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Biomedical subjects

J L Connolly

Publications and source records attributed to J L Connolly.

At least 55 records · Page 3Linked to original sources
PubMed1995

Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer.

Solid tumors must induce a vascular stroma to grow beyond a minimal size, and the intensity of the angiogenic response has been correlated with prognosis in breast cancer patients. Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a secreted protein that has been implicated in tumor-associated angiogenesis. Vascular permeability factor directly stimulates endothelial cell growth and also increases microvascular permeability, leading to the extravasation of plasma proteins, which alter the extracellular matrix in a manner that promotes angiogenesis. To determine whether VPF has a role in breast cancer, we used in situ hybridization to study VPF mRNA expression in normal breast tissue (13 specimens), comedo-type ductal carcinoma in situ (DCIS) (four specimens), infiltrating ductal carcinoma (12 specimens), infiltrating lobular carcinoma (two specimens), metastatic ductal carcinoma (three specimens) and metastatic lobular carcinoma (one specimen). Vascular permeability factor mRNA was expressed at a low level by normal duct epithelium but was expressed at high levels in tumor cells in all cases of comedo-type DCIS, infiltrating ductal carcinoma, and metastatic ductal carcinoma. In contrast, VPF mRNA was not expressed at high levels in infiltrating lobular carcinoma. We also used in situ hybridization to study the expression of two recently described endothelial cell surface VPF receptors, flt-1 and kdr. Vascular permeability factor receptor mRNA was strongly expressed in endothelial cells of small vessels adjacent to malignant tumor cells in DCIS, infiltrating ductal carcinoma, and metastatic ductal carcinoma. In contrast, no definite labeling for receptor mRNA was detected in infiltrating lobular carcinoma or nonmalignant breast tissue. The intense expression of VPF mRNA by breast carcinoma cells and of VPF receptor mRNA by endothelial cells of adjacent small blood vessels provides strong evidence linking VPF expression to the angiogenesis associated with comedo-type DCIS, infiltrating ductal, and metastatic ductal breast carcinoma.

Breast Neoplasms↗
PubMed1994

The relationship between microscopic margins of resection and the risk of local recurrence in patients with breast cancer treated with breast-conserving surgery and radiation therapy.

BACKGROUND: The relationships among the involvement of tumor at the final margins of resection, the presence of an extensive intraductal component (EIC), and the risk of local recurrence are important considerations in patients treated with conservative surgery and radiation therapy for early stage breast cancer but have not been defined adequately. METHODS: Between 1982 and 1985, 885 patients were treated for clinical Stage I or II invasive breast cancer. The study population was limited to 181 patients with an infiltrating ductal carcinoma who received a radiation dose to the surgical site of 60 Gy or greater, whose final microscopic margins of resection were evaluable, and who had at least 5 years of follow-up. A positive margin was defined as tumor present at the inked margin of resection, a close margin as tumor within 1 mm of the inked margin, and a negative margin as no tumor within 1 mm of the inked margin. A focally positive margin was defined as tumor at the margin in three or fewer low-power fields. In 157 patients (87%), the tumor was evaluable for the presence or absence of an EIC. The median follow-up was 86 months. RESULTS: In 12 of 181 patients (7%), a recurrence developed at or near the primary site (true recurrence/marginal miss [TR/MM]) within 5 years. The 5-year rate of TR/MM (with 95% confidence intervals) among patients with negative, close, focally positive, and more than focally positive margins was 0% (0-4%), 4% (0-20%), 6% (1-17%) and 21% (10-37%), respectively. Patients with positive margins also were more likely to have a distant failure within 5 years (14%, 8%, 25%, and 32% in the four groups, respectively). However, patients with positive margins more often had positive axillary lymph nodes than patients with negative or close margins (59% vs. 38%, P < 0.02). The 5-year rate of TR/MM was 20% for patients with an EIC-positive tumor and 7% for patients with an EIC-negative tumor. However, among the 127 patients with an EIC-negative tumor, the 5-year rate of TR/MM was less than 10% in all margin groups. Among the 30 patients with an EIC-positive tumor, the 5-year rate of TR/MM was 0% when margins were negative or close but 50% when margins were more than focally positive. CONCLUSIONS: These results provide support for the use of breast-conserving surgery and breast irradiation in all patients with uninvolved margins, whether the tumor is EIC-positive or EIC-negative. This study suggests that breast-conserving therapy (including a radiation boost to the primary site) also may be a reasonable option for some patients with an EIC-negative tumor and margin involvement.

Breast↗
PubMed1994

The relation between the surgery-radiotherapy interval and treatment outcome in patients treated with breast-conserving surgery and radiation therapy without systemic therapy.

PURPOSE: This analysis was performed to clarify the relationship between the surgery-radiotherapy interval and the risk of recurrence in patients treated with breast-conserving therapy for early stage invasive cancers. METHODS AND MATERIALS: We retrospectively analyzed data from 653 patients with American Joint Commission on Cancer Stage I or II, pathologically node-negative breast cancer treated by breast-conserving therapy without adjuvant systemic therapy between 1968 and 1985. All patients received a dose of at least 60 Gy to the tumor bed. Two hundred and eighty-three patients started radiotherapy within 4 weeks of surgery, 308 started 5-8 weeks after surgery, and 54 started 9-12 weeks after surgery. Median follow-up in the 531 survivors was 100 months. RESULTS: Pathologic features and treatment characteristics were well balanced between the groups with surgery-radiotherapy intervals of 0-4 weeks and 5-8 weeks. There was no statistically difference in the risk of overall recurrence among patients starting radiotherapy 5-8 weeks after surgery compared with those treated within 4 weeks. Analysis of the 5-year crude rates of failure further demonstrated no difference in the distribution of sites of failure in the 5-8 week group compared with the 0-4 week group. A multivariate model controlling for known risk factors, as well as potential treatment-related confounders, also failed to demonstrate an increased risk of recurrence with the longer surgery-radiotherapy interval (risk ratio = 0.89, p = 0.44). CONCLUSION: This retrospective analysis suggests that a delay of up to 8 weeks in the interval between the last breast surgery and the start of radiotherapy is not associated with an increased risk of recurrence in patients with early stage breast cancer treated with breast irradiation to at least 60 Gy without systemic therapy.

Analysis of Variance↗
PubMed1994

Relationship of patient age to pathologic features of the tumor and prognosis for patients with stage I or II breast cancer.

PURPOSE: This analysis was performed to clarify the relationship of young age at diagnosis to the pathologic features of the tumor and prognosis in patients with early-stage breast cancer. PATIENTS AND METHODS: We retrospectively analyzed data from 1,398 patients with American Joint Committee on Cancer Staging stage I or II breast cancer treated by breast-conserving therapy between 1968 and 1985. One hundred seven patients were younger than 35 years at the time of diagnosis. The median follow-up duration for the 1,032 survivors was 99 months. RESULTS: Patients younger than 35 years had a significantly higher overall recurrence rate (P = .002), as well as a greater risk for developing distant metastases (P = .03), when compared with older patients. The cancers in younger patients more commonly showed factors associated with a worse prognosis (including grade 3 histology, lymphatic vessel invasion [LVI], necrosis, and estrogen receptor [ER] negativity) as compared with older patients. In a proportional hazards model that included clinical and treatment-related variables, as well as these pathologic features, age younger than 35 years remained a significant predictor for time to recurrence (relative risk [RR], 1.70), time to distant failure (RR, 1.60), and overall mortality (RR, 1.50). CONCLUSION: Breast cancer patients younger than 35 years have a worse prognosis than older patients. This difference is only partially explained by a higher frequency of adverse pathologic factors seen in younger patients.

Actuarial Analysis↗
PubMed1993

Clinical and histologic aspects of proliferative and non-proliferative benign breast disease.

It has been known for years that benign breast disease is correlated with an increased risk for the development of breast cancer. Over the years, there have been many studies linking histological changes in benign breast biopsies and subsequent risk of breast cancer. In many of these reports, there was no attempt to standardize criteria and often the patient population under study was relatively small. Over the past decade, three large groups have agreed to use the same definition of benign changes and a unified set of criteria for the diagnosis of these lesions. The results from these three groups [Nashville, Nurses Health Study (NHS), and the Breast Cancer Detection Demonstration Project (BCDDP)] are strikingly similar. All three studies reported that if the biopsy revealed proliferative disease without atypia, the subsequent risk was approximately 1.5x. If the biopsy revealed atypical hyperplasia (AH), the risk was approximately 4.5x. If the patients with AH had a family history of breast cancer, their subsequent risk approached that of patients with in situ carcinoma (approximately 8-10x). In addition to family history, menopausal status seemed to play a role. In patients with AH, the breast cancer risk was much higher in pre- than post-menopausal patients. While the classification scheme proposed by Page and co-workers is useful in assigning different levels of risk to women with benign breast disease, it has not been universally accepted. Our major short-term goal should be to encourage pathologists to apply these criteria in a reproducible manner in their daily practice.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Diseases↗
PubMed1993

Prognosis following salvage mastectomy for recurrence in the breast after conservative surgery and radiation therapy for early-stage breast cancer.

PURPOSE: The prognosis and factors that influence prognosis following salvage mastectomy in patients with recurrence in the treated breast after conservative surgery (CS) and radiation therapy (RT) were investigated. MATERIALS AND METHODS: A total of 1,593 patients with stage I or II invasive breast cancer were treated following gross total excision of the tumor at the Joint Center for Radiation Therapy (JCRT) between 1968 and 1985. One hundred sixty-six of the 1,593 (10%) had subsequent recurrence in the breast. Of these, 123 had salvage mastectomy and constitute the study population. The recurrent tumor was predominantly invasive in 99 patients, noninvasive in 14, and focally invasive in 10. Following mastectomy, chemotherapy or hormonal therapy was administered to 29 patients. The median follow-up time was 39 months after salvage mastectomy. RESULTS: The 5-year actuarial rate of further local or distant relapse for the entire group was 41%. None of the 24 patients with focally invasive or noninvasive tumors had a subsequent relapse. In comparison, the 5-year actuarial rate of further relapse in the 99 patients with a predominantly invasive recurrence was 52% (P = .001). The method of detection of the recurrence, the age of the patient at initial diagnosis, the disease-free interval, and the location of the recurrence in the breast were not found to have a statistically significant association with the risk of further relapse. CONCLUSION: We conclude that the histology of the recurrent tumor is an important prognostic factor for the risk of further relapse. Patients with purely noninvasive or focally invasive tumors have an excellent prognosis following salvage mastectomy. In contrast, patients with predominantly invasive tumors are at substantial risk for further relapse.

Adult↗
PubMed1993

Contralateral breast cancer: clinical characteristics and impact on prognosis.

PURPOSE: To determine the characteristics of patients with unilateral breast cancer who subsequently develop contralateral breast cancer (CBC), to assess their prognosis relative to patients who do not develop a CBC, and to assess the feasibility of using conservative surgery (CS) and radiotherapy (RT) to treat CBC. MATERIALS AND METHODS: Of 1,624 women treated with CS and RT for unilateral stage I or II breast cancer at the Joint Center for Radiation Therapy, 77 developed an invasive CBC. Sixty-two CBCs were treated with CS and RT. The median follow-up duration was 95 months from the time of initial breast cancer diagnosis, and 63 months from CBC diagnosis. RESULTS: The cumulative actuarial rate of CBC was 7.0% at 10 years, and the annual incidence rate for CBC was relatively constant. Young age predicted for CBC. When age was analyzed by decade the relative risk (RR) for older patients compared with younger patients was 0.79 (95% confidence interval [CI], 0.62 to 1.01). The presence of lobular carcinoma in situ (LCIS), higher tumor stage, and lack of adjuvant systemic therapy also predicted for CBC with borderline significance. Multivariate analyses showed that CBC was associated with a statistically significant greater likelihood of local recurrence (LR) or distant recurrence (RR, 1.68; 95% CI, 1.03 to 2.71), and distant-only recurrence (RR, 2.17; 95% CI, 1.28 to 3.69). Among assessable patients treated with bilateral RT, 28 of 31 ipsilateral and 11 of 11 contralateral breasts had an excellent or good overall cosmetic outcome at 5 years, and treatment-related complications were minimal. CONCLUSION: We conclude that (1) young age is associated with a greater likelihood of CBC, (2) patients who develop a CBC have a greater subsequent risk of distant relapse as compared with patients without CBC, and (3) it is feasible to deliver sequential nonoverlapping bilateral RT without compromising the cosmetic outcome or increasing complications.

Adult↗
PubMed1992

A prospective study of benign breast disease and the risk of breast cancer.

OBJECTIVE: To examine the relation between proliferative benign breast disease with and without atypical hyperplasia and the subsequent risk of breast cancer. DESIGN: Case-control study nested within a prospective cohort study. Median follow-up after breast biopsy was 8 years (25th to 75th percentile, 5 to 14 years). PARTICIPANTS: Selected from a prospective cohort of 121,700 US registered nurses followed up from 1976 to 1986. Cases were women with breast cancer who had a prior biopsy for benign breast disease. Controls were randomly selected and matched on year of biopsy and year of birth from among women in the cohort who had a benign breast biopsy but who did not develop breast cancer. Included in the analysis were 121 cases and 488 controls. MAIN OUTCOME MEASURE: Development of breast cancer. RESULTS: Slides from the first benign breast biopsy were reviewed by two breast pathologists blinded to the outcome. The multiply adjusted relative risks (RRs) for breast cancer, relative to women with no proliferative disease, were 1.6 for proliferative disease without atypia (95% confidence interval [Cl], 1.0 to 2.5) and 3.7 for atypical hyperplasia (95% Cl, 2.1 to 6.8). Breast cancer risk was more strongly associated with atypical hyperplasia among premenopausal women (RR = 5.9; 95% Cl, 2.9 to 13.2) than postmenopausal women (RR = 2.3; 95% Cl, 0.9 to 5.9), but the association of breast cancer risk with proliferative disease without atypia did not differ across menopausal status. CONCLUSION: These results confirm the marked increase in breast cancer risk among women with atypical hyperplasia, particularly in premenopausal women, and suggest that these women should be encouraged to undergo frequent breast cancer screening.

Breast↗
PubMed1992

Interobserver reproducibility in the diagnosis of ductal proliferative breast lesions using standardized criteria.

Although the categorization of proliferative breast lesions provides valuable information regarding subsequent risk of breast cancer, the ability of pathologists to classify such lesions in a reproducible fashion has not been adequately evaluated. To assess further interobserver reproducibility in the categorization of proliferative breast lesions, six pathologists each reviewed 24 proliferative ductal lesions and classified them as either usual hyperplasia (H), atypical hyperplasia (AH), or carcinoma in situ (CIS). Before evaluation of the study slides, all the participants were instructed to use the diagnostic criteria of Page and co-workers and were provided with both a written summary of these criteria and a set of teaching slides with representative examples of each type of lesion. Complete agreement among all six pathologists was seen in 14 cases (58%); five or more agreed in 17 cases (71%); and four or more arrived at the same diagnosis in 22 cases (92%). No pathologist consistently rendered more "benign" or "malignant" diagnoses than any other. After assigning numerical values for each diagnostic category (H = 1, AH = 2, CIS = 3), the scores for the group of 24 cases did not differ significantly by pathologist (p = 0.68; average score range, 1.7-2.0). Our results indicate that with the use of standardized criteria, interobserver concordance in the diagnosis of proliferative ductal breast lesions can be obtained in the majority of cases.

Breast↗
PubMed1992

Mammographic features predicting an extensive intraductal component in early-stage infiltrating ductal carcinoma.

Several studies have shown that the presence of an extensive intraductal component in patients with infiltrating ductal carcinoma is a major factor for predicting local recurrence after breast-conserving surgery and radiotherapy. A prospective study of 101 consecutive mammograms in patients with stage I or II infiltrating ductal carcinoma was performed to determine the predictive values of mammographic features in determining the presence or absence of an extensive intraductal component. Thirty-five (35%) of the lesions contained a pathologically verified extensive intraductal component. Sixty-five percent (22/34) of lesions showing mammographic evidence of calcifications with or without a mass were associated with an extensive intraductal component (p less than .001). Lesions with calcifications greater than 3 cm in extent were significantly (p less than .05) more likely to have an extensive intraductal component (9/10; 90%) than those with calcifications less than 3 cm in extent (13/24; 54%). Only 17% (8/46) of patients in whom mammograms showed only a mass or architectural distortion and 24% (5/21) of patients who had a mass palpable clinically or who had normal findings on mammograms had lesions with an extensive intraductal component. We conclude that infiltrating ductal carcinomas associated with calcifications on mammography, especially if the calcifications are extensive, are likely to be associated with an extensive intraductal component. Carcinomas without calcifications that show masses or architectural distortion on mammography, or carcinomas with palpable masses and normal findings on mammography, are unlikely to have an extensive intraductal component.

Breast↗
PubMed1992

Ductal carcinoma in situ of the breast: correlation between mammographic calcification and tumor subtype.

OBJECTIVE: Histologic subtypes of ductal carcinoma in situ of the breast have been correlated with disease progression after local excision only. This study was undertaken to determine how the predominant type of calcification seen on mammography correlates with the predominant histologic tumor subtype, knowledge that could aid in the development of clinical criteria for selecting patients for appropriate local treatment. MATERIALS AND METHODS: A prospective double-blind study was performed to correlate the mammographic and histologic findings in 66 consecutive cases of ductal carcinoma in situ, or ductal carcinoma in situ associated with small invasive foci (n = 11), in which microcalcifications seen on mammograms were found in the ductal carcinoma during histologic evaluation of excisional biopsy specimens. Microcalcifications were categorized as predominantly linear or granular and were correlated with the predominant histologic subtype of ductal carcinoma in situ in the tissue containing the calcifications seen on mammograms. RESULTS: Predominantly linear calcifications were present in 47% (18/38) of ductal comedocarcinomas in situ compared with 18% (5/28) of cribriform, solid, or papillary subtypes (p = .01). Predominantly granular calcifications were present in 53% (20/38) of comedocarcinomas compared with 82% (23/28) of the noncomedo types (p = .01). In 94% (16/17) of cribriform ductal carcinomas in situ, granular microcalcifications were seen on mammograms. Seventy-eight percent (18/23) of linear calcifications in ductal carcinoma in situ were associated with the comedo subtype, whereas 53% (23/43) of the granular calcifications were associated with noncomedo subtypes. CONCLUSION: We conclude that the comedo subtype of ductal carcinoma in situ is more likely to be accompanied by linear calcifications than are the noncomedo subtypes, and noncomedo ductal carcinoma in situ is more likely to be associated with granular calcifications than is the comedo subtype when microcalcifications are seen on mammograms. However, there is considerable overlap, and the predominant histologic subtype cannot be predicted on the basis of the microcalcification type with a high degree of accuracy.

Adult↗
PubMed1992

Recurrence in the breast following conservative surgery and radiation therapy for early-stage breast cancer.

This report summarizes the experience of the Joint Center for Radiation Therapy (JCRT) in treating patients with clinical stage I and II breast cancer with conservative surgery and radiation therapy. The study population consisted of 1396 patients treated between 1968 and 1985. All patients underwent a gross excision of the tumor and received breast irradiation (with or without nodal irradiation) including a "boost" to bring the primary tumor site to a total dose of at least 60 Gy. The method of treatment evolved over the study-time period. During the interval from 1968 to 1982, patients typically underwent a limited gross excision of the tumor without regard to the microscopic margins of resection. During the period 1983 to 1985, film-screen mammography, inking of specimen margins, and reexcisions for inevaluable or involved margins were more commonly performed. With a median follow-up of 80 months, the 5-year crude rate of failure in the breast (as the first site of failure) was 8% (106/1396) and the crude rate of regional nodal/distant failure (as the first site of failure) was 16% (228/1396). The time-course of failures in the breast was protracted, occurring at a fairly constant rate over the first 7 years after treatment, but still seen beyond that point. Most recurrences in the breast (75%) developed at or near the original tumor site. The most important risk factor for developing a breast recurrence was the presence of an extensive intraductal component in the tumor. The cosmetic results following treatment were excellent or good in the majority of patients (87%) and were most adversely affected by extensive surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Neoplasms↗
PubMed1991

Results of treating ductal carcinoma in situ of the breast with conservative surgery and radiation therapy.

To determine the frequency, pattern, and time course of tumor recurrence in the breast, the outcome of 38 women with ductal carcinoma in situ (DCIS) treated with conservative surgery and radiation therapy between 1976 and 1985 was studied. Surgery typically consisted of local excision without evaluation of the microscopic margins of resection. The median radiation dose to the tumor site was 6400 cGy. With a median follow-up time of 81 months, eight patients (21%) have experienced a recurrence in the breast. The time course to recurrence was protracted in some cases, with failures occurring at 17, 27, 43, 63, 71, 83, 92, and 104 months. The 5-year and 8-year actuarial rates of tumor recurrence in the breast were 8% and 27%, respectively. Seven patients had a recurrence at or near the primary tumor site, four with invasive carcinoma, and one had an invasive recurrence at a site elsewhere in the breast. No clinical or pathologic factor was significantly associated with an increased risk of recurrence, but the number of patients in the study population was small. The authors reached the following conclusions for patients with DCIS treated with conservative surgery and radiation therapy without careful mammographic and pathologic evaluation: (1) recurrence in the breast may be seen in at least one fifth of the patients; (2) recurrence typically occurs at or near the primary site; and (3) recurrence can occur long after treatment. Careful mammographic and pathologic assessment may be useful in reducing the local recurrence rate and should be considered essential if patients are considered for conservative surgery and radiation therapy.

Adult↗
PubMed1991

The optimal extent of resection for patients with stages I or II breast cancer treated with conservative surgery and radiotherapy.

The optimal extent of breast resection before irradiation for treatment of early breast cancer has not been defined. Increasing the size of the resection may decrease the risk of local recurrence but will also have an adverse impact on the cosmetic outcome. The 5-year likelihood of a recurrence of the tumor was analyzed in relation to the volume of resected breast tissue in 507 patients with infiltrating ductal carcinoma treated with conservative surgery and radiation therapy between 1968 and 1982. Patients were stratified by clinical T-stage and for each T-stage patients were divided into three groups of equal numbers based on the volume of excised tissue. All patients had at least a gross excision of the tumor and the extent of breast resection was determined at the discretion of the surgeon without knowledge of the histologic features of the tumor. The median follow-up time was 100 months. The 5-year actuarial recurrence rates were analyzed in relation to clinical T-stage (T1 or T2) and the presence or absence of an extensive intraductal component (EIC+ or EIC-). For patients with EIC+ tumors, the largest resections were associated with a substantially lower risk of recurrence in the breast than the smallest resections. This effect was seen both for T1 tumors (10% versus 29%, p = 0.07) and for T2 tumors (9% versus 36%, p = 0.04). For patients with EIC-tumors, recurrence rates were significantly lower than for EIC+ tumors and were not influenced by the volume of resection to the same degree as EIC+ tumors. In the absence of an EIC, recurrence rates for the largest and smallest resections were 0% and 9% (p = 0.02) for T1 tumors and 3% and 6% (p = NS) for T2 tumors. It is concluded that a limited breast resection is acceptable for an EIC- tumor but that a more extensive resection is required for an EIC+ tumor. These results stress the importance of assessing the presence or absence of an EIC in determining the optimal extent of breast resection required before radiation therapy.

Breast Neoplasms↗