cycle). The primary efficacy end point was overall response rate (ORR) by independent review. RESULTS: Patients (N = 80) had received a median of three prior chemotherapy regimens (range 1-5). ORR was 21.3% [95% confidence interval (CI) 12.9-31.8; all partial responses (PRs)], stable disease (SD) occurred in 30 patients (37.5%) and the clinical benefit rate (complete response + PR + SD ≥6 months) was 27.5% (95% CI 18.1-38.6). Median duration of response was 3.9 months (95% CI 2.8-4.9), progression-free survival was 3.7 months (95% CI 2.0-4.4) and overall survival was 11.1 months (95% CI 7.9-15.8). The most frequent treatment-related grade 3/4 adverse events were neutropenia (95.1%), leukopenia (74.1%) and febrile neutropenia (13.6%). Grade 3 peripheral neuropathy occurred in 3.7% of patients (no grade 4). CONCLUSIONS: Eribulin exhibited efficacy and tolerability in Japanese patients with heavily pretreated MBC.

Correlation between docetaxel-induced skin toxicity and the use of steroids and H2 blockers: a multi-institution survey.

Steroids and H(2) blockers are commonly used as supportive care for taxane-containing chemotherapy, but they also affect docetaxel's primary metabolizer, cytochrome P(450) 3A4. This retrospective observational study was performed to better understand the effects of these compounds on docetaxel-induced skin toxicities, specifically hand-foot syndrome (HFS) and facial erythema (FE), a relationship that is currently poorly understood. Member institutions of the Japan Breast Cancer Research Group were invited to complete a questionnaire on the occurrence of grade 2 or higher HFS and FE among patients treated between April 2007 and March 2008 with docetaxel as an adjuvant or neoadjuvant chemotherapeutic treatment for breast cancer. We obtained data for 993 patients from 20 institutions. Twenty percent received H(2) blockers, and all patients received dexamethasone. Univariate and multivariate analyses revealed that H(2) blockers are associated with a significantly higher incidence of both HFS and FE. The incidence of FE was significantly higher for the docetaxel + cyclophosphamide (TC) regimen than for non-TC regimens combined. Dexamethasone usage did not affect the incidence of either HFS or FE. In conclusion, use of H(2) blockers as premedication in breast cancer patients receiving docetaxel significantly increases the risk of both HFS and FE.

FcγR2A and 3A polymorphisms predict clinical outcome of trastuzumab in both neoadjuvant and metastatic settings in patients with HER2-positive breast cancer.

BACKGROUND: Antibody-dependent-mediated cytotoxicity (ADCC) is one of the modes of action for trastuzumab. Recent data have suggested that fragment C γ receptor (FcγR) polymorphisms have an effect on ADCC. This prospective phase II trial aimed to evaluate whether these polymorphisms are associated with clinical efficacies in patients who received trastuzumab. PATIENTS AND METHODS: Patients in a neoadjuvant (N) setting received Adriamycin and cyclophosphamide followed by weekly paclitaxel/trastuzumab. Patients in a metastatic (M) setting received single trastuzumab until progression. In total, 384 distinct single nucleotide polymorphisms of different FcγR, HER2, and fucosyltransferase loci were assessed. RESULTS: Fifteen operable and 35 metastatic HER2-positive breast cancer patients were enrolled in each of the N and M settings, respectively. The FcγR2A-131 H/H genotype was significantly correlated with the pathologically documented response (pathological response) (P = 0.015) and the objective response (P = 0.043). The FcγR3A-158 V/V genotype was not correlated with the pathological response, but exhibited a tendency to be correlated with the objective response. Patients with the FcγR2A-131 H/H genotype had significantly longer progression-free survival in the M setting (P = 0.034). CONCLUSION: The FcγR2A-131 H/H polymorphism predicted the pathological response to trastuzumab-based neoadjuvant chemotherapy in early-stage breast cancer, and the objective response to trastuzumab in metastatic breast cancer.

Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies.

BACKGROUND: HER2-positive metastatic breast cancer (MBC) relapsing after trastuzumab-based therapy may require continued HER2 receptor inhibition to control the disease and preserve the patients' quality-of-life. Efficacy and safety of lapatinib monotherapy was evaluated in Japanese breast cancer patients after trastuzumab-based therapies. METHODS: In studies, EGF100642 and EGF104911 evaluated the efficacy and safety of oral lapatinib given 1500 mg once daily in patients with advanced or MBC. All patients progressed on anthracyclines and taxanes; HER2-positive patients had also progressed on trastuzumab. RESULTS: For HER2-positive tumours (n=100), objective response rate was 19.0% (95% confidence interval (CI): 11.8-28.1) and clinical benefit rate (CBR) was 25.0% (95% CI: 16.9-34.7). One out of 22 HER2-negative tumour was documented as complete response (n=22). The median time-to-progression (TTP) in the HER2-positive and HER2-negative groups was 13.0 and 8.0 weeks (P=0.007); median overall survival was 58.3 and 40.0 weeks, respectively. The most frequent adverse event was diarrhoea. TTP and CBR were significantly associated with HER2 expression. Patients with tumours harbouring an H1047R PIK3CA mutation or low expression of PTEN derived clinical benefit from lapatinib. CONCLUSION: Lapatinib monotherapy had shown anti-tumour activity in Japanese patients with HER2-positive MBC that relapsed after trastuzumab-based therapy, including those with brain metastases. Patients benefiting from lapatinib may have biomarker profiles differing from that reported for trastuzumab.

A phase II dose-ranging study of palonosetron in Japanese patients receiving moderately emetogenic chemotherapy, including anthracycline and cyclophosphamide-based chemotherapy.

BACKGROUND: The 5-HT(3) receptor antagonists (RAs) help maintain the standard of care, in various combinations with other agents, for prevention of chemotherapy-induced nausea and vomiting (CINV). Palonosetron is a new generation 5-HT(3) RA with indication not only acute but also delayed nausea and vomiting induced by moderately emetogenic chemotherapy (MEC). This study was carried out to determine the optimal dosage of palonosetron in combination with dexamethasone in patients in Japan. PATIENTS AND METHODS: This study evaluated the efficacy and safety of palonosetron in patients receiving MEC combined with dexamethasone. Patients received single doses of 0.075, 0.25, or 0.75 mg of palonosetron before MEC. Dexamethasone was infused before palonosetron, at 20 mg for the patients receiving paclitaxel (Taxol) and 8 mg for the patients not receiving paclitaxel. The primary end point was complete response (CR: no emetic episodes and no rescue medication) in the acute phase (0-24 h). RESULTS: In total, 204 patients (88 men, 116 women; 96 with paclitaxel, 108 without paclitaxel) were assessable for efficacy. No dose-response relationship was observed regarding the CR rate in the acute phase. CR rates increased dose dependently for delayed (24-120 h) and overall (0-120 h) phases in patients receiving anthracyclines and cyclophosphamide combination (AC/EC, n = 80); however, the difference in CR rates among doses was not statistically significant. The most commonly reported adverse events related to palonosetron were constipation and headache, confirming the class safety profile. CONCLUSION: This study indicates a statistically nonsignificant trend for the dose-response relationship for antiemetic protection in the delayed and overall phases in AC/EC patients (the regimen currently considered to be more emetogenic than MEC).

Phase III trial of doxorubicin plus cyclophosphamide (AC), docetaxel, and alternating AC and docetaxel as front-line chemotherapy for metastatic breast cancer: Japan Clinical Oncology Group trial (JCOG9802).

BACKGROUND: This randomized, multicenter, phase III trial compared doxorubicin plus cyclophosphamide (AC), single-agent docetaxel (D), and an alternating regimen of AC and docetaxel (AC-D) as first-line chemotherapy in metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients with MBC resistant to endocrine therapy were entered in a randomized study to receive either six cycles of AC (doxorubicin 40 mg/m2 plus cyclophosphamide 500 mg/m2), D (60 mg/m2), or alternating treatment with AC-D (i.e. three cycles of AC and three cycles of D). Treatment was administered every 3 weeks. RESULTS: A total of 441 patients were entered in a randomized study. Response rates were 30% for AC, 41% for D, and 35% for AC-D. The median times to treatment failure (TTFs) were 6.4, 6.4, and 6.7 months (one-sided log-rank test, P = 0.13 for AC versus D, P = 0.14 for AC versus AC-D) and median overall survival (OS) was 22.6, 25.7, and 25.0 months (P = 0.09 for AC versus D, P = 0.13 for AC versus AC-D) in the AC, D, and AC-D, respectively. CONCLUSION: There was no difference in the TTF among the three arms. However, there was a trend toward a better response and better OS in the D than in the AC.

Evaluation of the safety and tolerability of oral TAS-108 in postmenopausal patients with metastatic breast cancer.

BACKGROUND: The potential of TAS-108 for the treatment of breast cancer has been shown by preclinical studies. We therefore investigated the safe dosage, tolerability, and effectiveness on hormone levels and bone metabolism markers and the pharmacokinetics of TAS-108 administered in postmenopausal Japanese women with metastatic breast cancer. PATIENTS AND METHODS: The subjects had previously undergone standard endocrine therapeutic modalities. TAS-108 was given repeatedly to five patients each, at three dose levels (40, 80, and 120 mg p.o.) once a day after the first daily meal for a scheduled 8 weeks. Plasma concentrations of TAS-108 and its metabolites were measured at the scheduled time points. RESULTS: Fifteen patients received TAS-108 treatment. Orally administered TAS-108 was well tolerated at doses up to 120 mg and did not cause notable changes either in hormone levels or bone metabolism markers. Pharmacokinetic results indicated dose-dependent increases in plasma levels of TAS-108 and its metabolites. A steady state was achieved by 2 weeks at all dose levels, suggesting no marked accumulation. Clinical benefits were confirmed in 5 of 15 patients. CONCLUSIONS: Repeated oral administration of TAS-108 at doses up to 120 mg was well tolerated, and the plasma level of this compound increased dose-dependently.

Breast biopsy for mammographically detected non-palpable lesions using a vacuum-assisted biopsy device (Mammotome) and an upright-type stereotactic mammography unit.

BACKGROUND: It is planned to start screening mammography throughout Japan in the near future. However, a minimally invasive biopsy procedure for mammographically detected non-palpable breast lesions is not available in almost all Japanese hospitals. It is crucial to develop a useful minimally invasive biopsy method which can be applied without difficulty. METHODS: Eighty-nine biopsies for 88 mammographically detected non-palpable breast lesions, consisting of 70 lesions with microcalcifications alone, eight masses without calcifications and 10 with both masses and microcalcifications, were performed using the combination of a vacuum-assisted biopsy device (Mammotome) and an upright-type stereotactic mammography unit. RESULTS: Microcalcifications were confirmed radiographically in the tissue obtained from 78 biopsies among 81 biopsies for the lesions with microcalcifications (96.3%). All the lesions without calcifications were considered to be biopsied successfully. Five patients complained of nausea or fainted during the localization or biopsy procedure and an additional patient suffered from hyperventilation syndrome. Five cases experienced mild subcutaneous bleeding in the breasts. CONCLUSIONS: The biopsy technique using the combination of a vacuum-assisted biopsy device and an upright-type stereotactic mammography unit is a cost-effective, safe and very useful method for mammographically detected non-palpable breast lesions. It is expected to be a standard method of biopsy for such lesions in many developed countries other than the USA. However, it is important to make the patients relaxed during the biopsy to prevent mental strain.

Telomerase activity in soft-tissue and bone sarcomas.

The telomerase enzyme is a reverse transcriptase capable of replacing the telomeric DNA sequences that are lost at each cell division. Telomerase activation permits extended cell proliferation beyond normal senescence checkpoints, and accordingly, telomerase activity has been detected in a wide range of malignant cells and tissues but is absent in terminally differentiated somatic cells. To date, the majority of cancer-related telomerase analyses have been performed on carcinomas that originate from epithelial cells, and few reports have included tumors originating from nonepithelial cells. In this study, we used the PCR-based telomeric repeat amplification protocol (TRAP) to assay telomerase activity in nuclear protein extracts obtained from a range of malignant and benign connective tissue lesions. In total, 62 histologically diagnosed specimens were analyzed including 37 sarcomas, 7 benign mesenchymal tumors, 12 normal tissue samples, and 6 carcinoma metastases obtained from bone. Thirty (81%) of the 37 primary sarcoma samples contained telomerase activity, and four of the six carcinoma metastases were also positive. Conversely, telomerase activity was detectable in only one of seven benign lesions and in none of the 12 normal connective tissue controls. Tumors of connective tissue origin can sometimes be difficult to categorize and to evaluate microscopically with regard to clinical management. As is the case in carcinomas, the presence of telomerase activity appears to be indicative of malignancy in mesenchymal tumor biopsy material and therefore may be useful as an adjunct to the pathologist in the assessment of borderline cases.

Comparison of telomerase and CD44 expression as diagnostic tumor markers in lesions of the thyroid.

The analysis of the tissue expression patterns of both the telomerase enzyme and the adhesion molecule CD44 has highlighted these molecules as potential tumor markers. In this study, the expression of these markers was analyzed in frozen tissue samples of the same human thyroid lesions, and the data were compared to evaluate their application to tumor diagnosis. The study analyzed 12 malignant specimens, including 5 papillary, 3 follicular, 2 anaplastic, 1 medullary, and 1 low-grade Hurthle cell carcinoma and 17 specimens from benign lesions, including cases of adenoma, hyperplasia, and Graves' disease. Telomerase expression was analyzed by assay of enzyme activity using the telomeric repeat amplification protocol and by reverse transcription-PCR detection of human telomerase reverse transcriptase (hTERT) mRNA. Nine of 12 (75%) malignant samples and the two Graves' disease samples were evaluated as positive for telomerase activity by the telomeric repeat amplification protocol assay. The presence of hTERT mRNA was detected in 8 (67%) of 12 malignant tissues and in 5 (29%) of 17 benign thyroid tissue samples. The expression of CD44 transcripts containing variant exons 7, 8, and 11 was evaluated by reverse transcription-PCR/Southern blot analysis. Of the 12 malignant samples, 9 (75%) included transcripts containing exon 7, 10 (83%) included transcripts containing exon 11, and 11 (92%) included transcripts containing exon 8. However, these CD44 exons were also present in transcripts in a high proportion of benign samples. Five (28%), 10 (59%), and 6 (35%) benign samples contained CD44 transcripts, including variant exons 7, 8, and 11, respectively. The measurement of telomerase activity proved to be the most specific for the detection of thyroid carcinoma in frozen tissue samples as a single analyte, but diagnostic accuracy was increased by the combination of telomerase and CD44 analyses.

Introduction of gadd153 gene into gastric cancer cells can modulate sensitivity to anticancer agents in association with apoptosis.

Gadd 153 gene is known as one of the growth arrest and DNA damage inducible genes that may play an important role in signal transduction pathway(s) in response to DNA damage. We have investigated whether the introduction of gadd153 gene into gastric cancer cells could modulate the sensitivity to anticancer agents in association with apoptosis. The transfection of gadd153 gene into MKN45 gastric cancer cells (MKN45gadd153) increased the sensitivity to a variety of anticancer agents, compared to that of neo gene-transfected cells (MKN45neo). The sensitivity to CDDP and VP-16 was increased to a greater extent, whereas the sensitivity to 5-FU and taxotere was increased to a lesser extent. The increase of sensitivity to these drugs was associated with the increase of the formation of internucleosomal DNA ladders in apoptosis. The basal level of gadd153 mRNA was overexpressed in MKN45gadd153 cells, and its induction following the treatment of VP-16 and taxotere was found to a greater extent than that of MKN45neo cells. The analysis of mRNA expression in drug resistance-related genes including mdr1, mrp, topoisomerase II alpha showed that the increase of drug-sensitivity in MKN45gadd153 cells was not due to the changes in expression of drug resistance genes. These results suggest that the introduction of gadd153 gene into gastric cancer cells may modulate the sensitivity to certain anticancer agents by activating AP-1-associated signal transduction pathway(s) leading to apoptosis.

Laparoscopic resection of submucosal gastric tumors.

In order to elucidate the efficacy in gastric surgery, we evaluated seven resected cases of a submucosal gastric tumor in which laparoscopic techniques were used. The patients consisted of 1 man and 6 women. The tumors were located in the upper, middle, and lower third of the stomach in 4, 1, and 2 cases, respectively. Three tumors were located mainly on the anterior gastric wall, 2 were on the posterior wall, and 2 were on the lesser curvature. The resected tumor size averaged 3.2 x 2.6 cm. The tumors were classified as intraluminal type (4 cases) and the extraluminal type (3 cases) according to the classification of growth type. A histopathological examination identified 4 leiomyomas, 1 leiomyosarcoma, and 4 smooth muscle tumors of indeterminate malignant potential. After a tumor resection, no recurrence of the lesions occurred during the postoperative follow-up. An extraluminal growing tumor was easily resected by the laparoscopic method without any additional procedures, and this therefore seemed to be a good indication for the laparoscopic method. In contrast, an intraluminal tumor was found to be more difficult to resect using the laparoscopic method without a companion method, e.g., intraoperative endoscopy, because of the difficulties in the detection and resection of the tumor from the serosal side. A more efficient technique must therefore be developed for this type of tumor.

[Usefulness of percutaneous low output microwave tissue coagulation therapy for solitary liver cancer].

The possible use of percutaneous transhepatic low output microwave tissue coagulation therapy (PMCT) using ultra-sonography under local anesthesia for solitary liver cancer was studied. The subjects were 13 patients having primary or metastatic liver cancer with solitary liver tumor less than 3 cm in diameter, including 7 hepatocellular carcinomas and 6 metastatic liver cancers. PMCT was performed continuously 3 times at an output of 30 watts for 30 seconds at a time. Tumors less than 3 cm in diameter were completely coagulated by irradiation from 2 to 6 times, judging by enhanced CT. No tumor recurrence was recognized in the coagulation area. However, in two cases of metastasis from pancreatic carcinoma, multiple metastases were found at another site in the liver by 2 months after PMCT. Thus, the results suggest that PMCT is a useful therapy for small liver tumor as a local control.

Telomerase activity in lesions of the thyroid: application to diagnosis of clinical samples including fine-needle aspirates.

The telomerase enzyme is capable of replacing telomeric DNA sequences that are lost at each cell division. It has been suggested that the function of this enzyme is necessary for cells to become immortal, and in concordance with this hypothesis, telomerase activity has been detected in malignant tumor cells, whereas the enzyme is inactive in normal somatic cells. The measurement of this activity in human tissue samples may have diagnostic value, and in this study, we examined whether such a measurement may be useful for the detection of malignant cells within the thyroid. Telomerase activity was assayed using the telomeric repeat amplification protocol and related to the histological diagnosis of thyroid biopsy tissue samples and of cells obtained from the thyroid by fine-needle aspiration (FNA). Extracts from 9 of 11 (82%) carcinoma biopsy tissue samples contained telomerase activity, whereas enzyme activity was detected in only 2 of 14 (14%) benign tissue sample extracts. These two positive cases were subsequently diagnosed as Graves' disease with severe lymphocytic infiltration. Five of six (83.3%) histologically confirmed carcinoma FNA samples were identified by using the telomeric repeat amplification protocol assay, and two samples considered to be suspicious by FNA cytology were also positive. Conversely, only 4 of 48 (8.3%) benign FNA samples had telomerase. These promising data indicate that this sensitive assay could become a useful adjunct to microscopic cytopathology in the detection of cancer cells in small tissue biopsies and in fine-needle aspirates of the thyroid.

[Usefulness of percutaneous microwave tissue coagulation therapy for solitary liver cancer].

The possible use of percutaneous transhepatic microwave tissue coagulation therapy (PMCT) using ultra-sonography under local anesthesia for solitary liver cancer was studied. The subjects were 8 patients having primary or metastatic liver cancer with solitary liver tumor less than 4 cm in size, consisting of 2 hepatocellular carcinomas, and 6 metastatic carcinomas. PMCT was performed continuously 3 times at the output of 30 watts for 30 seconds at a time. Tumors less than 3 cm in size were completely coagulated by irradiation from 2 to 5 times judged by enhanced CT. No recurrence of tumor was recognized in the coagulation area. But in some cases, multiple metastases were found at another site in the liver by 3 months after PMCT. Thus, the results suggest that PMCT is a useful therapy for small liver tumor as a local control.

[A case of advanced hepatocellular carcinoma with portal invasion effectively treated by continuous intra-arterial chemotherapy with 5-fluorouracil].

A 79-year-old male diagnosed as advanced hepatocellular carcinoma with portal invasion was treated by continuous intra-arterial chemotherapy of 5-FU, which was continuously administered for 72 hours at a dose of 333 mg/mm/day every 2 weeks and repeated 12 times. Total dose of 5-FU was 14.4 g. Toxicity of this therapy was not recognized. Levels of AFP were reduced from 4385.6 ng/ml to 11.9 for 6 months. No tumor was recognized on CT scan at 6 months after starting this therapy, after 15 months of this therapy, the patient is alive and disease-free. Given the above results, continuous intra-arterial administration of this 5-FU therapy may be effective for patients with hepatocellular carcinoma.