Irene Wapnir

Abstract

The limited entry of anticancer drugs into the central nervous system represents a special therapeutic challenge for patients with brain metastases and is primarily due to the blood brain barrier (BBB). Albumin-bound Evans blue (EB) dye is too large to cross the BBB but can grossly stain tissue blue when the BBB is disrupted. The course of tumor development and the integrity of the BBB were studied in three preclinical breast cancer brain metastasis (BCBM) models. A luciferase-transduced braintropic clone of MDA-231 cell line was used. Nude mice were subjected to stereotactic intracerebral inoculation, mammary fat pad-derived tumor fragment implantation, or carotid artery injections. EB was injected 30 min prior to euthanasia at various timepoints for each of the BCBM model animals. Serial bioluminescent imaging demonstrated exponential tumor growth in all models. Carotid BCBM appeared as diffuse multifocal cell clusters. EB aided the localization of metastases ex vivo. Tumor implants stained blue at 7 days whereas gross staining was not evident until day 14 in the stereotactic model and day 28 for the carotid model. EB assessment of the integrity of the BBB provides useful information relevant to drug testing in preclinical BCBM models.

View details for DOI 10.1007/s10549-014-2854-5

View details for PubMedID 24510011

Abstract

Patients with isolated locoregional recurrences (ILRR) of breast cancer have a high risk of distant metastasis and death from breast cancer. We aimed to establish whether adjuvant chemotherapy improves the outcome of such patients.The CALOR trial was a pragmatic, open-label, randomised trial that accrued patients with histologically proven and completely excised ILRR after unilateral breast cancer who had undergone a mastectomy or lumpectomy with clear surgical margins. Eligible patients were enrolled from hospitals worldwide and were centrally randomised (1:1) to chemotherapy (type selected by the investigator; multidrug for at least four courses recommended) or no chemotherapy, using permuted blocks, and stratified by previous chemotherapy, oestrogen-receptor and progesterone-receptor status, and location of ILRR. Patients with oestrogen-receptor-positive ILRR received adjuvant endocrine therapy, radiation therapy was mandated for patients with microscopically involved surgical margins, and anti-HER2 therapy was optional. The primary endpoint was disease-free survival. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00074152.From Aug 22, 2003, to Jan 31, 2010, 85 patients were randomly assigned to receive chemotherapy and 77 were assigned to no chemotherapy. At a median follow-up of 4·9 years (IQR 3·6-6 ·0), 24 (28%) patients had disease-free survival events in the chemotherapy group compared with 34 (44%) in the no chemotherapy group. 5-year disease-free survival was 69% (95% CI 56-79) with chemotherapy versus 57% (44-67) without chemotherapy (hazard ratio 0·59 [95% CI 0·35-0·99]; p=0·046). Adjuvant chemotherapy was significantly more effective for women with oestrogen-receptor-negative ILRR (pinteraction=0·046), but analyses of disease-free survival according to the oestrogen-receptor status of the primary tumour were not statistically significant (pinteraction=0·43). Of the 81 patients who received chemotherapy, 12 (15%) had serious adverse events. The most common adverse events were neutropenia, febrile neutropenia, and intestinal infection.Adjuvant chemotherapy should be recommended for patients with completely resected ILRR of breast cancer, especially if the recurrence is oestrogen-receptor negative.US Department of Health and Human Services, Swiss Group for Clinical Cancer Research (SAKK), Frontier Science and Technology Research Foundation, Australian and New Zealand Breast Cancer Trials Group, Swedish Cancer Society, Oncosuisse, Cancer Association of South Africa, Foundation for Clinical Research of Eastern Switzerland (OSKK), Grupo Español de Investigación en Cáncer de Mama (GEICAM), and the Dutch Breast Cancer Trialists' Group (BOOG).

View details for DOI 10.1016/S1470-2045(13)70589-8

View details for Web of Science ID 000330228700028

View details for PubMedID 24439313

Abstract

Nipple-sparing mastectomies (NSM) have gained acceptance in the field of breast oncology. Ischemic complications involving the nipple-areolar complex (NAC) occur in 3-37 % of cases. Skin perfusion can be monitored intraoperatively using indocyanine green (IC-GREEN?, ICG) and a specialized infrared camera-computer system (SPY Elite?). The blood flow pattern to the breast skin and the NAC were evaluated and a classification scheme was developed.Preincision baseline and postmastectomy skin perfusion studies were performed intraoperatively using 3 mL of ICG. The pattern of arterial blood inflow was classified according to whether perfusion appeared to originate predominantly from the underlying breast tissue (V1), the surrounding skin (V2), or a combination of V1 and V2 (V3). Ischemia, resection, or delayed complications of NAC were recorded.Thirty-nine breasts were interrogated. Seven (18 %) demonstrated a V1 pattern, 18 (46 %) a V2 pattern, and 14 (36 %) a V3 pattern. Seven (18 %) NACs were removed; six intraoperatively and the seventh in a delayed fashion. Notably, five of the seven resected NACs had a V1 pattern. Overall, 71 % of all V1 cases demonstrated profound ischemic changes by intraoperative clinical judgment and SPY imaging. The rates of resection of the NAC differed significantly between perfusion patterns (Fisher's exact test, p = 0.0003).Three perfusion patterns for the NAC are defined. The V1 pattern had the highest rate of NAC ischemia in NSM. Imaging NAC and skin perfusion during NSMs is a useful adjunctive tool with potential to direct placement of mastectomy incisions and minimize ischemic complications.

View details for DOI 10.1245/s10434-013-3214-0

View details for PubMedID 24046104

Abstract

Although mastectomy is considered the gold standard for male breast cancer (MBC), the utilization of lumpectomy and its impact on outcomes in MBC patients has not been previously studied.The Surveillance, Epidemiology and End Results (SEER) database was used to identify all MBC patients who underwent either mastectomy or less than mastectomy (i.e., lumpectomy) between 1983 and 2009.A total of 4707 (86.8 %) men underwent mastectomy and 718 (13.2 %) underwent lumpectomy. A greater proportion of patients underwent lumpectomy later in the study period (1983 to 1986, 10.6 %, vs. 2007 to 2009, 15.1 %). A greater percentage of lumpectomy patients were 80 years or older (21.3 % vs. 16.3 %), had stage IV disease (7.3 % vs. 3.1 %), and received no lymph node sampling (34.3 % vs. 6.9 %). Only 35.4 % of patients underwent adjuvant radiotherapy after lumpectomy. Ten-year breast cancer-specific survival and overall survival were 82.8 % and 46.9 %, respectively, in lumpectomy patients vs. 77.3 % and 46.4 %, respectively, in mastectomy patients. On Cox proportional hazards regression, lumpectomy was not independently associated with worse breast cancer-specific survival (odds ratio 1.09, 95 % confidence interval 0.87-1.37) or overall survival (odds ratio 1.12, 95 % confidence interval 0.98-1.27) after controlling for age, race, stage, and grade, as well as whether radiotherapy was received.Lumpectomy is performed in a small but growing proportion of MBC patients. These patients are not only older and more likely to have advanced disease at the time of diagnosis, but they also are less likely to receive standard of care therapy, such as lymph node sampling and adjuvant radiotherapy. Despite these observations, breast cancer-specific survival is unaffected by the type of surgery.

View details for DOI 10.1245/s10434-013-2918-5

View details for Web of Science ID 000317308200021

View details for PubMedID 23460016

Abstract

Lumpectomy is performed in a small but growing proportion of men with breast cancer. It is unknown whether men undergoing breast-conserving surgery (BCS) receive care compliant with breast cancer treatment guidelines. Patients with breast cancer in the surveillance, epidemiology, and end results (SEER) database who underwent lumpectomy between 1983 and 2009 were identified. Gender differences in the receipt of lymph node staging and adjuvant radiation therapy were assessed. Multivariate logistic regression was utilized to evaluate the independent association of gender on these outcomes. The influence of gender on breast cancer-specific survival (BCSS) was analyzed. 382,030 of 824,408 (46.3 %) women compared to 712 of 6,039 (11.8 %) men with breast cancer underwent lumpectomy. Men were older, more likely to be black, less likely to have stage I disease and more likely to have stage IV disease. Only 59.2 % of men had lymph nodes sampled at the time of surgery compared to 81.6 % of women (p < 0.0001). In addition, only 35.4 % of men received adjuvant breast radiation therapy compared to 69.8 % of women (p < 0.0001). After controlling for age, race, stage, grade, and year of diagnosis, female gender was significantly associated with receiving adjuvant radiation therapy (OR 2.9, 95 % CI 2.4-3.4) and lymph node staging (OR 1.6, 95 % CI 1.3-1.90). Five- and ten-year BCSS were 88.0 and 83.5 % for men compared to 93.2 and 88.2 % for women (p < 0.001). Men with breast cancer are less likely to receive lymph node staging or adjuvant radiation therapy following BCS compared to women.

View details for DOI 10.1007/s10549-013-2517-y

View details for PubMedID 23572298

Abstract

Young women diagnosed with breast cancer typically face systemic treatments that may delay childbearing or permanently impair their fertility. These concerns add to the stress experienced by young cancer survivors. Timely counseling and providing fertility preservation through cryopreservation of eggs or embryos have become an important quality of life issue. We analyzed the impact of fertility preservation procedures on the initiation of treatment for breast cancer and discuss critical aspects of the process.

View details for DOI 10.1016/j.ygyno.2011.11.028

View details for Web of Science ID 000300751900018

View details for PubMedID 22173210

Abstract

Ipsilateral breast tumor recurrence (IBTR) is the most common failure event after lumpectomy for ductal carcinoma in situ (DCIS). We evaluated invasive IBTR (I-IBTR) and its influence on survival among participants in two National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized trials for DCIS.In the NSABP B-17 trial (accrual period: October 1, 1985, to December 31, 1990), patients with localized DCIS were randomly assigned to the lumpectomy only (LO, n = 403) group or to the lumpectomy followed by radiotherapy (LRT, n = 410) group. In the NSABP B-24 double-blinded, placebo-controlled trial (accrual period: May 9, 1991, to April 13, 1994), all accrued patients were randomly assigned to LRT+ placebo, (n=900) or LRT + tamoxifen (LRT + TAM, n = 899). Endpoints included I-IBTR, DCIS-IBTR, contralateral breast cancers (CBC), overall and breast cancer-specific survival, and survival after I-IBTR. Median follow-up was 207 months for the B-17 trial (N = 813 patients) and 163 months for the B-24 trial (N = 1799 patients).Of 490 IBTR events, 263 (53.7%) were invasive. Radiation reduced I-IBTR by 52% in the LRT group compared with LO (B-17, hazard ratio [HR] of risk of I-IBTR = 0.48, 95% confidence interval [CI] = 0.33 to 0.69, P < .001). LRT + TAM reduced I-IBTR by 32% compared with LRT + placebo (B-24, HR of risk of I-IBTR = 0.68, 95% CI = 0.49 to 0.95, P = .025). The 15-year cumulative incidence of I-IBTR was 19.4% for LO, 8.9% for LRT (B-17), 10.0% for LRT + placebo (B-24), and 8.5% for LRT + TAM. The 15-year cumulative incidence of all contralateral breast cancers was 10.3% for LO, 10.2% for LRT (B-17), 10.8% for LRT + placebo (B-24), and 7.3% for LRT + TAM. I-IBTR was associated with increased mortality risk (HR of death = 1.75, 95% CI = 1.45 to 2.96, P < .001), whereas recurrence of DCIS was not. Twenty-two of 39 deaths after I-IBTR were attributed to breast cancer. Among all patients (with or without I-IBTR), the 15-year cumulative incidence of breast cancer death was 3.1% for LO, 4.7% for LRT (B-17), 2.7% for LRT + placebo (B-24), and 2.3% for LRT + TAM.Although I-IBTR increased the risk for breast cancer-related death, radiation therapy and tamoxifen reduced I-IBTR, and long-term prognosis remained excellent after breast-conserving surgery for DCIS.

View details for DOI 10.1093/jnci/djr027

View details for Web of Science ID 000288554900008

View details for PubMedID 21398619

Abstract

Breast cancer brain metastases are on the rise and their treatment is hampered by the limited entry and efficacy of anticancer drugs in this sanctuary. The sodium iodide symporter, NIS, actively transports iodide across the plasma membrane and is exploited clinically to deliver radioactive iodide into cells. As in thyroid cancers, NIS is expressed in many breast cancers including primary and metastatic tumors. In this study NIS expression was analyzed for the first time in 28 cases of breast cancer brain metastases using a polyclonal anti-NIS antibody directed against the terminal C-peptide of human NIS gene and immunohistochemical methods. Twenty-five tumors (84%) in this retrospective series were estrogen/progesterone receptor-negative and 15 (53.6%) were HER2+. Overall 21 (75%) cases and 80% of HER2 positive metastases were NIS positive. While the predominant pattern of NIS immunoreactivity is intracellular, plasma membrane immunopositivity was detected at least focally in 23.8% of NIS-positive samples. Altogether, these findings indicate that NIS expression is prevalent in breast cancer brain metastases and could have a therapeutic role via the delivery of radioactive iodide and selective ablation of tumor cells.

View details for DOI 10.1007/s11060-009-9971-8

View details for Web of Science ID 000273788700004

View details for PubMedID 19618116

Abstract

Protecting future childbearing motivates young women with breast cancer to seek oocyte or embryo cryopreservation. Concerns about delays in cancer treatment may influence patients and practitioners considering these procedures. In this study, we compared timing of chemotherapy in women who underwent ovarian stimulation/oocyte retrieval (OR) and embryo cryopreservation with those who did not.Eighty-two women younger than 40 years of age, who received adjuvant chemotherapy for breast cancer, were retrospectively identified. Nineteen underwent OR and 63 did not (CON). The timing of OR, surgery, and chemotherapy were compared with the time intervals between diagnosis and treatments in the CON group.The mean ages of women were 33.7 years (OR group) and 35.2 years (CON group); 84.2% of OR and 25.4% of CON were nulliparous. The median time from initial diagnosis to reproductive endocrinology consultation was 30.1 days (range 4 to 133 days) and from referral to OR was 32 days (range 13 to 66 days). The median times from initial diagnosis to chemotherapy in OR versus CON groups were 71 days (range 45 to 161 days) and 67 days (range 27 to 144 days), respectively, p < 0.27. The median time interval from definitive operation to chemotherapy was similar in the two groups: 30 days (OR; range 14 to 100 days) and 29 days (CON; range 12 to 120 days), p < 0.79.Fertility preservation is an important component of quality of life for young women with breast cancer. The time investment required for OR and cryopreservation is manageable and does not significantly prolong the time interval from diagnosis to start of adjuvant chemotherapy.

View details for DOI 10.1016/j.jamcollsurg.2009.08.006

View details for Web of Science ID 000271876400008

View details for PubMedID 19854400

Abstract

Locoregional failure (LRF) after breast-conserving therapy (BCT) is associated with increased risk of distant disease and death. The magnitude of this risk has not been adequately characterized in patients with lymph node-negative disease.Our study population included 3,799 women randomly assigned to five National Surgical Adjuvant Breast and Bowel Project protocols of node-negative disease (ie, B-13, B-14, B-19, B-20, and B-23) who underwent lumpectomy and whole breast irradiation with or without adjuvant systemic therapy. Cumulative incidences of ipsilateral breast tumor recurrence (IBTR) and other locoregional recurrence (oLRR) were calculated, along with distant-disease-free interval (DDFI) and overall survival (OS) after these events. Cox models were employed to model mortality by using clinical and pathologic factors jointly with these events.Four hundred nineteen patients (11.0%) experienced LRF: 342 (9.0%) experienced IBTR, and 77 (2.0%) experienced oLRR. The 12-year cumulative incidences of IBTR and oLRR in patients treated with adjuvant systemic therapy were 6.6% and 1.8%, respectively. Overall, 37.1% of IBTRs and 72.7% of oLRRs occurred within 5 years of diagnosis. Older age, black race, higher body mass index (BMI), larger tumors, and occurrence of IBTR or oLRR were significantly associated with increased mortality. The 5-year OS after IBTR and oLRR were 76.6% and 34.9%, respectively. Adjusted hazard ratios for mortality associated with IBTR and oLRR were significantly higher in estrogen receptor (ER)-negative patients than in ER-positive patients (P = .002 and P < .0001, respectively). Patients with early LRF had worse OS and DDFI than those with later-occurring LRF.Although LRF is uncommon in patients with node-negative breast cancer who are treated with lumpectomy, radiation, and adjuvant systemic therapy, those who do develop LRF have substantially worse OS and DDFI.

View details for DOI 10.1200/JCO.2008.19.8424

View details for Web of Science ID 000266195400011

View details for PubMedID 19349544

Abstract

The sodium iodide symporter (NIS) mediates iodide transport into cells and has been identified in approximately 70% of breast cancers. Functional NIS expression raises the possibility of using (131)I for therapeutic targeting of tumor cells. Treatment of triple-negative breast cancers [estrogen/progesterone receptor-negative and HER2-negative (ER-/PR-/HER2-)] is primarily limited to chemotherapy. Our aim was to characterize NIS expression in this subset of tumors.Archival tissue sections from 23 women with triple-negative breast cancer were analyzed for NIS expression using immunohistochemical methods and an anti-human NIS antibody. Tumors were evaluated for the presence of plasma membrane immunoreactivity. One patient with a NIS-expressing positive tumor underwent (123)I scintigraphic imaging with dosimetric analysis.Fifteen cases (65.2%) demonstrated NIS-positivity with 11 tumors (47.8%) exhibiting strong expression. Plasma membrane immunoreactivity was observed in four breast cancers and was equivocal in another four tumors. Tumor-specific radioiodide uptake was demonstrated by (123)I scintigraphy in a patient with a large primary breast cancer unresponsive to neoadjuvant therapy. The tumor concentrated 2.05, 1.53, and 1.96 times more isotope than normal breast tissue at 1, 5, and 21 h. The relative increased uptake is consistent with positive NIS expression in the tumor on definitive surgery; however, the cumulative concentration in the tumor was not sufficient to achieve a therapeutic effect, had the isotope been (131)I.NIS is strongly expressed in a significant proportion of triple-negative breast cancer cells, suggesting a potential role for NIS-directed (131)I-radioablative strategies in this patient population.

View details for DOI 10.1245/s10434-008-0280-9

View details for Web of Science ID 000263976000026

View details for PubMedID 19184238

Abstract

In this phase III, multinational, randomized trial, the International Breast Cancer Study Group, Breast International Group, and the National Surgical Adjuvant Breast and Bowel Project will attempt to define the effectiveness of cytotoxic therapy for patients with locoregional recurrence of breast cancer. We will evaluate whether chemotherapy prolongs disease-free survival and, secondarily, whether its use improves overall survival and systemic disease-free survival. Quality of life measurements will be monitored during the first 12 months of the study. Women who have had a previous diagnosis of invasive breast cancer treated by mastectomy or breast-conserving surgery and who have undergone complete surgical excision of all macroscopic disease but who subsequently develop isolated local and/or regional ipsilateral invasive recurrence are eligible. Patients are randomized to observation/no adjuvant chemotherapy or to adjuvant chemotherapy; all suitable patients receive radiation, hormonal, and trastuzumab therapy. Radiation therapy is recommended for patients who have not received previous adjuvant radiation therapy but is required for those with microscopically positive margins. The radiation field must encompass the tumor bed plus a surrounding margin to a dose of >or= 40 Gy. Radiation therapy will be administered before, during, or after chemotherapy. All women with estrogen receptor-positive and/or progesterone receptor-positive recurrence must receive hormonal therapy, with the agent and duration to be determined by the patient's investigator. Adjuvant trastuzumab therapy is permitted for those with HER2- positive tumors, provided that intent to treat is declared before randomization. Although multidrug regimens are preferred, the agents, doses, and use of supportive therapy are at the discretion of the investigator.

View details for DOI 10.3816/CBC.2008.n.035

View details for Web of Science ID 000256914800013

View details for PubMedID 18650162

Abstract

Infertility is a concern to young women diagnosed with breast cancer. Advances in fertility technology have made it possible to bank fertilized embryos.Twenty-three women, ages 27 to 40 years, underwent stimulation/oocyte retrieval before the start of adjuvant therapies. Time intervals between retrieval and therapeutic procedures were analyzed.The average stimulation to egg retrieval was 11.5 days (range 9-20 d). The average time interval from first evaluation to oocyte retrieval was 33.3 days (range 10-65 d). Overall, the mean time from definitive surgery to initiation of chemotherapy was 46.8 days (n = 20). For 6 patients referred by surgeons, the mean time from fertility consult to retrieval was 48.8 days (range 16-118 d), and from definitive surgery to initiation of chemotherapy was 45 days (range 15-93 d).Egg retrieval cryopreservation can be integrated with breast cancer work-up and surgical procedures. Early referrals to a fertility specialist by surgeons will help patients' safeguard future childbearing.

View details for DOI 10.1016/j.amjsurg.2007.06.008

View details for Web of Science ID 000249933000011

View details for PubMedID 17826059

Abstract

Locoregional failure after breast-conserving surgery is associated with increased risk of distant disease and death. The magnitude of this risk in patients receiving chemotherapy has not been adequately characterized.Our study population included 2,669 women randomly assigned onto five National Surgical Adjuvant Breast and Bowel Project node-positive protocols (B-15, B-16, B-18, B-22, and B-25), who were treated with lumpectomy, whole-breast irradiation, and adjuvant systemic therapy. Cumulative incidences of ipsilateral breast tumor recurrence (IBTR) and other locoregional recurrence (oLRR) were calculated. Kaplan-Meier curves were used to estimate distant-disease-free survival (DDFS) and overall survival (OS) after IBTR or oLRR. Cox models were used to model survival using clinical and pathologic factors jointly with IBTR or oLRR as time-varying predictors.Four hundred twenty-four patients (15.9%) experienced locoregional failure; 259 (9.7%) experienced IBTR, and 165 (6.2%) experienced oLRR. The 10-year cumulative incidence of IBTR and oLRR was 8.7% and 6.0%, respectively. Most locoregional failures occurred within 5 years (62.2% for IBTR and 80.6% for oLRR). Age, tumor size, and estrogen receptor status were significantly associated with IBTR. Nodal status and estrogen and progesterone receptor status were significantly associated with oLRR. The 5-year DDFS rates after IBTR and oLRR were 51.4% and 18.8%, respectively. The 5-year OS rates after IBTR and oLRR were 59.9% and 24.1%, respectively. Hazard ratios for mortality associated with IBTR and oLRR were 2.58 (95% CI, 2.11 to 3.15) and 5.85 (95% CI, 4.80 to 7.13), respectively.Node-positive breast cancer patients who developed IBTR or oLRR had significantly poorer prognoses than patients who did not experience these events.

View details for DOI 10.1200/JCO.2005.04.3273

View details for Web of Science ID 000237371500012

View details for PubMedID 16648502

Abstract

Optical imaging has made it possible to monitor response to anticancer therapies in tumor xenografts. The concept of treating breast cancers with (131)I is predicated on the expression of the Na(+)/I- symporter (NIS) in many tumors and uptake of I- in some. The pattern of (131)I radioablative effects were investigated in an MCF-7 xenograft model dually transfected with firefly luciferase and NIS genes. On Day 16 after tumor cell implantation, 3 mCi of (131)I was injected. Bioluminescent imaging using d-luciferin and a cooled charge-coupled device camera was carried out on Days 1, 2, 3, 7, 10, 16, 22, 29, and 35. Tumor bioluminescence decreased in (131)I-treated tumors after Day 3 and reached a nadir on Day 22. Conversely, bioluminescence steadily increased in controls and was 3.85-fold higher than in treated tumors on Day 22. Bioluminescence in (131)I-treated tumors increased after Day 22, corresponding to tumor regrowth. By Day 35, treated tumors were smaller and accumulated 33% less (99m)TcO(4)(-) than untreated tumors. NIS immunoreactivity was present in <50% of (131)I-treated cells compared to 85-90% of controls. In summary, a pattern of tumor regression occurring over the first three weeks after (131)I administration was observed in NIS-expressing breast cancer xenografts.

View details for DOI 10.2310/7290.2006.00008

View details for Web of Science ID 000239285900004

View details for PubMedID 16954021

Abstract

The Na(+)/I(-) symporter (NIS) is a key plasma membrane protein that mediates active iodide (I(-)) transport in the thyroid, lactating breast, and other tissues. Functional NIS expression in thyroid cancer accounts for the longstanding success of radioactive iodide ((131)I) ablation of metastases after thyroidectomy. Breast cancer is the only other cancer demonstrating endogenous functional NIS expression. Until now, NIS activity in breast cancer metastases (BCM) was unproven.Twenty-seven women were scanned with (99m)TcO(4)(-) or (123)I(-) to assess NIS activity in their metastases. An (131)I dosimetry study was offered to patients with I(-)-accumulating tumors. Selective down-regulation of thyroid NIS was tested in 13 patients with T(3) and in one case with T(3) + methimazole (MMI; blocks I(-) organification). NIS expression was evaluated in index and/or metastatic tumor samples by immunohistochemistry.I(-) uptake was noted in 25% of NIS-expressing tumors (two of eight). The remaining cases did not show NIS expression or activity. Thyroid I(-) uptakes were decreased to

View details for Web of Science ID 000222457300002

View details for PubMedID 15240514

Abstract

Extrathyroidal cancers could potentially be targeted with (131)I, if the Na(+)/I(-) symporter (NIS) were functional. Using immunohistochemical methods we probed 1278 human samples with anti-NIS antibody, including 253 thyroid and 169 breast conventional whole tissue sections (CWTS). Four high density tissue microarrays containing a wide variety of breast lesions, normal tissues, and carcinoma cores were tested. The results of the normal microarray were corroborated in 50 CWTS. Nineteen of 34 normal tissues, including bladder, colon, endometrium, kidney, prostate, and pancreas, expressed NIS. Nineteen of 25 carcinomas demonstrated NIS immunopositivity; 55.7% of 479 carcinoma microarray cores expressed NIS, including prostate (74%), ovary (73%), lung (65%), colon (62.6%), and endometrium (56%). NIS protein was present in 75% benign thyroid lesions, 73% thyroid cancers, 30% normal-appearing, peritumoral breasts, 88% ductal carcinomas in situ, and 76% invasive breast carcinoma CWTS. Comparatively, breast microarray cores had lower immunoreactivity. Plasma membrane immunopositivity was confirmed in thyrocytes, salivary ductal, gastric mucosa, and lactating mammary cells. In other tissues, immunoreactivity was predominantly intracellular, particularly in malignant lesions. Thus, NIS is present in many normal epithelial tissues and is predominantly expressed intracellularly in many carcinomas. Elucidating the regulatory mechanisms that render NIS functional in extrathyroidal carcinomas may make (131)I therapy feasible.

View details for DOI 10.1210/jc.2002-021544

View details for Web of Science ID 000182211000072

View details for PubMedID 12679487

Abstract

The sodium/iodide symporter mediates active iodide transport in both healthy and cancerous thyroid tissue. By exploiting this activity, radioiodide has been used for decades with considerable success in the detection and treatment of thyroid cancer. Here we show that a specialized form of the sodium/iodide symporter in the mammary gland mediates active iodide transport in healthy lactating (but not in nonlactating) mammary gland and in mammary tumors. In addition to characterizing the hormonal regulation of the mammary gland sodium/iodide symporter, we demonstrate by scintigraphy that mammary adenocarcinomas in transgenic mice bearing Ras or Neu oncogenes actively accumulate iodide by this symporter in vivo. Moreover, more than 80% of the human breast cancer samples we analyzed by immunohistochemistry expressed the symporter, compared with none of the normal (nonlactating) samples from reductive mammoplasties. These results indicate that the mammary gland sodium/iodide symporter may be an essential breast cancer marker and that radioiodide should be studied as a possible option in the diagnosis and treatment of breast cancer.

View details for Web of Science ID 000165473800029

View details for PubMedID 10932223

Abstract

Excessive deposition of extracellular matrix or neomatrix is a characteristic of desmoplastic invasive breast carcinomas. Type I and III collagens are abundant neomatrix components. Archival breast tissue sections were studied using 35S-labeled cDNA probes for alpha 1(I) and alpha 1(III) procollagen and in situ hybridization. Among the 33 invasive breast cancers, hybridization was seen forming a gradient-like pattern in fibroblasts closest to tumor cells. In the 10 ductal carcinomas in situ studied, a ring-like pattern of hybridization was seen in proximity to the basement membrane zone. Adjacent normal and benign tissues did not demonstrate the patterns of hybridization described in malignant tissues. Gene expression for neomatrix interstitial collagens occurs before there is evidence of invasion in carcinoma of the breast.

View details for Web of Science ID A1997YE40000005

View details for PubMedID 9371230

Abstract

Breast cancers are three dimensional solids but very few are spherical. We hypothesized that calculations based on the greatest diameter would not accurately reflect tumor volume and that three dimensional measurements would affect tumor staging.165 invasive carcinomas measuring 2.5 cm or less and having three measured diameters (a > or = b > or = c) noted were evaluated. Tumor volume was calculated using four geometric models: the spherical 4/3 pi (a/2)3, prolate spheroid 4/3 pi (a/2) (c/2)2, oblate spheroid 4/3 pi (a/2)2 (b/2), and ellipsoid 4/3 pi (a/2 x b/2 x c/2). The ellipsoid correctly determined the volume for any tumor shape. All cases were stratified according to the TNM staging system. Differences in mean volume calculated as a sphere and ellipsoid for each tumor subclass were analyzed using Student's T test. The reclassification of tumors by the ellipsoid formula was determined.Seventy-six (46.1%) had tumors with three different diameters while only six (3.6%) were true spheres having three identical diameters. Mean tumor volume analysis of T1a, T1b, T1c, and T2 tumors demonstrated a statistically significant overestimation of volume when utilizing the sphere formula instead of the ellipsoid formula (p < 0.05). The differences in volume were more dramatic as the diameters increased. A total of 41 tumors were moved into smaller T subclasses including 10 node positive patients.Tumor volume analysis demonstrates that use of only the greatest diameter poorly reflects the true volume of a lesion and consistently overestimates volume. The ellipsoid formula accurately calculates volume for these three dimensional tumors and when utilized has significant relevance to staging small invasive breast cancers.

View details for Web of Science ID A1996VR62000002

View details for PubMedID 8932872

Abstract

The concept of prophylactic mastectomy was nurtured in the shadow of the radical mastectomy. It evolved as preferable to the mutilation caused by the procedure. It developed during a time when the difference between benignancy and malignancy was not as clear and when patients with benign disease were thought to be at significant risk. The idea of surgical prophylaxis accompanied by a superior cosmetic result, in comparison to the radical mastectomy is a noble one. In retrospect, however, it is clear that the indications were ill defined, based often on unfounded risk and predicated on patient and physician anxiety. The scope of risk in carcinoma of the breast has been narrowed, with new information identifying only specific subsets of women with proliferative types of benign disease as more susceptible to the subsequent development of carcinoma. Extensive reviews of material taken at biopsy that had been validated longitudinally have provided data to substantiate this contention. The concept of familial high risk must take into account the number of affected family members, at age diagnosis, menopausal status and bilaterality. The majority of indicants that motivated and propitiated the performance of the bulk of prophylactic mastectomies have lost their relevance. Prophylactic mastectomy for carcinoma, therefore, can perhaps be reserved for women with biopsy-proved, high-risk lesions or an exceptional familial risk, or both, or hereditary risk. Such women must choose for themselves and accept the uncertainty of hypothetic risk reduction, life-long continued surveillance and an altered body image. Guiding patients in the decision should involve a multidisciplinary team composed of a surgical oncologist, geneticist, pathologist, psychotherapist and plastic surgeon. As a concept, the reduction of risk is appealing, but remains yet to prove itself superior to rigorous clinical surveillance with high-quality mammography. The experience reflected in the literature of a seemingly low rate of subsequent carcinoma cannot be judged, because it seems that operations were applied indiscriminantly to patients selected by unknown means and from an unknown population pool. Success based on protecting those not at increased risk only invalidates the operation further. Most surgical and medical oncologists recognize that carcinoma of the breast is either localized or disseminated at the time of the initial diagnosis.(ABSTRACT TRUNCATED AT 400 WORDS)

View details for Web of Science ID A1990DR88900018

View details for PubMedID 2200150