Locally recurrent soft tissue sarcoma of the extremities

BACKGROUND: The management of locally recurrent extremity soft tissue sarcoma remains challenging. This study was undertaken to evaluate the long-term outcome after therapy for isolated locally recurrent soft tissue sarcoma (STS) of the extremity. METHODS: Between January 1, 1980, and December 31, 1990, 52 patients were treated at The University of Texas M. D. Anderson Cancer Center for locally recurrent extremity STS. The records of the subset of these patients (n = 36) with isolated local recurrence were examined to document clinicopathologic and treatment factors and to evaluate outcome using the end points of local recurrence-free, recurrence-free, and overall survival. RESULTS: Limb-sparing conservative surgery was possible in 24 patients (75%). Twelve (33%) of 36 patients were treated by surgery alone, 23 patients (64%) were treated with combined modality therapy (surgery plus radiation and/or chemotherapy), and 1 patient had radiotherapy only. Sixteen (44%) of 36 patients had no further recurrence of any type at a median follow-up of 58 months (range, 4 to 173 months). The 5-year actuarial local recurrence-free, recurrence-free, and overall survival rates were 72%, 45%, and 77%, respectively. CONCLUSIONS: Limb-sparing conservative surgery is possible in the majority of patients with isolated locally recurrent STS. Durable local control can be established with individualized local treatment strategies. These results support aggressive multimodality limb-sparing treatment approaches for these patients.     

The role of stereotactic radiosurgery in the treatment of malignant skull base tumors

PURPOSE: To determine the efficacy and toxicity of stereotactic radiosurgery in the treatment of malignant skull base tumors. METHODS AND MATERIALS: Thirty-two patients with 35 newly diagnosed or recurrent malignant skull base tumors < or = 33.5 cm3 were treated using the Leksell Gamma unit. Tumor histologies included: adenoid cystic carcinoma [12], basal cell carcinoma [1], chondrosarcoma [1], chordoma [8], nasopharyngeal carcinoma [3], osteogenic sarcoma [2], and squamous cell carcinoma [8]. RESULTS: After a median follow-up of 2.3 years, 83% +/- 15% (+/-95% confidence interval) of patients experienced a symptomatic response to treatment. Local control at the skull base was 95 +/- 9% at 2 years and 78 +/- 23% at 3 years. Local-regional control above the clavicles was 75 +/- 15% at 1 year and 51 +/- 20% at 2 years. Overall and cause specific survival were identical, 82 +/- 13% at 1 year, 76 +/- 14% at 2 years, and 72 +/- 16% at 3 years. One patient developed a radiation-induced optic neuropathy 12 months after radiosurgery. CONCLUSION: Stereotactic radiosurgery using the Leksell Gamma Unit can provide durable tumor control and symptomatic relief with acceptable toxicity in the majority of patients with malignant tumors 4 cm or less in size involving the skull base. Further evaluation of more patients with longer follow-up is warranted.     

High Raf-1 kinase activity protects human tumor cells against paclitaxel-induced cytotoxicity

The p16 tumor suppressor gene is thought to play an important role in cell cycle regulation by encoding for protein products that can inhibit the progression from G1 to S phase in the cell cycle. Recently, the p16 gene has been found to be mutated or deleted in a variety of different types of primary human malignant tumors and human-derived malignant tumor cell lines. In this study, primary ductal pancreatic adenocarcinomas from 32 human patients were analyzed immunohistochemically for expression of p16 protein, with emphasis on the role of abberant p16 protein expression as a prognostic indicator. In addition, the same tumors were also assessed for p53 protein expression, AgNOR counts, and DNA ploidy. Nineteen out of the 32 cases (59%) showed positive immunoreactivity for p16 protein in their tumors and a significant association was found between lack of p16 protein expression, and both advancing clinical stage classification of disease, and poorer survival (p<0.05). The rate of positive immunoreactivity for p53 protein expression was 59%, however, no clear association was found between p53 protein expression, and either clinical stage of disease, or survival. These findings suggest that alteration of the p53 gene may be a relatively early event in pancreatic tumorigenesis, whereas alteration of the p16 gene is more likely to be correlated with tumor progression in pancreatic malignancies. Further survival analysis revealed that all five of the 32 cases that survived for three years or longer had positive immunostaining for p16 protein, and a relatively low level of AgNOR counts. In four out of five of these patients, the tumors also exhibited negative immunostaining for p53 protein and DNA diploidy. These findings suggest that molecular analysis of patient tumor sections may yield potentially useful prognostic indicators for patients undergoing surgical resection for pancreatic cancer.     

Primary chondrosarcoma of long bones and limb girdles

BACKGROUND: Chondrosarcomas are common solid malignant tumors of bone, second in incidence only to osteosarcomas. The biologic evolution of chondrosarcomas is slow, requiring long follow-up intervals for meaningful survival analysis. METHODS: This study describes the clinicopathologic profiles of 344 patients, 194 male and 150 female (M:F, 1.3:1.0), with primary chondrosarcoma of long bones and limb girdles seen at 1 institution over a period of 80 years. RESULTS: The average age at presentation was 46 years (range, 5-82 years). The pelvis was the most common location (1.7% of all patients). Local pain was the most frequently reported initial symptom (81.4%). Survival analysis was limited to 233 patients whose primary treatment was given at the Mayo Clinic. All 233 patients had potential follow-up of at least 5 years. The overall 5-year survival rate was 77% (the expected rate was 96%). Local recurrence developed in 19.7% of patients and metastatic lesions in 13.7%. The recurrence rate was higher for tumors of the shoulder and pelvis than for tumors of long bones. Radiographically, chondrosarcomas had a characteristic appearance, including a combination of bone expansion and cortical thickening. Entering the tumor at surgery increased the risk of local recurrence. Histologic tumor grade was an important predictor of local recurrence and metastasis. CONCLUSIONS: With adequate initial surgical intervention, chondrosarcoma is primarily a local disease with a low metastatic rate.     

Surgical aspects in the multidisciplinary treatment of soft tissue sarcomas

Sarcomas are rare malignant tumors with a large variety of histologic subtypes. The surgical approach depends more on the histologic grade, the size and the site of the tumor. Radiologic diagnosis relies predominantly on MR-imaging. Discernible improvements have taken place in soft tissue sarcoma patient survivorship and quality of life over the past 20 years, with overall 5-year survival currently at approximately 50-80%. The place of surgery in the treatment of soft-tissue sarcoma is defined in the light of a review of the recent literature. Radical surgical resection is the mainstay of therapy. Local recurrence is the most common type of failure. Local recurrence is resectable and limb preservations possible in the majority of patients. Survival after treatment of local recurrence is determined mainly by the grade and secondarily by the size of the tumor. The essential risk factor for local recurrence is the quality of surgical resection, defined by the definitive resection margins. A lateral safety margin of 5 cm and of 2 cm to the depth should be respected. In sarcoma of the extremity the compartment is defined based on clinical, radiographic, histopathologic and operative findings. The use of muscle flaps to fill the surgical defects can improve the functional result and reduce the complication rate. Only about 5% of the patients need amputation. Evaluation of functional results must be based on objective criteria. In retroperitoneal sarcoma the significant factors for determining prognosis are grade and completeness of exzision. Multidisciplinary treatment according to common protocols is essential. Shifts in treatment have taken place over the past decade, from single-modality treatment involving radical surgery with compartment resection to sophisticated limb-salvage strategies combined with radiation therapy. In case of inadequate surgery e.g. in a large tumor with positive margins in high-grade soft tissue sarcomas the addition of radiotherapy can improve local control, but cannot ensure that obtained by adequate surgery. Patients with large (greater than 5 cm), high grade soft tissue sarcoma are at high risk for distant recurrence and disease-related mortality. Investigations of combined modality therapy with newer chemotherapy agents and dose intensification treatment strategies are warranted.     

Preoperative radiation, surgical margins, and local control of extremity sarcomas of soft tissues

The relationship between status of the surgical margin and local control of soft tissue sarcoma of the extremities by preoperative radiation therapy has been assessed in 132 consecutive patients from 1974 to 1988. The 5-year actuarial local control rate was 94% for all patients; the rates were 97% and 82% for the 104 tumors with negative margins and the 28 tumors with positive margins, respectively. The local control rate was independent of the extent of the negative margin. For primary sarcomas, the local control rates were 96%, 97%, and 100%, respectively, for margins that were negative at < or = 1 mm or > 1 mm, or the specimens were negative for tumor; for positive margins the result was 83%. The overall local control rate was lower (not significant) for recurrent than for primary sarcomas: 88% vs. 94%. On the other hand, when stratifying by margin status, no difference was observed in local control results, i.e.: (1) 97% and 91% for primary and recurrent tumors with negative margins, respectively, and (2) 83% and 80% for primary and recurrent tumors with positive margins, respectively. Local control was not significantly higher in those patients who were treated by surgical resection (S), radiation (RT), and re-excision of the previous tumor bed than in those whose radiation therapy was started after the biopsy and followed by one surgical resection. For primary sarcomas that were resected with negative margins the results were: 100% of 15 patients treated by S-RT-S and 96% of 75 patients treated by RT-S.     

Recurrence of meningiomas versus proliferating cell nuclear antigen (PCNA) positivity and AgNOR counting

Meningiomas have a wide range of biological potential and clinical behaviour. Histological findings are helpful in recognizing the malignant potential but often fail to correlate with clinical behaviour. This study attempts to correlate the silver nucleolar organizer regions (AgNORs) and proliferating cell nuclear antigen (PCNA) with clinicopathological features of biological activity. Thirty-four completely resected meningiomas were classified as benign [19], atypical [6] and malignant [9]. Forty-eight initial and recurrent tumour materials were investigated for staining of AgNORs and immunohistochemistry using monoclonal antibodies against PCNA (clone 19A2 and PC10). There were no difference between the recurrent and non-recurrent cases with regards to AgNOR, PC10 and 19A2 values. Also, no significant difference was found between the primary and recurrent tumours. Both PC10 and 19A2 labelling indices (LI) showed a significant difference between benign and malignant meningiomas. The 19A2 LI was 0.56 +/- 0.21 in benign and 2.45 +/- 16 in atypical meningiomas. The 19 A2 counts showed significant difference between benign and atypical tumours but PC10 values failed to show such a correlation AgNOR and PCNA indices were not found to be useful in predicting recurrences compared to the surgical procedure and histopathological criteria.     

Triple arthrodesis with lateral column lengthening for treatment of severe planovalgus deformity

The occurrence of abnormal nuclear DNA content in major salivary gland adenomas is not well known and its correlation with tumor recurrence has not been documented previously. From 1987 to 1991, 119 consecutive major salivary gland adenomas were operated on at Turku University Central Hospital. These tumors were analyzed by flow cytometry and 100 (84%) were found to be diploid, 12 (10%) near-diploid and 7 (6%) aneuploid with DNA indexes > 1.15. The mean proliferation rate measured as a percentage of cells in the S-phase fraction was 2.5 +/- 1.6%. The histological slides were then blindly reclassified according to current World Health Organization classification. As a result histological classification was changed in 3 tumors: malignant cells were found in 2 aneuploid tumors and 1 diploid neoplasm. Preoperative cytological fine-needle aspiration biopsy had been considered as possibly malignant in 2 of these cases. Among all case material 10 specimens were recurrent tumors; although the tendency to recur depended on the extent and adequacy of the surgery performed, multiple recurrences were associated with non-diploid tumors.     

Prognostic features of teratomas with malignant transformation: a clinicopathological study of 21 cases

PURPOSE: Teratomas with malignant transformation comprise up to 6% of metastatic teratomas. The prognosis of patients with these tumors can vary considerably. We delineate factors that may be related to prognosis in a cohort of men with teratoma with malignant transformation. MATERIALS AND METHODS: We analyzed pathological features, treatment, response, recurrence, time to recurrence, subsequent followup and survival for 21 patients (median age 28 years) diagnosed with teratoma with malignant transformation during a 7-year period at our institution. RESULTS: Malignant nongerm cell elements were present in the primary tumor in 11 cases (52%). Of 18 patients with testicular primaries 17 (94%) presented with metastatic disease. Despite aggressive treatment with surgery and chemotherapy 17 of 21 cases (81%) recurred (median time 6 months). Overall, 5 patients (24%) died of disease (median survival 23 months), 5 (24%) are alive with metastases (median followup 41 months) and 11 (52%) have no evidence of disease (median followup 50 months). Progression/recurrence was substantially greater for 2 of 2 cases with a mediastinal origin, 3 of 4 with rhabdomyosarcomatous differentiation and 5 of 6 with neural differentiation compared with the remainder of the cohort (p < 0.05). CONCLUSIONS: Teratomas with malignant transformation are usually metastatic at presentation, have a high recurrence rate and are more aggressive than teratomas without malignant transformation. Prognosis is especially poor for mediastinal teratomas with malignant transformation and for those with neural or rhabdomyosarcomatous differentiation. Complete surgical resection of residual or recurrent disease appears to offer the best chance for prolonged survival.     

Postradiation sarcoma of bone: review of 78 Mayo Clinic cases

Postradiation sarcoma of bone is an uncommon but serious sequela of radiation therapy. Seventy-eight Mayo Clinic patients have been treated for sarcomas arising in irradiated bones. They received their initial radiotherapy for a wide variety of nonneoplastic and neoplastic conditions, both benign and malignant. Thirty-five sarcomas arose in bone that was normal at the time of radiotherapy, and 43 arose in irradiated preexisting osseous lesions. The latent period between radiotherapy and diagnosis of sarcoma averaged 14.3 years. Ninety percent of the postradiation sarcomas were either osteosarcomas or fibrosarcomas; chondrosarcoma, malignant (fibrous) histiocytoma, malignant lymphoma, Ewing's tumor, and metastasizing chondroblastoma also occurred. Prompt radical surgery, when feasible, is usually the treatment of choice for the sarcoma. About 30% of patients with sarcomas of the extremities or craniofacial bones survived 5 years without recurrence; there were no disease-free survivors among patients with tumors of the vertebral column, pelvis, or shoulder girdle. The low risk of sarcoma following radiotherapy for the treatment of cancer should not be a contraindication to its use in these patients; however, radiation therapy for benign bone tumors should be reserved for lesions that are not amenable to surgical treatment. An unusual case is also reported herein in which a fibrosarcoma was discovered in the humerus of a patient who had received radiotherapy 55 years previously for a verified osteosarcoma in the same site.     

Nucleolar organizer regions in human maxillary sinus squamous cell carcinoma

A silver colloid technique for nucleolar organizer regions (AgNOR) was applied to paraffin sections of maxillary sinus squamous cell carcinomas (MSSCC) of 25 patients. The patients were divided into two groups, one with MSSCC recurring in the primary lesion after treatment with radiotherapy, chemotherapy and/or surgery and one without recurrence. Notable differences between the numbers of NOR in neoplastic epithelia and the normal mucosa were observed (P = 0.0001), but there were no differences between the numbers of NOR in the recurrent and non-recurrent carcinomas. This investigation found no prognostic importance in the number of AgNOR in MSSCC.     

Fine-needle aspiration biopsy of synovial sarcoma. A cytomorphologic analysis of primary, recurrent, and metastatic tumors

Thirteen fine-needle aspiration specimens from 10 patients with histologically proven synovial sarcoma are described. The aspiration biopsy specimens were obtained from the primary tumor in five cases, locally recurrent tumors in four cases, pulmonary metastases in three cases, and mediastinal metastasis in one case. Patient's ages ranged from 22 years to 65 years; there were four women and six men. All cases had a confirmation biopsy and/or resection specimen that were reviewed. Histologic subtypes included monophasic fibrous (5 cases), monophasic epithelial (1 case), biphasic (3 cases), and poorly differentiated (1 case). The majority of the aspiration biopsy specimens were similar with moderate to marked smear cellularity dominated by cohesive clusters of spindle-shaped cells with ovoid, hyperchromatic nuclei and scanty tapering cytoplasm. Nucleoli were not prominent. Epithelial tumor cells with ovoid to round, mostly regular, centrally to eccentrically located nuclei, surrounded by scant to abundant cytoplasm predominated in one case (monophasic epithelial) and were admixed with spindle cells in a second (classical biphasic). Multi-nucleated tumor giant cells were not observed in any of the tumors. In biphasic synovial sarcoma, the neoplastic spindle cells are generally more numerous and frequent than the epithelial cells, making distinction from monophasic synovial sarcoma or other spindle cell soft tissue tumors difficult. Although synovial sarcoma may be diagnosed by fine-needle aspiration cytology, clinical correlation, especially in monophasic types, is necessary to minimize errors in sarcoma classification.     

Effects of apafant on PAF-induced downregulation of beta-adrenoceptors in guinea pigs

The phase S ratio in cell cycles were analyzed in livers with hyperplastic foci (HPF) and in livers without HPF by nuclear DNA determinations using flow cytometry, and by staining with argyrophilic proteins of the nucleolar organizer region (AgNOR). Flow cytometric analysis was done on 50 fresh frozen specimens of livers resected from 50 patients with hepatocellular carcinoma (HCC). Paraffin sections from the same patients were analyzed using AgNOR staining. There were 25 cases each with and without HPF. We examined the stage of fibrosis and the grade of inflammatory activity according to the modified Scheuer and Desmet scale. The incidence of HCC recurrence among these patients was also studied. The average phase S ratio of the livers of the patients with HPF was 6.5 +/- 3.2%, and that of the livers of the patients without HPF was 4.0 +/- 2.5%. The ratio differed significantly between the two groups (P < 0.01). The average AgNOR score for HPF lesions of the HPF-positive cases was 1.60 +/- 0.34, that for non-HPF lesions in the HPF-positive cases was 1.29 +/- 0.12, and that for the HPF-negative cases was 1.19 +/- 0.14. Significant differences were found between the average AgNOR scores for HPF lesions of the HPF-positive cases and the non-HPF lesions of the HPF-positive cases (P < 0.01), as well as between the non-HPF lesions in the HPF-positive cases and the HPF-negative cases (P < 0.05). Severe fibrosis (stage 3) and cirrhosis (stage 4) were found in 76% of HPF-positive cases and 48% of HPF-negative cases. The livers of HPF-positive patients were significantly more cirrhotic than those of HPF-negative patients (P < 0.05). The association between HPF and the inflammatory grade was not significant (P > 0.05). The incidence of HCC recurrence among HPF-positive cases was significantly higher than that among the HPF-negative cases (P < 0.05). The average phase S ratio of the recurrent HPF-positive patients was 7.48 +/- 3.48%, significantly higher than that of HPF negative cases (5.57 +/- 3.06%, P < 0.05). Hyperplastic foci of the liver was shown to be a highly proliferative lesion. The proliferative activity of the non-HPF lesions in the HPF-positive patients was also higher than that of the HPF-negative patients. Hyperplastic foci tended to be present in cirrhotic livers, but it was not associated with the grade of inflammatory activity of the liver. Hyperplastic foci may represent an important predictor of recurrence after hepatic resection.     

Circumferential margin involvement after mesorectal excision of rectal cancer with curative intent. Predictor of survival but not local recurrence?

PURPOSE: This study examines the prognostic significance of circumferential margin involvement by tumor in resected specimens after potentially curative rectal cancer surgery. METHODS: During an eight-year period, all patients with rectal cancer were prospectively audited. For tumors of the middle and lower thirds of the rectum, a total mesorectal excision was performed; for tumor of the upper third, mesorectal excision proceeded at least 5 cm distal to the primary tumor. Resected specimens were subjected to careful histologic assessment, and patients undergoing curative procedures were entered into a surveillance program to detect both local and distant recurrence. RESULTS: Of 218 patients in the cohort, 9 had no resection, 14 underwent local excision, 1 had pre-operative radiotherapy, and 42 patients (20 percent) had palliative resections and were excluded from further analysis. This left 152 patients having a curative resection, of whom 20 (13 percent) had tumor within 1 mm of the circumferential margin. After follow-up until death or a median period of 41 months, recurrent disease was seen in 24 percent of patients with a negative margin and 50 percent with a positive margin. Both disease-free survival and mortality were significantly related to margin involvement (log-rank, P = 0.01 and P = 0.005, respectively). Local recurrence, however, was not significantly different in the two groups (11 and 15 percent, respectively; log-rank, P = 0.38). CONCLUSIONS: When mesorectal excision is performed, circumferential margin involvement is more an indicator of advance disease than inadequate local surgery. Patients with an involved margin may die from distant disease before local recurrence becomes apparent.     

Soft tissue sarcomas

Soft tissue sarcomas are relatively rare tumors with an annual incidence of 5000 to 6000 in the United States. The primary therapy is surgical resection with an adequate margin of normal tissue. For patients at high risk local control is improved with postoperative adjuvant radiation. Local recurrence rates vary depending on the anatomic site. In extremity lesions one third of patients will have locally recurrent disease with a median disease-free interval of 18 months. Treatment results for extremity local recurrence may approach those for primary disease. Isolated pulmonary metastases may be resected with 20% to 30% 3-year survival rates. Patients with sarcomas in other sites present similar but more difficult problems in terms of local control and management of disseminated disease. Patients with unresectable pulmonary metastases or extrapulmonary metastatic sarcoma have a uniformly poor prognosis and are best treated with systemic chemotherapy.     

Coronary bypass surgery: what is changing? Analysis of 3834 patients undergoing primary isolated myocardial revascularization

We have previously demonstrated in primary cancer of the uterine cervix that tumor hypoxia, as determined polarographically, is strongly associated with clinical malignant progression of the disease. Having applied a similar methodological approach to investigate loco-regional relapses, we found a pronounced shift to more hypoxic oxygenation profiles in the recurrent tumors than in the primary tumors. Median pO2 values in 53 pelvic recurrences were significantly lower than the median pO2 values of 117 primary tumors of comparable sizes (7.1 +/- 1.1 mmHg vs. 12.1 +/- 1.0 mmHg, p = 0.0013). The differences in tumor oxygenation between primary and recurrent tumors mirrored the differences in the patients' 5-year survival probabilities. In the cohort of patients with pelvic relapses, median tumor pO2 < 4 mmHg indicated a significantly shorter median survival time as compared to median tumor pO2 > or = 4 mmHg. Our results further support our thesis that in cervical cancer, tumor hypoxia and clinical aggressiveness in terms of resistance to therapy and tumor dissemination, are interrelated.     

Tumor-associated antigens as prognostic factors for recurrence in 382 patients with primary transitional cell carcinoma of the bladder

This prospective study was designed to assess the prognostic value of tumor-associated antigens, designated 19A211, M344, T138, and T43, with respect to recurrence of primary superficial bladder cancer. Between September 1990 and April 1992, all patients with primary superficial bladder tumors treated by endoscopic resection in 15 participating hospitals were enrolled. Immunostaining for 19A211 and M344 was performed on paraffin-embedded material, and for T43 and T138 on frozen tissue. Antigenic expression was evaluated blindly by a single pathologist. Patients were followed up with the standard schedule of control cystoscopies. Cox regression was used to estimate hazard ratios (HRs) for first recurrence, and Poisson regression was used to estimate recurrence rate ratios and tumor rate ratios adjusted for primary tumor characteristics. By March 1994, 2254 follow-up cystoscopies had been performed on 368 of the 382 study patients, and tumor recurrence was detected in 55.7% of patients. Positivity to 19A211 was detected in 90% of primary tumors, its expression being associated with a decrease in first recurrence hazard ]HR, 0.65; 95% confidence interval (CI), 0.42-1.03] and in recurrence rate (recurrence rate ratio, 0.70; 95% CI, 0.53-0.92). Positivity to T138 was detected in 15% of tumors, and its expression was associated with an increase in first recurrence hazard (HR, 1.43; 95% CI, 0.92-2.22) and in recurrence rate (recurrence rate ratio, 1.31; 95% CI, 1.00-1.72). Positivity to M344 was detected in 71% of tumors, and its expression was associated with an increase in tumor rate (tumor rate ratio, 1.77; 95% CI, 1.41-1.97). T43 expression was not associated with recurrence end points. In conclusion, recurrence of superficial bladder cancer was associated with antigenic expression of 19A211, T138, and M344, independently of primary tumor characteristics.     

Stromal tumors of the jejunum and ileum: a clinicopathologic study of 39 cases

Recently, cell size, cell density, and growth pattern were found to be reliable histologic parameters in separating benign from malignant duodenal stromal tumors. However, there are few data on the histologic features and important prognostic parameters of stromal tumors from other parts of the small bowel. Thus, we studied the clinical and pathologic features of 39 stromal tumors of the jejunum and ileum to determine which parameters would be most useful in distinguishing a benign from a malignant tumor. In all cases, the following histologic parameters were recorded: (a) predominant growth pattern (organoid, fascicular, solid, or mixed), (b) cellularity (low or high), (c) predominant cell type (spindled, epithelioid, or mixed), (d) nuclear pleomorphism (minimal, moderate, or severe), (e) the presence or absence of tumor cell necrosis, (f) the presence or absence of mucosal infiltration, (g) the presence or absence of skeinoid fibers, and (h) the number of mitotic figures per 50 high-power microscopic fields (HPF). Clinical follow-up was obtained in all cases, and the patients were considered to have suffered an adverse outcome if they developed metastatic disease or died as a complication of their tumor. In the absence of these features, patients were not considered to have suffered an adverse outcome. Twenty-five patients suffered an adverse outcome. Twenty-one patients died of disease from 1 month to 9 years (median: 2 years). One patient died at 4 days because of postoperative complications. Three patients were alive with metastatic disease at 6 months, 6 years, and 7 years. Twenty-four of these 25 patients developed metastatic disease, most commonly to the liver. Fourteen patients did not suffer an adverse outcome. Eleven patients were alive without disease from 2 to 11 years (median: 3 years), and three patients died of unrelated causes at 1, 1, and 3 years. Although there was some overlap in features between clinically benign and malignant tumors, features that were significantly associated with an adverse outcome included tumor size > 5 cm, mitotic counts > 5 mitotic figures per 50 HPF, high cellularity, the absence of a predominant organoid growth pattern, the absence of skeinoid fibers, the presence of severe nuclear pleomorphism, and the presence of mucosal infiltration and tumor cell necrosis (p < 0.05 using the chi-square and Fisher's exact tests). Features that were significantly associated with decreased survival included tumor size > 5 cm, mitotic counts > 5 mitotic figures per 50 HPF, high cellularity, the absence of skeinoid fibers, and the presence of tumor cell necrosis (p < 0.05 using the Mantel-Haenszel log-rank test). Given the fact that there is some overlap in these features between clinically benign and malignant tumors, a multiparametric analysis using the above features is the most effective way of predicting clinical behavior.     

Local recurrence versus new primary: clinical analysis of 82 breast relapses and potential applications for genetic fingerprinting

PURPOSE: The purpose of this study was to perform a detailed clinical pathological analysis of breast relapses in patients treated with conservative surgery and radiation therapy in an effort to classify those relapses as true local recurrences or second primary tumors, and to assess the prognostic and therapeutic implications of such a classification system. METHODS AND MATERIALS: Of 990 patients treated with conservative surgery and radiation therapy at our facilities prior to December 1987, 82 patients have experienced a relapse in the conservatively treated breast as the primary site of failure. Patients were classified as having new primary tumors if they fulfilled any one of the following criteria: a) breast relapse occurring at a site distinctly removed from the original tumor; b) histology of the breast relapse compared with the original tumor consistent with a new primary; or c) DNA flow cytometry converting from an aneuploid primary to a diploid relapse. RESULTS: As of 2/92, with a median follow-up of 5.4 years from the time of breast relapse, the overall 5-year survival rate following breast relapse was 55%. Forty-seven patients were classified as true recurrences and 33 patients were classified as new primaries. Patients classified as true recurrences had a shorter median time to breast relapse than patients classified as new primaries (3.16 years vs. 5.42 years, p < .05) and an inferior post breast recurrence survival rate compared to patients classified as new primaries (36% vs. 89%, p < .05). Residual disease outside of the recurrent tumor bed was also noted to be more frequent in patients classified as true recurrences compared to patients classified as new primaries (48% vs. 16%, p < .05). CONCLUSION: Based on the clinical and pathological criteria outlined, it appears that a significant portion of patients experiencing a relapse in the conservatively treated breast may have new primary tumors as opposed to true local relapses. Distinction between a true recurrence and a new primary tumor may have significant prognostic implications. Uncertainties associated with the clinical and pathological criteria are presented and further investigations with genetic fingerprinting techniques to establish the clonality of breast relapses are presented and discussed.     

Selective activation of rolipram-sensitive, cAMP-specific phosphodiesterase isoforms by phosphatidic acid

BACKGROUND: Regulatory coupling of cell proliferation and apoptosis is suggested by recent findings with regard to certain tumors, such as the finding of tumor resistance to anticancer therapy caused by inhibition of apoptosis. The processes leading to apoptosis appear to be regulated by a variety of oncogenes and tumor suppressor genes. In the current study, the relation between apoptosis and expression of retinoblastoma protein (pRB) was assessed in 50 primary anaplastic astrocytomas (AAs) and 46 recurrent tumors in the same patients as the primary tumors after macroscopic total surgical resection and chemoradiotherapy. METHODS: Apoptotic cells were identified by the in situ 3'-end labeling technique. Proliferative potential, pRB expression, and p53 expression were evaluated immunohistochemically using anti-Ki-67 (MIB-1), anti-pRB, and anti-p53 antibodies, respectively. The prognostic value of these biologic markers in AA patients undergoing treatment was also evaluated. RESULTS: The mean apoptotic index (AI) was 0.91 +/- 0.70% for specimens obtained at the initial surgery and 2.32 +/- 1.71% for those obtained at recurrence. There was no apparent correlation between the AI and the MIB-1 staining index (MI) in primary AAs, whereas significantly higher AI and MI were observed in recurrent pRB negative cases than in their pRB positive counterparts. The survival of patients with AAs showing a high MI and negative pRB immunostaining was significantly shorter than in the other cases. Neither the size of the apoptotic fraction nor the p53 expression in primary tumor correlated with the overall survival. CONCLUSIONS: The clinical outcome of patients with AA may be associated with aberrant pRB function and increased proliferative activity rather than an inability of tumor cells to undergo apoptosis.