Prognostic Implications of Pathological Lymph Node Status After Preoperative Chemotherapy for Operable T3N0M0 Breast Cancer

Background: Although preoperative chemotherapy has become the standard of care for inoperable locally advanced breast cancer, its role for downstaging resectable primary tumors is still evolving. The purpose of this study was to determine whether the prognostic information from an axillary node dissection in patients with clinical T3N0 breast cancer was altered by preoperative chemotherapy compared with surgery de novo.Methods: Between 1976 and 1994, 91 patients with clinically node-negative operable T3 breast cancer received doxorubicin-based combination chemotherapy on protocol at one institution. Fifty-three patients received both preoperative and postoperative chemotherapy (PreopCT), and 38 received postoperative chemotherapy only (PostopCT). All patients underwent axillary lymph node dissection as part of their definitive surgical treatment. There were no differences between the PreopCT and PostopCT groups in median age (51 vs. 49 years), median tumor size at presentation (6 cm vs. 6 cm), tumor grade, or estrogen receptor status (estrogen receptor negative 38% vs. 32%). The median follow-up time was 7 years.Results: Patients in the PreopCT group had fewer histologically positive lymph nodes (median, 0 vs. 3, P < .01), and a lower incidence of extranodal extension (19% vs. 42%, P 5 .02). By univariate analysis, the number of pathologically positive lymph nodes (P < .01) and extranodal extension (P < .01) were predictors of disease-specific survival in PreopCT patients. Multivariate analysis showed that extranodal extension was the only independent prognostic factor in PreopCT patients (P < .01). Overall, PreopCT and PostopCT patients had similar 5-year disease-free survival rates (66% vs. 57%); however, PreopCT patients had worse disease-free (P 5 .01) and diseasespecific survival (P 5 .04) when survival was compared after adjustment for the number of positive lymph nodes. Furthermore, PreopCT patients with 4–9 positive lymph nodes had a lower 5-year disease-free survival rate than PostopCT patients with 4–9 positive nodes (17 vs. 48%, P 5 .04).Conclusions: Axillary lymph node status remains prognostic after chemotherapy. Pathologically positive lymph nodes after preoperative chemotherapy are associated with a worse prognosis than the same nodal status before chemotherapy.     

Tongue piercing. The new "rusty nail"?

BACKGROUND: Cephalic tetanus is a rare form of the tetanus caused primarily by wounds or other infectious processes involving the head and neck. This condition frequently progresses to the generalized form of tetanus with the attendant risks and complications. METHODS: A case report of a young female who developed an unusual form of tetanus after a tongue piercing is presented here. We discuss this disorder as it applies to the contemporary caregiver with a focus on its presentation and recognition. RESULTS: A delay in diagnosis of 13 days from presentation occurred. The patient had a slow, uneventful but incomplete recovery course. She never developed significant airway compromise, nor did she demonstrate any evidence of hemodynamic instability but continued to have right facial weakness up to 6 months after discharge. CONCLUSIONS: A few factors were identified that contributed to the significant delay in diagnosis. The unusual nature of the disease and a lowered index of suspicion on the part of the initial caregivers were probably the major causes. Fortunately, no major adverse sequelae resulted from the delay. However, if this case heralds the onset of a rise in the incidence of tetanus, early recognition and diagnosis would seem essential to avoid much of the morbidity and mortality associated with the disease.     

Apoptosis and p53 in inverting papilloma of the sinonasal tract

The objective of this study was to identify apoptotic bodies and p53 positivity in inverting papilloma lesions to study these two as biomarkers in premalignant lesions. Archival specimens of 15 patients with inverting papilloma between the years 1992 and 1995 were retrieved. In situ end labeling technique was used to identify apoptotic bodies. Immunohistochemistry was used to detect p53 in the same specimens. The clinical course was evaluated conducting a retrospective chart review in these patients. Compared to normal epithelium, inverting papilloma lesions had a greater proportion of apoptotic bodies, which was nearly statistically significant (average 0.506/100 cells for inverting papilloma compared with 0.1/100 cells for the normal surrounding tissue). Four cases of inverting papilloma were p53 positive. There was, however, no association between p53 positive staining and the apoptotic rate. The minimum follow-up for patients was 2 years. All had a uniformly good clinical outcome with only one patient who was p53 positive showing concurrent squamous cell carcinoma. We concluded that inverting papilloma contained a higher average number of apoptotic bodies compared with normal surrounding sinonasal tissue. This showed a trend toward a positive between the apoptotic rate and premalignancy, suggesting both increased cellular proliferation and increased cell death may occur in such lesions. In this study p53 did not show a positive association with the apoptotic rate, suggesting that p53 may not be directly involved in the apoptotic regulatory pathway in inverting papillomas.     

RNA interference targeting of A1 receptor-overexpressing breast carcinoma cells leads to diminished rates of cell proliferation and induction of apoptosis

To determine if A1 adenosine receptors mediate breast tumorigenesis, we evaluated A1 receptor expression in human tumor cell lines and human primary breast tumor tissues using both quantitative RT-PCR and Western blot analysis. A1 receptor mRNA expression is upregulated in all breast tumor cell lines examined (n=7) compared to normal mammary epithelial cells/cell lines (n=3) as determined by quantitative RT-PCR analysis. Western blot analysis indicates that protein expression of A1 adenosine receptor is higher in 15 (62.5%) of 24 human primary breast tumor tissues than in matched normal breast tissue. To explore its cellular function, the A1 adenosine receptor was depleted by small interfering RNA (siRNA) in MDA-MB-468 human breast tumor cells. Depletion of A1 receptors in MDA-MB-468 breast tumor cells attenuated both cell growth and cell proliferation as measured by cell number counts and [(14)C]-thymidine incorporation, respectively. Cell cycle analysis indicated that depletion of A1 receptors by siRNA impairs G(1) checkpoint, leading to marked accumulation of cells in G(2)/M phase, in agreement with the inhibitory effect on cell proliferation. Further supporting this finding, synchronization studies of Hela cells in various cell cycle phases suggest that A1 receptor expression is suppressed in G(2)/M cells and depletion of A1 receptor expression by siRNA produced differential expression of several key cell cycle regulators, i.e., accumulation of the cyclin-dependent kinase inhibitor p27 with concomitant reduction of CDK4 and cyclin E proteins. In addition to the impact on cell cycle progression, depletion of A1 receptors by siRNA results in substantial cell death and apoptosis as determined by FACS analysis and annexin V staining method. Together these findings suggest that the A1 adenosine receptor may contribute to tumor cell growth and survival in breast tumor cells.     

Clinical trials in amyotrophic lateral sclerosis: the tenuous past and the promising future

The past decade of research in amyotrophic lateral sclerosis has contributed to a greater understanding of the disease process, the development of relevant animal models, and the identification of several therapeutic approaches that may delay disease progression. Completed and ongoing clinical trials and the process of selecting drugs for clinical trials are presented.     

Predictors of systemic recurrence and disease-specific survival after ipsilateral breast tumor recurrence

BACKGROUND: In patients with breast carcinoma, ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy (BCT) is an independent predictor of systemic recurrence and disease-specific survival (DSS). However, only a subgroup of patients with IBTR develop systemic recurrences. Therefore, the management of isolated IBTR remains controversial. The objective of the current study was to identify determinants of systemic recurrence and DSS after IBTR. METHODS: The medical records of 120 women who underwent BCT for Stage 0-III breast carcinoma between 1971 and 1996 and who subsequently developed isolated IBTR were reviewed. Clinicopathologic factors were studied using univariate and multivariate analyses for their association with DSS and the development of systemic recurrence after IBTR. RESULTS: The median time to IBTR was 59 months. At a median follow-up of 80 months after IBTR, 45 patients (37.5%) had a systemic recurrence. Initial lymph node status was the strongest predictor of systemic recurrence according to the a univariate analysis (P = 0.001). Other significant factors included lymphovascular invasion (LVI) in the primary tumor, time to IBTR < or = 48 months, clinical and pathologic IBTR tumor size > 1 cm, LVI in the recurrent tumor, and skin involvement at IBTR. In a multivariate logistic regression analysis, initially positive lymph node status (relative risk [RR], 5.3; 95% confidence interval [95% CI], 1.4-20.1; P = 0.015) and skin involvement at IBTR (RR, 15.1; 95% CI, 1.5-153.8; P = 0.022) remained independent predictors of systemic recurrence. The 5-year and 10-year DSS rates after IBTR were 78% and 68%, respectively. In a multivariate Cox proportional hazards model analysis, only LVI in the recurrent tumor was found to be an independent predictor of DSS (RR, 4.6; 95% CI, 1.5-14.1; P = 0.008). CONCLUSIONS: Patients who initially had lymph node-positive disease or skin involvement or LVI at IBTR represented especially high-risk groups that warranted consideration for aggressive, systemic treatment and novel, targeted therapies after IBTR. Determinants of prognosis after IBTR should be taken into account when evaluating the need for further systemic therapy and designing risk-stratified clinical trials.     

Improving local control with breast-conserving therapy: a 27-year single-institution experience

BACKGROUND: The risk of ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy (BCT) is associated with treatment and tumor-related variables, such as surgical margin status and the use of systemic therapy, and these variables have changed over time. Correspondingly, the authors of the current study hypothesized that the contemporary multidisciplinary management of breast carcinoma would lead to an improvement in IBTR rates after BCT. METHODS: Between 1970 and 1996, 1355 patients with pathologic Stage I-II invasive breast carcinoma underwent BCT (breast-conserving surgery and adjuvant radiation therapy) at The University of Texas M. D. Anderson Cancer Center. Contemporary methods of analyzing surgical margins were in routine use by 1994. To analyze the effect of this variable and others, patient and tumor characteristics and IBTR rates in patients treated during 1994-1996 were compared with those in patients treated from 1970 to 1993. RESULTS: Characteristics were similar in patients treated during 1994-1996 (n = 381) and those treated before 1994 (n = 974) except for patients aged >50 years (63.3% vs. 51.7%, P < 0.001), and patients who had a family history of breast carcinoma (37.9% vs. 30.8%, P = 0.017). Patients treated after 1994 were less likely to have positive or unknown margins (2.9 % vs. 24.1 %, P = 0.0001), more likely to receive chemotherapy (40.5% vs. 26%, P < 0.001), and more likely to receive hormonal therapy (33.3% vs. 19.4%, P < 0.001), but less likely to receive radiation boosts to the primary tumor bed (59.8% vs. 89%, P < 0.001). The 5-year cumulative IBTR rate was significantly lower among patients treated in 1994-1996 than among patients treated before 1994 (1.3% vs. 5.7%, P = 0.001) largely because of the drop in IBTR rates among patients aged < or = 50 years (1.4 % vs. 9.1 %, P = 0.0001). On multivariate analysis, age > 50 (hazards ratio [HR] = 0.401; P = 0.0001), presence of negative surgical margins (HR = 0.574; P = 0.017), and use of adjuvant hormonal therapy (HR = 0.402; P = 0.05) were independent predictors of improved 5-year IBTR-free survival. On subgroup analysis, use of chemotherapy was associated with increased IBTR-free survival among women aged < or = 50 years (HR = 0.383; P = 0.001). Although 5-year cumulative IBTR rates were lower among women aged > 50 years than among younger women before 1994 (2.6 % vs. 9.1%, P < 0.0001), no such difference was found in the group treated in 1994-1996 (1.2 % for age > 50 yrs vs. 1.4 % for < or = 50 yrs, P = 0.999). CONCLUSIONS: The IBTR rate after BCT appears to be declining, especially among patients < 50 years of age. However, long-term follow-up is necessary to confirm this finding. This finding may reflect changes in surgical approaches and pathologic evaluation as well as an increased use of systemic therapy. The current low incidence of IBTR with multidisciplinary management of breast carcinoma may result in more patients choosing BCT over mastectomy.     

Management of suspected scaphoid fractures in accident and emergency departments--time for new guidelines

INTRODUCTION: The objectives of this work were to assess the clinical knowledge of clinicians in the accident and emergency (A&E) departments in England & Wales and evaluate the current trend for the acute management of radiologically normal, but clinically suspected, fractures of the scaphoid. SUBJECTS AND METHODS: We conducted a telephone survey on 146 A&E senior house officers (SHOs) in 50 different hospitals. This survey assessed the clinicians'' experience, their clinical and radiological diagnostic methods, and their initial treatment of suspected scaphoid fractures. RESULTS: The majority (55.8%) of SHOs performed only one clinical test to diagnose suspected scaphoid fractures. Overall, 41% were unable to cite the number of the radiographic views taken and only 10% of departments have direct access to further radiological investigation. There is wide variation in the early treatment of this injury, with the scaphoid cast used most commonly (46%). The majority of SHOs (89%) were unable to describe the features of immobilisation. The mean follow-up period was 10 days, and 53% of cases were followed-up by the senior staff in A&E. Of SHOs, 54% were not aware of any local guidelines for the management of suspected scaphoid fractures in their departments, and 92% were not aware of the existence of the 1992 British Association for Accident and Emergency Medicine (BAEM) guidelines. CONCLUSIONS: The clinical knowledge and the management of suspected scaphoid fractures in A&E are unsatisfactory. We, therefore, suggest that the dissemination of up-to-date guidelines could help to educate clinicians to provide better care to the patients.