Eisei Shin

p53 Gene Mutations Associated with Anaplastic Transformation of Human Thyroid Carcinomas

Anaplastic carcinoma of the thyroid gland, which is one of the most aggressive, malignant tumors in humans, is considered to originate from preexisting differentiated thyroid cancer. To define the genetic alterations associated with such progression, we examined nine cases of anaplastic thyroid carcinoma for mutation in exons 4–9 of the p53 tumor suppressor gene. Preliminary screening for mutation by RNase protection analysis demonstrated that two out of nine anaplastic carcinomas contained sequence alterations in the p53 gene. Subsequent DNA sequencing identified the mutated nucleotides in these two cases; one was a nonsense mutation at codon 165, and the other was a single‐base deletion at codon 176 resulting in the creation of a stop codon downstream due to frameshift. The fact that no mutations were detected in coexisting foci of papillary carcinomas from the same patients shows that these mutations of the p53 gene occurred after development of papillary carcinomas. These results suggest that p53 gene mutation triggers the progression from differentiated into anaplastic carcinoma in the human thyroid gland.

Deletion Mapping of Chromosome 1p and 22q in Pheochromocytoma

To identify the localization of tumor suppressor genes, 22 pheochromocytomas (9 hereditary and 13 sporadic) were examined for loss of heterozygosity (LOH) on the short arm of chromosome 1 and on the long arm of chromosome 22 by using 11 polymorphic DNA markers on each chromosome arm. LOH on 1p was observed in 12 of 22 informative cases (55%) and on 22q in 8 of 20 informative cases (40%). There was no significant difference in the frequency of LOH on 1p or 22q between hereditary and sporadic cases. We could localize the commonly deleted regions as distal to D1S73 and proximal to D1S63 on 1p and distal to D22S24 and proximal to D22S1 on 22q. In addition, the relationship between LOH on 1p and 22q was studied in 20 pheochromocytomas which were informative for probes on both chromosome arms. Of eight tumors that showed LOH on 22q, allelic loss on 1p was also detected in seven. Thus, LOH on 22q was correlated significantly with LOH on 1p (P= 0.0249; Fishers exact test). These results suggest that inactivation of multiple tumor suppressor genes may be required for development and progression of hereditary and non‐hereditary pheochromocytoma.

Metastatic breast cancer with resistance to both anthracycline and docetaxel successfully treated with weekly paclitaxel

Abstract We report the case of a 38-year-old woman who underwent surgery for stage III-b breast cancer, and whose liver metastasis failed to respond to both docetaxel (administered at 30–40 mg/m2 every 2 weeks as a 1-h intravenous infusion) and epirubicin (administered as a 40–60 mg/m2 bolus hepatic arterial infusion). For subsequent treatment, this patient was managed with weekly paclitaxel. The regimen showed some usefulness for the treatment of the liver metastasis, as indicated by an improvement in performance status and tolerable toxicity. This case demonstrates that weekly paclitaxel may be well tolerated and useful for patients with extensive metastatic breast cancer that was resistant to treatment. Our findings also suggest that paclitaxel could be used as a salvage therapy in patients with anthracycline- and docetaxel-resistant breast cancer.

Phase II Study of Weekly Paclitaxel for Docetaxel-Resistant Metastatic Breast Cancer in Japan

Abstract:  The purpose of the study was to evaluate the efficacy of weekly paclitaxel (PTX) against metastatic breast cancer (MBC) that was resistant to docetaxel (DTX) given every 3 weeks. A multicenter phase II study was performed. Women with MBC resistant to DTX were eligible for enrollment. DTX resistance was defined as no tumor response to DTX and stable disease, partial response, or complete response to DTX preceding disease progression. PTX 80 mg/m2 was administered over 1 hour once a week for 3 weeks per 4‐week cycle. Among 47 enrolled patients, 46 patients were assessable for response and toxicity. The overall objective response rate (complete responses [CRs] and partial responses [PRs]) was 17.4% and overall clinical benefit rate (CRs, PRs, and stable disease ≥24 weeks) was 26.1%. The median time to progression was 11 weeks. There were a few severe hematologic toxicities related to the therapy, with grade 4 neutropenia (4.3%) and thrombocytopenia (2.2%). Grade 3 anaphylaxis and grade 3 neuropathy were observed in one patient (2.2%) each. The median delivered dose intensity was 77.6 mg/m2/week, 97.1% of the planned dose intensity. Weekly PTX has activity in patients with MBC resistant to DTX every 3 weeks. 

New Technique of Laparoscopic-Assisted Excision of a Cholecystocolic Fistula: Report of a Case

Abstract Cholecystocolic fistula is a rare complication of gallstone disease that is most commonly diagnosed at the time of surgery. It is generally considered to be a contraindication to laparoscopic cholecystectomy because of the difficulties involved in its management intraoperatively. Laparoscopic stapling or suturing techniques have been reported as feasible and safe methods for repairing such fistulas; however, these procedures are not always able to be performed due to technical difficulties. We exteriorized a cholecystocolic fistula through an umbilical incision, whereby it was repaired safely and easily. This report describes our new technique for managing a cholecystocolic fistula found incidentally during a laparoscopic cholecystectomy.

Hyperfunctioning intrathyroid parathyroid adenoma: Report of two cases

We report herein two cases of intrathyroid parathyroid adenoma, which is a rare condition in patients with hyperparathyroidism. In the first patient, an excised intrathyroid nodule was diagnosed to be parathyroid adenoma postoperatively. In the second patient, preoperative localization studies suggested the possibility of an intrathyroid adenoma. When a pathological gland is not found during surgery for primary hyperparathyroidism, an ectopic parathyroid gland including an intrathyroid adenoma should thus be considered.

A prospective study on the prognostic significance of urokinase-type plasminogen activator levels in breast cancer tissue

Abstract Urokinase-type plasminogen activator (u-PA), which cleaves plasminogen to yield plasmin, is a serine protease of fibrinolysis and is presumed to play a key role in extracellular proteolysis and facilitate the migration of cancer cells. This study was conducted prospectively to evaluate the prognostic significance of u-PA antigen level in breast cancer tissues. u-PA concentrations in the cytosol of 226 breast cancer tissues were determined prospectively by enzyme-linked immunosorbent assay using cytosol fractions prepared for steroid hormone assay. The median follow-up period of the patients was 60 months. Various prognostic factors were evaluated by univariate analysis or multivariate analysis using the Cox proportional-hazards method. Patients with primary breast cancer containing high levels of u-PA had a significantly shorter disease-free survival than patients with low levels of u-PA antigens. In multivariate analysis, a high level of u-PA was an independent risk factor for disease-free survival, being independent of age, axillary node status, and estrogen receptor status. Among the major prognostic factors, a high u-PA antigen level, lymph node involvement, and a positive estrogen receptor status were the most important for predicting relapse-free survival (P=0.044, P<0.0001, P=0.0039). This first prospective study confirmed the prognostic significance of the u-PA antigen level in association with other major prognostic factors. The results of our present study suggest that u-PA in breast cancer tissue might be involved in breast cancer invasion and metastasis.

A case control study on risk factors involved in inflammatory breast recurrence after breast-conserving surgery

Recurrence that poses the biggest problem after breast-conserving surgery is local recurrence. Particularly, in the case of inflammatory breast recurrence which is rare but has a specific pathologic nature, it is important to elucidate the pathology and risk factors and to consider appropriate countermeasures. In the present study, we classified 133 cases of recurrence following breast-conserving surgery, collected from 18 key hospitals/institutes in Japan. Recurrence types were divided into three groups, namely, inflammatory breast recurrence, noninflammatory breast recurrence and distant metastasis only, and the risk factors involved in recurrence were investigated by the case control study allotting 2 controls to each case. The study population consisted of 9 cases of the inflammatory type, 64 cases of the noninflammatory type and 60 cases of distant metastasis. The significant risk factor for inflammatory breast recurrence was positive lymph node metastasis, which was significantly more frequent in lymphatic invasion-positive cases unlike in the distant metastasis group. The positive surgical margin and nonradiation therapy which have been shown to be significant risk factors for noninflammatory breast recurrence were entirely unrelated with inflammatory breast recurrence. In addition, the inflammatory-type recurrence time was as short as about 12 months irrespective of whether radiation therapy was performed or not. The inflammatory type was accompanied with local wide extension (cancerous embolus of the dermal lymphatic vessels), and distant metastasis (lymphangitis carcinomatosa) at the time of recurrence, and further surgery was impossible in most cases, with a significantly poorer prognosis than the other recurrence types. These findings suggest that this recurrence corresponds to the so-called ‘occult’ case of primary inflammatory breast carcinoma. We think it important to predict this recurrence by close pathological examination, particularly in patients with lymph node metastasis, and to consider appropriate measures.

Expression of p16 and cyclin-dependent kinase 4 proteins in primary breast carcinomas

The immunolocalization of the p16 and cdk4 proteins was investigated in 65 retinoblastoma gene product (pRB)-positive and 20 pRB-negative breast carcinomas. These proteins were expressed in similar lesions in 84.6% of the pRB-positive and 100% of the pRB-negative carcinomas. Diffuse expression of p16 was observed in 73.8 and 70.0% of the pRB-positive and -negative cases, respectively. cdk4 and p16 expression was significantly more heterogeneous in tumors of larger sizes and/or at higher stages. These findings suggest that p16 can be induced regardless of pRB status and Rb gene function in primary breast carcinoma and that it modulates the cell cycle progression in association with cdk4.

A Retrospective Study of Breast Cancer Patients Treated with Quadrantectomy without Radiation Therapy.

BackgroundRadiation therapy after breast-conserving surgery (BCS) reduces the risk of local recurrence. However, whether radiation therapy is necessary for all patients undergoing BCS remains unclear.MethodsIn order to determine the selection criteria for patients who can safely omit radiation therapy and to confirm the survival benefit of quadrantectomy without radiation therapy, we reviewed 107 patients who underwent quadrantectomy without radiation therapy between February 1988 and July 1995.ResultsThe 5-year overall survival, disease-free survival and cumulative local recurrence rates were 93.7%, 80.7% and 12.1% respectively. There were no significant differences of 5-year overall survival (94.0% vs 94.1%) and disease-free survival rates (83.1% vs 70.0%) between patients with or without tamoxifen. The 5-year cumulative local recurrence rate of patients with tamoxifen, however, tended to be lower (p=0.0810) than that of patients without tamoxifen. The 5-year cumulative local recurrence rate of the patients aged 45 or less was significantly higher than that of patients aged from 45 to 55 years and those over 55 (p=0.0090 and 0.0089, respectively). In ER positive patients, the 5-year cumulative local recurrence rate of patients with tamoxifen tended to be lower (p=0.0791) than that of patients without tamoxifen.ConclusionThe survival rate of quadrantectomy without radiation therapy was acceptable. While the risk of local recurrence following quadrantectomy without radiation therapy is substantial, radiation therapy following quadrantectomy might not be necessary in elderly ER positive women receiving adjuvant tamoxifen therapy.