Impact of boost irradiation with surgically placed radiopaque clips on local control in breast-conserving therapy.

BACKGROUND: The purpose of this study was to determine whether boost irradiation relying on radiopaque clips placed surgically around the resected margin of breast cancer contributes to increasing the local control rate in patients with close or positive margins in breast-conserving therapy (BCT). METHODS: Among 837 patients with breast cancer who underwent BCT between November 1987 and December 1998, 181 patients with close or positive surgical margins received boost irradiation following conventional tangential whole breast irradiation. Since 1994, four radiopaque clips were surgically placed around the resected margin of the breast cancer in 155 patients treated with wide excision. The four clips were clearly and accurately identified with a CT-simulator (CT-S). The boost irradiation field was automatically determined with a safety margin of 3 cm according to one-to-one correspondence of radiopaque clips to pathologically close or positive surgical margins. In the remaining 26 patients treated before 1994, the boost irradiation field was determined according to the skin tattoo of the primary tumor. RESULTS: The median follow-up period of the 155 patients receiving the radiopaque clips was 42 months (range: 19 to 78), and that of the 26 patients without the clips was 87 months. Local recurrence was observed in two of the 155 patients who underwent boost irradiation using the radiopaque clips 39 and 54 months after the surgery, while 4 of the 26 patients developed local recurrence 14, 23, 51, and 76 months after BCT. In three of the four patients without the clips developing local recurrences, local recurrences were observed at the margin of the boost irradiation field. The 5-year local recurrence-free survival rate of patients who received boost irradiation with the radiopaque clips was 97%, and that of patients without the clips was 88%. The difference of local recurrence-free survival rates between the patients with and without the clips was significant (p<0.05). CONCLUSION: Surgically placed radiopaque clips appear to be useful for determining adequate boost field in the BCT using the CT-S and help increase the local control rate.

Meningeal carcinomatosis in patients with breast cancer: report of 8 patients.

BACKGROUND: Meningeal carcinomatosis (MC) is an uncommon but aggressive complication of advanced breast cancer with a recently increasing incidence. Although the prognosis is extremely poor for MC patients, early diagnosis and appropriate treatment are important. SUBJECTS AND METHODS: We reviewed 8 cases of MC from breast cancer at Kyoto University Hospital from 1990 to 1999. The median age was 51.5 years. All patients had widespread systemic metastases when diagnosed with MC. clinical symptoms were categorized into 3 groups: cranial nerve symptoms, spinal nerve symptoms, and other symptoms. Imaging studies were positive for MC in only 4 patients. Initial CSF cytology studies were positive in 4 patients, and repeated CSF cytology yielded positive results in the remaining 4 patients. Thus the median interval between the onset of any clinical symptom of MC and the initiation of treatment was 22.5 days (range 7 to 120 days ). All patients received whole brain radiotherapy (WBRT). Four patients were given intrathecal chemotherapy and/or intrathecal immunotherapy in addition to WBRT. RESULTS: Improvement of cranial nerve symptoms, spinal nerve symptoms, and other symptoms were observed in 3/5, 1/3, and 5/7 patients, respectively. Patients with cranial nerve symptoms who started WBRT within 29 days of the onset of the symptoms showed at least partial recovery whereas patients who started WBRT later showed no recovery. The median survival was 123 days (53 to 310 days). MC was the direct cause of death in 1 of 8 patients. CONCLUSION: When MC is clinically suspected, neither a negative imaging study nor a single negative CSF cytology can rule out MC. Prompt initiation of WBRT with or without intrathecal chemotherapy may be important for recovery from cranial nerve symptoms.

A case of allergic reaction to surgical metal clips inserted for postoperative boost irradiation in a patient undergoing breast-conserving therapy.

We report a case of a 28-year-old woman with right-sided breast cancer. The patient had been treated for atopic dermatitis since her infancy. She underwent breast-conserving surgery (BCS) in July 1998, and three titanium clips were placed at the margin of the excision cavity at the time of surgery. Two months after surgery, the patient exhibited a rapid exacerbation of atopic dermatitis. Various drugs were suspected to be the cause of the allergic reaction, but the results of a bi-digital O-ring test (BDORT) suggested an allergic reaction to titanium clips. In August 1999, the patient underwent a second operation to remove the titanium clips under local anesthesia. Allergy to surgical titanium clips is a rare complication, but in patients with a history of severe allergic diseases, a preoperative immunologic examination should be performed and the patient's history of metal allergy should be investigated.

Cosmetic results and complications after breast conserving therapy for early breast cancer.

BACKGROUND: The cosmetic and functional results of breast conserving therapy for early breast cancer were evaluated. These are important endpoints in the assessment of breast conserving therapy in addition to tumor control and survival. The factors suspected to influence cosmesis were also analyzed. METHODS: In 206 patients with stage I and II breast cancer treated by wide excision and axillary dissection followed by radiation therapy, the cosmetic results and complications were analyzed. The cosmetic outcome was assessed by a scoring method and breast retraction assessment (BRA). As complications, arm edema and restriction of shoulder movement and late skin reactions were analyzed. RESULTS: Of the 206 patients 92% showed an excellent to good cosmetic score before radiation therapy. The score deteriorated, but gradually improved and stabilized after 1 year. Eighty-one percent of the patients had an excellent to good cosmetic score at 3 years. The BRA of the 206 patients was 1.8 cm on average before radiation therapy. It increased to 2.3 cm after termination of radiation therapy, and did not change thereafter. Tumor size over 2 cm (p = 0.005) and tumors in the inner quadrant (p = 0.003) were factors which negatively affected the cosmetic score at 3 years. Tumor size over 2 cm (p = 0.003), tumors in the upper quadrant (p = 0.005), or a nipple-tumor distance of more than 2 cm (p = 0.01) were also negative factors for the BRA at 3 years. Arm edema, restriction of shoulder movement, and late skin reaction were generally mild, and were observed in 12%, 0% and 34% of patients at 3 years, respectively. CONCLUSIONS: The overall cosmetic results of breast conserving therapy are acceptable and the complication rate is low. Tumor characteristics, tumor size, location and nipple-tumor distance are factors that affect cosmesis.

Determination of optimal radiation energy for different breast sizes using CT-simulator [correction of simulatior] in tangential breast irradiation.

BACKGROUND: The purpose of this study is to determine and recommend the optimal radiation source according to breast size for tangential irradiation in breast conserving therapy. METHODS: Twenty-eight patients treated at our department from January 1994 to January 1996 were studied. The dose distribution within the irradiated breast was calculated using a (60)Co-gamma ray and 6 MV-X ray. Then we compared 3-D dose distributions of the (60)Co-gamma ray and 6 MV-X ray in different-sized breasts. Three parameters (breast volume, chest wall separation, and breast height) were adopted as representative of breast size. We also examined correlations among the three parameters. RESULTS: When the breast size was large (breast volume >400 cm(3), chest wall separation > 19.5 cm, or breast height > 6.5 cm), the average volume of normal tissue which received more than 110% of the isocenter dose ("hot spot") was significantly greater with the (60)Co-gamma ray than with the 6 MV-X ray (p < 0.05). A similar result was obtained with regard to hot spots in the clinical target volume. The cold area that received less than 95% of the isocenter dose was greater using a 6 MV-X ray when the breast size was small (breast volume <200 cm(3), chest wall separation <17.5 cm, or breast height <5.0 cm). However, the difference was not significant. There was a significant correlation between breast volume and chest wall separation (r =0.849, p <0.001). Breast volume and breast height were also significantly correlated (r =0.813, p <0.001). CONCLUSIONS: Since breast volume and shape are different in each patient, the optimal energy should be selected for each case to obtain uniform dose distribution in breast-conserving therapy. Chest wall separation or breast height, which are measurable without a 3-D planning system, can substitute for breast volume as parameters for breast size. We recommend that the (60)Co-gamma ray not be used for treating large breasts, those with chest wall separation > or =19.5 cm or breast height > or =6.5 cm.

Results of breast-conserving therapy for early stage breast cancer: Kyoto University experiences.

This study evaluated the results of breast-conserving therapy (BCT). Nine hundred six patients who underwent BCT at our hospital between November 1987 and February 1998 were analyzed. The mean age was 48 years. According to the Union Internationale Contre le Cancer 1997 classification system, stages 0, I, IIA, IIB, IIIA, and IIIB were 37, 400, 344, 117, 7, and 1, respectively. Radiation therapy consisted of 50 Gy to the ipsilateral whole breast. Boost irradiation of 10 Gy was administered to 186 of 231 patients with close or positive margins. Nearly all patients received adjuvant chemohormonal therapy with tamoxifen and 5-fluorouracil or its derivatives for 2 years. The minimum and median follow-up periods were 18 and 52 months, respectively. The 5-year overall survival, cause-specific survival, local recurrence-free survival, and disease-free survival rates were 97.3%, 98.4%, 98.1%, and 91.5%, respectively. Local recurrence in preserved breast occurred in 20 patients 7 to 86 months after surgery. Multivariate analysis revealed that the most predictive factor for disease-free survival rates and distant failures was the number of pathologically positive lymph nodes (p < 0.0001), and that the factor for local failure was marginal status (p = 0.005). This study demonstrated that BCT was suitable for the treatment of early-stage breast cancer with its reasonable survival rates and acceptable toxicity.

Increased heating efficiency of hyperthermia using an ultrasound contrast agent: a phantom study.

It is known that there are large temperature elevations in proximity to air bubbles during US (ultrasound) heating. The existence of tiny air bubbles in the target tissue may enhance the temperature elevation in US hyperthermia. To examine this hypothesis, phantom tissue experiments using an US contrast agent consisting of tiny air bubbles surrounded by a 5% (w/v) human albumin shell (Alb) were performed. As a phantom tissue, a 2 cm cube of beef was used. The phantom tissue was heated with or without the US contrast agent by an US hyperthermia device for 3 min. The heating device was operated at 1.5 MHz with the US intensity of 0.9 W/cm2. Physiological saline solution, iodized oil, and ethanol were used for control experiments. The effect of multiple needle punctures to the beef phantom was also examined. The temperature elevation rate (TER) was defined as the ratio of temperature elevation by heating with Alb or control materials to the temperature elevation by US heating alone. The TER of Alb was 1.7, whereas the TERs of the control materials and of the multiple needle punctures were approximately 1. The administration of Alb significantly increased the temperature in US hyperthermia. In addition, the heating efficiency of Alb was compared to the effect of an increase in the US intensity. Phantom tissue was heated at various US intensities. When the US intensity was increased from 0.9 to 1.8 W/cm2, the temperature elevated by approximately 1.7-fold. Thus, the effect of the administration of Alb was almost equivalent to the effect of increase in US power intensities from 0.9 to 1.8 W/cm2 in the present experimental settings. The results suggest that the US contrast agent can be a potential enhancer in US hyperthermia.

Gallstone ileus with impaction at the neck of a Meckel's diverticulum.

We report a case of gallstone ileus in which the stone impacted at the neck of a Meckel's diverticulum. CT demonstrated the gallstone as a calcified mass in the lower abdomen. Gallstone ileus was diagnosed although a more accurate diagnosis was not obtained pre-operatively. The site of impaction was not typical and a blind loop filled with contrast materials was evident. We believe that this is the first report demonstrating this rare condition with imaging.

A phase I and II clinical trial of a newly developed ultrasound hyperthermia system with an improved planar transducer.

PURPOSE: The clinical usefulness of a newly developed ultrasound hyperthermia system was evaluated. METHODS AND MATERIALS: The hyperthermia system uses a modified planer transducer operated at frequencies of 0.5, 1.0, and 1.5 MHz. The transducer has a nonvibrating part at the center to reduce the central hot spot. Frequency sweeping technique is also used to eliminate the annular hot spot around the center. Thirty-eight tumors in 29 patients were examined in this study. In 35 tumors, hyperthermia was given in conjunction with irradiation and/or chemotherapy, and in the remaining 3 tumors, hyperthermia alone was given. In all, a total of 153 hyperthermia sessions were performed. RESULTS: The number of hyperthermia sessions per tumor ranged from 1 to 7 (mean, 4.0 +/- 1.3). The number of intratumor thermometry points per session ranged from 1 to 8 (mean, 4.3 +/- 1.5). The average intratumor temperature for tumors with a maximum depth of <3 cm, 3-6 cm, and >6 cm was 42.1 +/- 1.2, 41.7 +/- 1.4, and 39.9 +/- 2.0 degrees C, respectively. The percentage of monitored intratumor points with temperature exceeding 42 degrees C was 56 +/- 31%, 43 +/- 34%, and 21 +/- 24%, respectively. Of the 30 evaluable tumors treated with combined irradiation, 12 showed complete response, 14 partial response, and 4 no change. Observed complications included pain at the treatment site in 13 of the 153 treatment sessions and vesicle formation in 3 of the 38 treatment sites. No serious complication was seen. CONCLUSIONS: These results indicate that the newly developed ultrasound hyperthermia system is clinically useful for the treatment of localized superficial and subsurface tumors with a maximum tumor depth of no more than 6 cm.

Anti-metastatic therapy by urinary trypsin inhibitor in combination with an anti-cancer agent.

We have demonstrated that urinary trypsin inhibitor (UTI) purified from human urine is able to inhibit lung metastasis of mouse Lewis lung carcinoma (3LL) cells in experimental and spontaneous metastasis models. In this study, we have investigated whether UTI in combination with an anti-cancer drug, etoposide, can prevent tumour metastasis and show an enhanced therapeutic effect. Subcutaneous (s.c.) implantation of 3LL cells (1 x 10(6) cells) in the abdominal wall of C57BL/6 female mice resulted in macroscopic lung metastasis within 21 days. Microscopic lung metastasis was established by day 14 after tumour cell inoculation, and surgical treatment alone after this time resulted in no inhibition of lung metastasis. The number of lung tumour colonies in the group of mice which received surgery at day 21 was greater than in mice which had tumours left in situ (P = 0.0017). Surgical treatment on day 7, followed by UTI administration (s.c.) for 7 days, led to a decrease in lung metastasis compared with untreated animals. A significant inhibition of the formation of pulmonary metastasis was obtained with daily s.c. injections of UTI for 7 days immediately after tumour cell inoculation. UTI administration did not affect the primary tumour size at the time of operation. In addition, etoposide treatment alone led to a smaller primary tumours and yielded reduction of the formation of lung metastasis in the group of mice which received surgery at day 14 (P = 0.0026). Even in mice which received surgical treatment on day 14, followed by the combination of UTI (500 micrograms per mouse, days 14, 15, 16, 17, 18, 19 and 20) with etoposide (40 mg kg-1, days 14, 18 and 22), there was significant reduction of the formation of lung metastasis (P = 0.0001). Thus, the combination of an anti-metastatic agent with an anti-cancer drug, etoposide, might provide a therapeutically promising basis for anti-metastatic therapy.

Impact of urokinase-type plasminogen activator and its inhibitor type 1 on prognosis in cervical cancer of the uterus.

The present study was undertaken to assess the role of tumor-associated urokinase-type plasminogen activator (uPA) and its inhibitor type 1 (PAI-1) as a predictor for early relapse and poor prognosis in patients with stage II cervical cancer of the uterus. We have investigated the localization of uPA and PAI-1 immunohistochemically in formalin-fixed paraffin-embedded tissue sections. uPA and PAI-1 were analyzed antigenically, enzymologically, and zymographically in 28 patients with pelvic lymph node involvement and in 34 cases without nodal spread, as well as in 10 cases with normal cervix. In cancer tissues, strong staining for uPA was found in areas with invasive growth and degradation of surrounding normal tissue, while most tumor nests showed a mild or a moderate, evenly distributed PAI-1 staining. A significantly higher lymph node-positive rate was observed in patients having tumors with strong uPA and/or PAI-1 stainings than in those with tumors with weak stainings. In spite of significantly higher PAI-1 levels in the primary neoplastic tissues, uPA was found to be increased as well, both in antigen level and in activity. Most of PAI-1 obtained from cancer extracts is the latent form. These results suggest that cancer-associated increase in uPA seems not to be affected (or inhibited) by PAI-1 in areas where tumor cells are invading normal tissue. The overall survival and progression-free survival rate was worst in patients with the strong uPA staining confined to the tumor stromas and also with the strong PAI-1 staining at tumor nests, indicating that the greater localization of uPA in stromal cells than in malignant cells is a predictor of early relapse and poor prognosis in patients with cervical cancer of the uterus. Thus, the staining intensities and the localization of uPA and PAI-1 in tissue specimens appear to be predictors of increasing risk for lymph node metastasis, suggesting that some tumor cells recruit stromal cells to produce uPA and that PAI-1 may not act as a defense mechanism for tumor cell invasion and metastasis in the leading edge of tumor growth.

[Urokinase-type plasminogen activator as a predictor for lymph nodes metastasis of uterine cervical cancer].

The present study was undertaken to assess the role of tumor infiltrating lymphocytes and polymorphonuclear leukocyte-derived human leukocyte elastase (HLE) as an inactivator of urokinase-type plasminogen activator (uPA) activity. We have investigated the localization of pro-uPA/uPA and HLE immunohistochemically and quantitated in paraffin-embedded formalin-fixed uterine cervical cancer tissue sections (stage II) in 13 patients with positive lymph-nodes metastasis and in 16 cases with node-negative. The invasively growing and metastasizing tumor cells consistently contained uPA enzyme activity. When investigated immunohistochemically with antibody to uPA, different parts of individual tumors showed a pronounced heterogeneity in staining intensity. Strong staining was found in the areas with invasive growth and degradation of surrounding normal tissue. A statistically significant higher node-positive rate was observed in patients having tumors with strong uPA stainings than in those with weak stainings. On the other hand, inflammatory cells such as polymorphonuclear cells were located in aggregates or diffusely spread within tumor stromal tissue. The inflammatory reaction seemed to be most intense at the border between the surrounding normal stromas and the tumor tissue. These cells produced and secreted HLE. A statistically significant higher node-positive rate was observed in patients having tumors with weak HLE stainings than in those with strong stainings. Thus, uPA and HLE staining intensities in tissue specimens appear to be independent predictors of increasing and decreasing risk for node-positive, respectively, suggesting that HLE may act as a defence against tumor cell invasion and metastasis.

Biochemical markers as a predictor for lymph-node involvement in patients with cervical-cancer of the uterus.

The present study was undertaken to assess the role of tumor associated urokinase-type plasminogen activator (uPA) and tumor infiltrating granulocyte-derived elastase as a positive and a negative predictor for lymph node involvement in patients with stage II cervical cancer of the uterus. uPA and uPA binding proteins (uPA receptors) were quantitated enzymologically and/or immunologically in cell membrane preparations obtained from cancer tissues. The cell membrane preparations express pro-uPA/uPA, uPA is bound to a specific type of surface receptors, of which more than 50% are saturated. Most of the receptor-bound uPA is enzymologically inactive pro-uPA. We have investigated the localization of pro-uPA/uPA and granulocyte elastase immunohistochemically and semiquantitated in formalin-fixed paraffin-embedded tissue sections in 13 patients with pelvic lymph node involvement and in 16 cases without lymph node involvement. Strong uPA staining was found in areas with invasive growth and degradation of surrounding normal tissue. A significant higher lymph node positive rate was observed in patients who had tumors with strong uPA staining than in those with weak staining (p<0.05). In contrast, phagocytic cells were found close to the tumor cells, and were located in aggregates or diffusely spread within tumor stroma surrounding the tumor nests. The inflammatory reaction seems to be most intense at the border between surrounding normal stromal cells and malignant epithelial cells. These cells produced and secreted granulocyte elastase.

[The effect of granulocyte elastase inhibitor (urinastatin) vaginal suppository on patients with imminent premature delivery].

Cervical maturation, dilatation and uterine contraction in imminent premature delivery are closely related to chemical mediators from activated granulocytes which infiltrate into the cervix. It is known that urinastatin (urinary trypsin inhibitor, UTI) inhibits many kinds of chemical mediators from granulocytes and macrophages such as granulocyte elastase (elastase) and interleukin 1. We examined the effect of a UTI suppository on uterine contraction and the elastase level in cervical mucus in cases of imminent premature delivery. We treated 43 cases of imminent premature delivery with tocolysis index 3 or 4 with 4 kinds of therapy: Group A (N = 12): ritodorine drop infusion therapy; Group B (N = 9): daily UTI suppository (1,000U) therapy; Group C (N = 14): daily UTI suppository + ritodorine drop infusion therapy; Group D: daily UTI suppository + ritodorine drop infusion + antibiotics (oral cepharosporine) therapy. The elastase level of cervical mucus before treatment was 0.76 +/- 0.40 micrograms/ml in group A, 0.93 +/- 0.43 micrograms/ml in group B, 0.85 +/- 0.40 micrograms/ml in group C and 0.90 +/- 0.41 micrograms/ml in group D. There was no significant difference between these groups. The elastase level in cervical mucus was 0.75 +/- 0.47 micrograms/ml in group A, 0.27 +/- 0.35 micrograms/ml in group B, 0.27 +/- 0.33 micrograms/ml in group C and 0.30 +/- 0.19 micrograms/ml in group D, respectively. The elastase level was decreased significantly in groups B, C and D. The time taken to depress uterine contraction was 65 +/- 66 min in group A, 375 +/- 336 min in group B, 70 +/- 64 min in group C and 58 +/- 53 min in group D, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)