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Biomedical subjects

W F Symmans

Publications and source records attributed to W F Symmans.

At least 19 recordsLinked to original sources
PubMed2026

Surgical Management of Young Women with High-Risk Breast Cancer Receiving Neoadjuvant Systemic Therapy on the I-SPY2 Trial.

BACKGROUND: Mastectomy rates in women with breast cancer are higher in younger women than in older women. The impact of this more extensive surgery on overall survival (OS) and locoregional recurrence in younger women is unknown, especially after neoadjuvant systemic therapy (NST). This study evaluated surgical management and outcomes of patients aged &#x2264; 45 versus > 45 years enrolled in multicenter NST clinical trial, I-SPY2.0 (NCT01042379, PMID 37325931). METHODS: We conducted a secondary data analysis comparing locoregional treatment in patients aged &#x2264; 45 versus > 45 years with clinical or molecular high-risk clinical stage II-III breast cancer treated from April 2010 to June 2022. Multivariate Cox proportional hazards models were used to evaluate associations between type of breast surgery with OS and locoregional recurrence-free interval by age group and tumor receptor subtype. RESULTS: Of 1737 patients, 698 (40.2%) were aged &#x2264; 45 years. There were no significant differences in patient or tumor characteristics or residual cancer burden distribution between age groups. Although breast-conserving surgery was significantly less common in younger women (36.8% vs 48.5%, p < 0.001), surgery type was not associated with OS or locoregional recurrence-free interval for patients aged &#x2264; 45 years. CONCLUSIONS: Greater extent of breast surgery was not associated with improved outcomes in women aged &#x2264; 45 years. Choice of surgical procedure in the management of breast cancer is multifactorial, but young age alone&#xa0;does not warrant mastectomy following NST.

Breast cancer↗
PubMed2005

A single-gene biomarker identifies breast cancers associated with immature cell type and short duration of prior breastfeeding.

The pathogenesis of breast cancers that do not express estrogen receptors or Her-2/neu receptors (ER-/HER2- phenotype) is incompletely understood. We had observed markedly elevated gene expression of gamma-aminobutyric acid type A (GABA(A)) receptor subunit pi (GABApi, GABRP) in some breast cancers with ER-/HER2- phenotype. In this study, transcriptional profiles (TxPs) were obtained from 82 primary invasive breast cancers by oligonucleotide microarrays. Real-time reverse transcription-polymerase chain reaction (RT-PCR) was used to measure GABApi gene expression in a separate cohort of 121 invasive breast cancers. GABApi gene expression values from TxP and RT-PCR were standardized and compared with clinicopathologic characteristics in the 203 patients. GABApi gene expression was increased in 16% of breast cancers (13/82 TxP, 20/ 121 RT-PCR), particularly in breast cancers with ER-/HER2- phenotype (60%), and breast cancers with basal-like genomic profile (60%). The profile of genes coexpressed with GABApi in these tumors was consistent with an immature cell type. In multivariate linear regression analysis, the level of GABApi gene expression was associated with ER-/HER2- phenotype (P < 0.0001), younger age at diagnosis (P = 0.0003), and shorter lifetime duration of breastfeeding (< or = 6 months) in all women (P = 0.017) and specifically in parous women (P = 0.013). GABApi gene expression was also associated with combinations of high grade with ER-/HER2- phenotype (P = 0.002), and with Hispanic ethnicity (P = 0.036). GABApi gene expression is increased in breast cancers of immature (undifferentiated) cell type and is significantly associated with shorter lifetime history of breastfeeding and with high-grade breast cancer in Hispanic women.

Biomarkers, Tumor↗
PubMed2004

Gene expression profiles predict complete pathologic response to neoadjuvant paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide chemotherapy in breast cancer.

PURPOSE: The goal of this study was to examine the feasibility of developing a multigene predictor of pathologic complete response (pCR) to sequential weekly paclitaxel and fluorouracil + doxorubicin + cyclophosphamide (T/FAC) neoadjuvant chemotherapy regimen for breast cancer. PATIENTS AND METHODS: All patients underwent one-time pretreatment fine-needle aspiration to obtain RNA from the cancer for transcriptional profiling using cDNA arrays containing 30721 human sequence clones. Analysis was performed after profiling, and 42 patients' clinical results were available, 24 of which were used for predictive marker discovery; 18 patients' results were used as an independent validation set. RESULTS: Thirty-one percent of patients had pCR (six discovery and seven validation), defined as disappearance of all invasive cancer in the breast after completion of chemotherapy. We could identify no single marker that was sufficiently associated with pCR to be used as an individual predictor. A multigene model with 74 markers (P <or=.09) was built using data from the discovery samples and tested on the validation samples. Overall, a 78% (14 of 18) predictive accuracy was observed, with a 100% (three of three) positive predictive value for pCR, a 73% (11 of 15) negative predictive value, a sensitivity of 43% (three of seven), and a specificity of 100% (11 of 11). The expected response rate to T/FAC neoadjuvant therapy in unselected patients is 28%. CONCLUSION: Our results suggest that transcriptional profiling has the potential to identify a gene expression pattern in breast cancer that may lead to clinically useful predictors of pCR to T/FAC neoadjuvant therapy.

Adult↗
PubMed2001

Fine-needle aspiration cytology of Hodgkin disease: a study of 89 cases with emphasis on false-negative cases.

UNLABELLED: INTRODUCTION. Although the cytologic features of Hodgkin disease (HD) has been well described, HD accounts for most of the false-negative fine-needle aspiration (FNA) biopsies of malignant lymphomas. In this study, the authors examined the factors contributing to a false-negative diagnosis of HD. METHODS: Eighty-nine cases from 72 patients (23 females and 49 males) with HD evaluated by FNA were identified between 1990 and 1999. The patients' ages ranged from 5 to 90 years (median, 38 years). Eighty-five FNAs were from lymph nodes, and 4 were from extranodal sites. Histologic correlation was available for all patients. RESULTS: Based on the original cytologic diagnosis, 43 (48.3%) cases had a positive diagnosis of HD, 20 (22.5%) suspicious or atypical diagnosis, 13 (14.6%) a benign diagnosis (false-negative cases), and 10 (11.2%) were nondiagnostic. Three (3.4%) additional cases had a malignant diagnosis other than HD. After review, three false-negative cases were reclassified as HD and seven as atypical lymphoid proliferation. Three of these 10 cases also showed conspicuous collections of histiocytes mimicking poorly formed granulomas. In those "atypical" cases, only rare Reed-Sternberg (R-S) cells variants were identified. No R-S cells or its variants were identified in the remaining three false-negative cases; subsequent excisional biopsy showed partial involvement of the lymph node by HD in two cases. Among the nondiagnostic cases, nine cases showed considerable fibrosis in the resected lymph node. In addition, six cases were performed without on-site assessment. CONCLUSIONS: The cytologic diagnosis of HD can be challenging when classic R-S cells are absent. Contributing factors for a false-negative diagnosis include obscuring reactive inflammatory cells, fibrosis of the involved lymph nodes, partial involvement of the lymph node by HD, sampling error, and misinterpretation. On-site assessment significantly minimizes the false-negative diagnostic rate. Furthermore, additional material can be obtained for ancillary studies. Cancer (Cancer Cytopathol)

Adolescent↗
PubMed2001

Mammotome core biopsy for mammary microcalcification: analysis of 160 biopsies from 142 women with surgical and radiologic followup.

BACKGROUND: Although stereotaxic fine-needle aspiration biopsy or core biopsy (14-gauge) have proven to be accurate techniques for the evaluation of mammographically detected microcalcification, the development of the Mammotome Biopsy System (Biopsys Medical, Inc., Irvine, CA) has led many medical centers to use this vacuum-assisted device for the sampling of microcalcification. METHODS: One hundred forty-two women underwent 160 stereotaxic Mammotome core biopsies of mammographic calcification over a 1-year period. The stereotaxic procedure was performed by radiologists using the Mammotome Biopsy System. Microcalcification was evident on specimen radiographs and microscopic slides in 99% of the cases. Excisional biopsy was recommended for diagnoses of atypia or carcinoma. Patients with benign diagnoses underwent mammographic followup. RESULTS: One hundred thirty-two benign, 12 atypical, and 15 adenocarcinoma diagnoses (comprising 1 lobular adenocarcinoma in situ [LCIS], 1 invasive ductal adenocarcinoma [IDC], and 13 intraductal adenocarcinomas [DCIS]: 10 comedo, 1 cribriform, 2 mixed cribriform and micropapillary) were rendered. Surgical excision in eight patients with atypia on Mammotome biopsy (two refused surgery, two were lost to followup) showed ductal hyperplasia in three, atypical ductal hyperplasia (ADH) in three and DCIS (low grade, solid) in two patients. Surgical excisions in 14 patients diagnosed with carcinoma (1 patient lost to followup) showed ADH in 3, ADH and LCIS in 1, residual DCIS in 8, IDC in 1, and microinvasive carcinoma in 1 patient. CONCLUSIONS: A diagnosis of atypia on Mammotome biopsy warranted excision of the atypical area, yet the underestimation rate for the presence of carcinoma remained low. The likelihood of an invasive component at excision was low for microcalcification diagnosed as DCIS on Mammotome biopsy. Mammotome biopsy proved to be an accurate technique for the sampling and diagnosis of mammary microcalcification.

Adenocarcinoma↗
PubMed2001

What is the role of cytopathologists in stereotaxic needle biopsy diagnosis of nonpalpable mammographic abnormalities?

The popularity of screening mammography has led to increased detection of mammographic lesions that require pathologic diagnosis. Stereotaxic needle biopsy techniques to sample such lesions can be used to either identify those lesions that require excision from those that can be followed, or to confirm a mammographic impression of malignancy prior to excision. Stereotaxic core biopsy (SCBX) and stereotaxic fine needle aspiration (SFNA) have rarely been directly compared. For this review we undertook a uniform re-analysis of the data that was presented in the published studies of SFNA and/or SCBX. The main endpoint was the negative predictive value (NPV) that measures the frequency that a benign diagnosis is truly benign. There was variability in NPV (likely due to sampling methods) and specific aspects of sampling techniques are discussed. The NPV was compared to indicators of selection of lesions to biopsy (frequency of invasive cancer in the study population), mammographic characteristics (masses or microcalcifications), and the reported nondiagnostic rates. The general conclusion is that SFNA and SCBX are equivalent in accuracy, with considerable variability that reflects the types of lesions that are selected for biopsy and the thoroughness of sampling. For SFNA studies, nondiagnostic rates were inversely related to NPV, and therefore have clinical implications. This was not shown for SCBX studies, and probably reflects an inability to correctly identify non-representative tissue biopsies. The main advantage for including cytologic methods with stereotaxic breast biopsy is immediate sample assessment, and this advantage can also be applied to core needle procedures.

Biopsy, Needle↗
PubMed2001

Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy.

PURPOSE: Neoadjuvant chemotherapy for breast cancer creates new possibilities for the analysis of biological factors in the tumor and/or host, which may play a role in the response to treatment. In this study we analyzed whether changes in local antitumor immunity take place after neoadjuvant paclitaxel therapy and if they correlate with response to treatment. EXPERIMENTAL DESIGN: Neoadjuvant chemotherapy (paclitaxel, 200 mg/m2 q2w, 4 treatments) was followed by definitive surgical management. Histological sections from the pre- and post-treatment surgical specimens of 25 patients were analyzed for the extent of lymphocytic infiltration and presence of tumor infiltrating lymphocytes (TILs). The cumulative apoptotic response in the tumor after the first dose of paclitaxel was also studied in 10 of 25 patients. RESULTS: Pretreatment lymphocytic infiltrate in the tumor was minimal in the majority of patients and showed no relationship with clinical response. In the patients without TILs before treatment, development of TILs after treatment was noted in 0/3 (0%) patients with stable disease, 3/12 (25%) patients with clinical partial response, and 4/6 (67%) patients with clinical complete response and pathological residual disease. These correlated with the tumor cell apoptotic response to the first dose of paclitaxel. CONCLUSIONS: These results suggest that development of TILs after treatment correlates with clinical response to neoadjuvant paclitaxel therapy. The possible mechanism(s) whereby neoadjuvant chemotherapy may lead to induction of antitumor T cells is discussed. Immunological processes may influence the response of breast cancer patients to neoadjuvant treatment.

Adult↗
PubMed2000

Use of E-cadherin and CD44 aids in the differentiation between reactive mesothelial cells and carcinoma cells in pelvic washings.

BACKGROUND: The presence of malignant cells in peritoneal washings is an independent prognostic factor in the evaluation of gynecologic malignancies. The differentiation between reactive mesothelial cells and carcinoma cells can be a diagnostic challenge based on morphology alone. The expression of some cell adhesion molecules may be helpful in the differential diagnosis. METHODS: To evaluate the specificity of 2 transmembrane cell adhesion proteins (E-cadherin and CD44) in the differentiation of mesothelial cells from carcinoma cells in pelvic washings, formalin fixed, paraffin embedded cell blocks of pelvic washings from 19 cases of metastatic ovarian adenocarcinoma and 16 cases of benign peritoneal washings were immunostained with monoclonal antibodies to E-cadherin and CD44. The staining patterns were evaluated blindly by three observers. Positive staining was defined as uniform membranous staining for each marker. RESULTS: Fourteen benign peritoneal washings (87.5%) demonstrated immunoreactivity with anti-CD44. On the contrary, only four adenocarcinomas (21.1%) demonstrated anti-CD44 immunoreactivity. E-cadherin expression was identified in only 2 benign peritoneal washings (12.5%) whereas 16 adenocarcinomas (84.2%) strongly expressed E-cadherin. The differences in immunostaining for both CD44 and E-cadherin between benign and malignant peritoneal washings were statistically significant. The combination of positive staining for E-cadherin and negative staining for CD44 was 100% specific for metastatic adenocarcinoma, whereas a combination of negative staining for E-cadherin and positive staining for CD44 was 100% specific for reactive mesothelial cells. CONCLUSIONS: Both E-cadherin and CD44 reliably distinguish reactive mesothelial cells from adenocarcinoma. The combination of E-cadherin/CD44 is highly specific and is a useful diagnostic adjunct with which to distinguish benign reactive mesothelial cells from adenocarcinoma in pelvic washings.

Adenocarcinoma↗
PubMed2000

Aspiration biopsy and the clinical management of patients with malignant melanoma and palpable regional lymph nodes.

BACKGROUND: The presence of lymph node metastases in patients with malignant melanoma implies a significant decrease in survival. The authors investigated the efficacy of fine-needle aspiration biopsy (FNAB) in the diagnosis of metastatic malignant melanoma in 115 patients with melanoma and clinically suspicious regional lymph nodes. METHODS: One hundred thirty-three FNABs were performed by cytopathologists after referral from surgeons or oncologists using a 25-gauge or 27-gauge needle. RESULTS: The cytologic diagnosis was negative in 35, atypical in 1, suspicious in 2, and positive for malignant melanoma in 95. Regional lymph node dissections were performed in 78 patients. Of these, 70 positive FNABs were confirmed with no false-positive results. The atypical FNAB was proven positive for malignant melanoma at surgery. Of the two suspicious FNABs, one was confirmed as positive and one showed dermatopathic lymphadenopathy. Of the 35 negative FNAB specimens, 5 patients underwent surgery; 3 FNABs were found to be negative and 2 FNABS were falsely negative. Twenty patients with negative aspirates were followed clinically for 22-45 months (mean, 32 months); 19 patients had no evidence of disease and 1 patient died of disseminated melanoma. CONCLUSIONS: FNAB of palpable lymphadenopathy in patients with malignant melanoma can provide a rapid and accurate assessment of lymph node status and expedite the therapeutic management of these patients.

Adult↗
PubMed2000

Invasive carcinoma in clinically suspicious breast masses diagnosed as adenocarcinoma by fine-needle aspiration.

BACKGROUND: Fine-needle aspiration (FNA) biopsy of palpable breast masses along with clinical and radiologic findings can provide rapid distinction between benign and malignant lesions. A preoperative determination of invasive or in situ carcinoma assists in the planning of definitive treatment. Previous studies have concentrated on whether cytologic features adequately distinguish invasion, but to the authors' knowledge the predictive value of clinicopathologic correlation has not been investigated. The authors attempted to determine whether a malignant cytologic diagnosis for a palpable breast mass is sufficient for its definitive surgical management as an invasive neoplasm. METHODS: The authors reviewed 351 FNAs from palpable breast lesions with a cytologic diagnosis of "adenocarcinoma." The presence of invasive disease was determined by histologic demonstration of invasive carcinoma in the corresponding surgical specimen or by identifying metastatic carcinoma in the absence of another primary source. RESULTS: Three hundred forty-three (97.7%) palpable tumors diagnosed as adenocarcinoma by FNA proved to be invasive adenocarcinoma. The remaining eight tumors contained high grade ductal carcinoma in situ, and two of these contained foci suggestive of microinvasion. CONCLUSIONS: A palpable breast mass with an FNA diagnosis of adenocarcinoma usually represents invasive carcinoma. A definitive treatment plan therefore can be planned based on these clinical and FNA findings.

Adenocarcinoma↗
PubMed2000

The incidence of positive margins with breast conserving therapy following mammotome biopsy for microcalcification.

BACKGROUND AND OBJECTIVES: The ability to achieve clean margins with breast conserving therapy varies greatly even when the diagnosis of carcinoma is known beforehand. Although several reports reveal that the incidence of positive margins decreases after stereotaxic core biopsy of nonpalpable lesions and fine-needle aspiration biopsy of palpable lesions, the data on the results following mammotome biopsy (mmbx) is scanty. METHODS: Two hundred and ninety-eight biopsy specimens for mammographically indeterminate microcalcification from 1/97 through 3/30/98 were reviewed. Biopsies were performed using the biopsys method utilizing an 11-gauge multidirectional, vacuum-directed device. RESULTS: Ten percent (n = 31) of the mammotome biopsies were atypical and 9% (n = 27) were malignant. These 58 cases (19%) were recommended for surgical excision. The incidence of positive margins in this subset was determined. Of patients who underwent lumpectomy as their initial surgical procedure 69% had negative surgical margins. Seventy-seven percent of patients with carcinoma diagnosed by mammotome biopsy had definitive initial surgery with a single surgical procedure. CONCLUSIONS: Mmbx facilitates fewer surgical procedures to achieve negative margins, and thus provides a better cosmetic result.

Adult↗
PubMed2000

Paclitaxel-induced apoptosis and mitotic arrest assessed by serial fine-needle aspiration: implications for early prediction of breast cancer response to neoadjuvant treatment.

The extent of tumor reduction from neoadjuvant chemotherapy for breast cancer correlates with outcome. We investigated whether the initial cellular responses to paclitaxel are related to the extent of tumor reduction. Eleven women with breast cancer received paclitaxel (every 2 weeks for 4 cycles) as neoadjuvant treatment. Serial fine-needle aspirations (FNA; 25-gauge, 1 pass) were obtained before treatment and at 24, 48, 72, and 96 h after the first paclitaxel dose. Microscopic counts of apoptotic and mitotic indices were performed. The change in cancer volume from treatment was determined using radiological measurements with allowance for change in the histopathological amount of cancer. Apoptotic and mitotic responses usually subsided within 4 days. The duration of the initial apoptotic response was different for women with different treatment results. Cumulative apoptotic response for the first 4 days inversely correlated with the proportion of residual cancer after neoadjuvant treatment. FNA is a versatile clinical method to obtain breast cancer cells for therapy response studies. Apoptotic response to the first dose of paclitaxel is almost complete within 4 days, implying that more frequent (weekly) paclitaxel dosing might be beneficial. The apoptotic response to the first dose of paclitaxel appeared to predict the amount of cancer reduction from this treatment. This is a promising start toward the development of an early chemopredictive assay for paclitaxel treatment of breast cancer.

Antineoplastic Agents, Phytogenic↗
PubMed1999

A prospective comparison of stereotaxic fine-needle aspiration versus stereotaxic core needle biopsy for the diagnosis of mammographic abnormalities.

BACKGROUND: Confidence in a negative stereotaxic breast biopsy result allows for safe clinical and mammographic follow-up, whereas a positive or equivocal diagnosis leads to excision. Direct comparison of stereotaxic core needle biopsy (SCBX) and fine-needle aspiration (SFNA) is needed, and should be based on the use of appropriate current methods of practice, and address the indication of each for different types of mammographic lesions. METHODS: The diagnostic accuracy of SFNA, SCBX, and combined SFNA with SCBX performed at a community radiology practice were assessed for different mammographic lesions and levels of radiologic suspicion. Negative predictive values (NPVs) measured the confidence that a negative diagnosis (failure to identify atypia or malignancy) was benign and therefore suitable for follow-up. A benign outcome was accepted only after surgical excision or > or =24 months' follow-up of the lesion. Positive predictive values (PPVs) [final diagnoses at least atypical (A) or carcinoma (CA)] also were calculated. RESULTS: SFNA was performed for 495 lesions and was combined with SCBX for 252 of these. Nondiagnostic (SFNA, 2%; SCBX, 8%) and atypical (SFNA, 7%; SCBX, 3%) rates were low. The authors obtained 94% follow-up (81% > or = 24 months). NPVs were all SFNAs, 99%; SCBXs, 95% (corresponding SFNAs, 98%); and SFNA with SCBX, 99%. NPVs were 100% for masses, ill-defined densities, and architectural distortions. NPVs for microcalcifications (for low, moderate, and high suspicion) were all SFNAs, 97% (100, 95, and 75); SCBXs, 93% (94, 93, and 67), corresponding SFNAs, 96% (100, 94, 75); and SFNA with SCBX, 98% (100, 97, 75). All false-negative lesions were microcalcifications. Calcium was recognized in 98% of SFNA specimens and in 89% of SCBX specimens from microcalcifications. No calcium was identified in the histologic sections in 63% (5 of 8) SCBX false-negative specimens. PPVs(A) were atypical (SFNA, 46%; SCBX, 88%) and suspicious (SFNA, 93%). PPVs(CA) were SFNA carcinoma, 100%; SCBX in situ, 89%; and SCBX invasive, 100%. CONCLUSIONS: SFNA identified benign lesions more reliably for follow-up, particularly microcalcifications. Based on these results, the authors suggest 1) added SCBX if on-site SFNA assessment is nondiagnostic, atypical, or positive (and needs preoperative confirmation of invasion); 2) either SCBX or SFNA for masses, architectural distortions, and ill-defined densities; 3) SFNA for microcalcifications, with SCBX added for moderately and highly suspicious lesions; and 4) surgical excision for all highly suspicious microcalcifications.

Biopsy, Needle↗
PubMed1999

Benign proliferative nipple duct lesions frequently contain CAM 5.2 and anti-cytokeratin 7 immunoreactive cells in the overlying epidermis.

Benign proliferative nipple duct lesions (PNDLs) pose a diagnostic problem for clinicians and pathologists. Clinically, they may be associated with skin changes typically present in Paget's disease of the nipple. The identification of numerous scattered cells in the epidermis that are immunoreactive for low-molecular-weight cytokeratin may lead to further confusion with Paget's disease. We studied the nipple epidermis in nine cases of PNDL and compared them with 26 histologically normal nipples from mastectomy specimens. CAM 5.2 and anticytokeratin 7 (CK7) immunoreactive cells were identified in the epidermis of seven of nine nipples associated with PNDL. The cytokeratin-positive cells appeared cytologically benign and were dispersed singly (scattered in seven of seven cases and frequent in four of seven cases) or formed small aggregates with occasional tubular structures (three of seven cases) in the basal and middle layers of the epidermis. In two of seven cases, these epidermal immunoreactive cells showed continuity with the underlying PNDL, suggesting the spread or continuation of lesional cells to the epidermis. Dispersed single immunoreactive cells were identified in small numbers (scattered) in the basal layer of the epidermis in 12 of 26 normal nipples and more frequently in 1 of 12 cases. In all cases, the intraepidermal cells were negative for carcinoembryonic antigen (CEA) and Her-2/neu. We conclude that intraepidermal CAM 5.2 and anti-CK7 immunoreactive cells, which are normally present in the nipple epidermis, may proliferate and form aggregates when there is an underlying PNDL. The presence of these cells does not imply Paget's disease when the intraepidermal cells have a bland cytologic appearance, fail to overexpress Her-2/neu, and there is no carcinoma within the PNDL or elsewhere in the breast.

Adult↗
PubMed1999

Concurrent paclitaxel and radiation therapy for breast cancer.

Few studies have evaluated the role of concurrent chemoradiation therapy in the management of locally advanced breast cancer. The availability of radiosensitizing chemotherapeutic agents that are effective in breast cancer and the encouraging results achieved by concurrent chemoradiation in other malignancies have prompted us to investigate this approach. Paclitaxel is a promising agent for use with concurrent radiotherapy because of its single-agent efficacy profile and its radiosensitizing effects. A clinical protocol of preoperative paclitaxel and radiation in locally advanced breast cancer is ongoing at our institution to test feasibility, measure pathologic response at mastectomy, and explore association of pathologic response with molecular tumor markers. Initially, the study was designed to test weekly paclitaxel at a dose of 60 mg/m2 during radiation therapy, delivered 5 days a week at 200 cGy fractions to a total dose of 50 Gy over 5 weeks. Due to severe skin toxicity in the first two patients, the protocol was amended to change the scheduling of paclitaxel to 30 mg/m2 twice weekly and to reduce the radiation to 180 cGy fractions to a total dose of 45 Gy, delivered 5 days a week over 5 weeks. Presently, 13 patients have been accrued; preliminary data indicate good tolerance to twice-weekly paclitaxel, and four of eight evaluable patients have achieved pathologic response (one patient who received the weekly regimen and three who received the twice-weekly regimen). In addition, sequential fine-needle aspirations of palpable breast cancers were obtained in patients enrolled in a parallel study of preoperative single-agent paclitaxel (200 mg/m2 every 2 weeks, for a total of four cycles before breast surgery). Preliminary results suggest that a steep increase in the mitotic index occurs during the first day after paclitaxel administration and plateaus between the second and the third day, then decreases to pretreatment values. The peak apoptotic index occurs at approximately 72 hours after paclitaxel administration and decreases at approximately 98 hours. These initial findings suggest that twice-weekly dosing of paclitaxel may optimize recruitment of cells into the G2/M phase of the cell cycle, the most radiosensitive phase.

Antineoplastic Agents, Phytogenic↗
PubMed1998

NF1 inactivation cooperates with N-ras in in vivo lymphogenesis activating Erk by a mechanism independent of its Ras-GTPase accelerating activity.

We crossed transgenic mice overexpressing the N-ras proto-oncogene (RasTg) with mice carrying one inactivated copy of the NF1 tumor suppressor gene (NF1+/-) to assess their possible cooperation in tumorigenesis. We have found a significant increase in the incidence of lymphomas in animals with both lesions (RasTg NF1+/-), as compared with animals with single lesions. The mechanism of this cooperation appears to be independent of the NF1 GTPase activating activity since the level of Ras-GTP in primary cultures of tumor tissue do not differ among animals with double and with single lesions. Nevertheless, the finding of significantly higher levels of Erk-1 and Erk-2 activation in lymphomas in the RasTg NF1+/- than in the RasTg group suggests that this cooperative effect may be in part explained by increased signaling through the Erk pathways. Consistent with a role for Erk activation in transformation is the additional observation that Erk-1 and Erk-2 activation is significantly increased in lymphomas as compared with normal spleen. This activation is likely to occur by phosphorylation of previously synthesized and inactive Erk proteins since, despite differences in activation, Erk-1 and Erk-2 expression is similar in normal and lymphoid tissue in all groups. The observed cooperation in in vivo lymphomagenesis between N-ras overexpression and NF1 inactivation emphasizes the importance of searching for additional functions for the NF1 protein and of intensifying the screening for NF1 mutations in human lymphomas.

3T3 Cells↗