Heat shock protein 27 overexpression in breast cancer lymph node metastasis

Background: Heat shock protein 27 (hsp-27) is overexpressed in 67% pure ductal carcinoma in situ (DCIS), in 50% DCIS associated with invasive ductal carcinoma (IDC), and in 25% IDC alone. If this decrease in hsp-27 expression has a role in the progression of malignancy in IDC, we postulate a further reduction in expression in nodal metastasis. Methods: To test this hypothesis, we evaluated the distribution of hsp-27 in primary IDC and in synchronous regional lymph node metastasis within the same patient by immunohistochemistry. Results: Nine of 30 primary IDCs (30%) and 22 of 30 lymph node metastases (73%) overexpressed hsp-27. Contrary to our hypothesis, of 21 IDCs with no or low hsp-27 expression, 13 (62%) had overexpression of this protein within nodal metastasis. Conclusions: hsp-27 appears to confer cytoprotection for metastatic cells, which may help explain why hsp-27 overexpression is associated with reduced disease-free survival in breast carcinomas.     

Response to HER-2 Pulsed DC1 Vaccines is Predicted by Both HER-2 and Estrogen Receptor Expression in DCIS

Background

Patients with estrogen-independent (ER^neg) human epidermal growth factor receptor-2 (HER-2)-positive ductal carcinoma in situ (DCIS) treated with lumpectomy alone or lumpectomy and radiation are at increased risk of developing subsequent breast cancer events.

Methods

Thirty-eight patients with HER-2 expressing DCIS received a HER-2 pulsed autologous dendritic cell (DC1) vaccine administered over 4–6 weeks before surgical resection. HER-2 and estrogen receptor (ER) expression were determined by immunohistochemistry. In 35 patients, CD4^pos T-cell sensitization to HER-2 peptides was identified by ELISPOT. In 19 patients, CD8^pos T-cell responses were identified by ELISA. Clinical and immune responses postvaccination were compared between intermediate-expressing HER-2 (2+) and high-expressing HER-2 (3+) patients, as well as ER^neg and estrogen-dependent (ER^pos) patients.

Results

There was no significant difference in immune response after HER-2 vaccination in patients with HER-2 (2+) and (3+) tumors or ER^neg and ER^pos tumors. Complete tumor regression rates were similar in patients with HER-2 (2+) and (3+) DCIS. Overall, clinical response rates were similar in patients with ER^neg and ER^pos DCIS, but complete tumor regression was significantly more common in patients with ER^neg DCIS.

Conclusions

Despite equivalent immune responses after vaccination in patients with HER-2 (2+), HER-2 (3+), ER^neg and ER^pos DCIS, HER-2 pulsed DC1 induces more complete responses in patients with ER^neg DCIS. These data provide a rationale for developing vaccinations to reduce recurrence in patients with ER^neg DCIS for whom there are currently limited adjuvant options.     

HER-2 overexpression is not associated with increased ipsilateral breast tumor recurrence in DCIS treated with breast-conserving surgery followed by radiotherapy

BackgroundWe evaluated the clinical implications of human epidermal growth factor receptor (HER)-2 overexpression after adjuvant radiotherapy (RT) for ductal carcinoma in situ (DCIS).MethodsWe reviewed 215 patients with DCIS who underwent breast-conserving surgery followed by RT. The association between HER-2 overexpression and ipsilateral breast tumor recurrence (IBTR) was evaluated.ResultsHER-2 overexpression was associated with comedo-type architecture, high nuclear grade, and negative hormonal receptors. The median follow-up duration was 75 months. Sixteen patients experienced IBTR; seven as DCIS recurrence and nine as invasive recurrence. The IBTR rate was 11.4% at 10 years. There was no significant difference in IBTR according to HER-2 expression (P = 0.1764), neither in invasive nor DCIS recurrence. Time to recurrence was shorter in HER-2 positive tumors (P = 0.0697).ConclusionAdjuvant RT seems to counteract the negative effect of HER-2 overexpression in DCIS, while time to recurrence was relatively shorter.     

Type I Receptor Tyrosine Kinases as Targets for Therapy in Breast Cancer

Breast carcinomas express high levels of type I tyrosine kinase receptors and their ligands. For these reason therapies directed at these receptors have the potential to be useful anti-cancer agents. A series of monoclonal antibodies (MAbs)³ directed against the EGF receptor and the closely related erbB2/HER2/neu receptor are currently under evaluation. These MAbs have shown promising preclinical activity and chimeric and humanized MAbs have been produced in order to obviate the problem of host immune reactions. These antibodies are currently being tested in clinical trials either alone or in combination with chemotherapeutic agents. Clinical activity with anti-HER2/neu MAbs has been documented in patients with advanced breast cancer. In addition, compounds that inhibit receptor tyrosine kinases have shown significant preclinical activity and are potential candidates for clinical testing.     

Magnetic resonance imaging of trabecular bone structure in the distal radius: Relationship with X-ray tomographic microscopy and biomechanics

The contribution of trabecular bone structure to bone strength is of considerable interest in the study of osteoporosis and other disorders characterized by changes in the skeletal system. Magnetic resonance (MR) imaging of trabecular bone has emerged as a promising technique for assessing trabecular bone structure. In this in vitro study we compare the measures of trabecular structure obtained using MR imaging and higher-resolution X-ray tomographic microscopy (XTM) imaging of cubes from human distal radii. The XTM image resolution is similar to that obtained from histomorphometric sections (18 µm isotropic), while the MR images are obtained at a resolution comparable to that achievable in vivo (156×156×300 µm). Standard histomorphometric measures, such as trabecular bone area fraction (synonymous with BV/TV), trabecular width, trabecular spacing and trabecular number, texture-related measures and three-dimensional connectivity (first Betti number/volume) of the trabecular network have been derived from these images. The variation in these parameters as a function of resolution, and the relationship between the structural parameters, bone mineral density and the elastic modulus are also examined. In MR images, because the resolution is comparable to the trabecular dimensions, partial volume effects occur, which complicate the segmentation of the image into bone and marrow phases. Using a standardized thresholding criterion for all images we find that there is an overestimation of trabecular bone area fraction (3 times), trabecular width (3 times), fractal dimension (1.4 times) and first Betti number/ volume (10 times), and an underestimation of trabecular spacing (1.6 times) in the MR images compared with the 18-µm XTM images. However, even for a factor of 9 difference in spatial resolution, the differences in the morphological trabecular structure measures ranged from a factor of 1.4 to 3.0. We have found that trabecular width, area fraction, number, fractal dimension and Betti number/volume measured from the XTM and MR images increases, while trabecular spacing decreases, as the bone mineral density and elastic modulus increase. A preliminary bivariate analysis showed that in addition to bone mineral density alone, the Betti number, trabecular number and spacing contributed to the prediction of the elastic modulus. This preliminary study indicates that measures of trabecular bone structure using MR imaging may play a role in the study of osteoporosis.     

Higher expression of oncoproteins c-myc,c-erbB-2/neu,PCNA, and p53 in metastasizing colorectal cancer than in nonmetastasizing tumors

Background: Expression of individual oncogenes may predict outcome in patients with metastatic colorectal cancer (CRC). We studied the oncogene profile in the tumors of patients with CRC and assessed their value as predictors of liver metastases. Methods: The oncoproteins c-myc, c-erbB-2/neu (c-neu), PCNA and p53, were measured by immunohistochemistry in sections of metastasizing human CRC (n=34) and their liver secondaries as well as in sections of nonmetastasizing CRC (n=25). Results: The metastasizing primary CRC expressed proliferating-cell nuclear antigen (PCNA), c-neu, and c-myc at significantly higher levels than the nonmetastasizing primary cancer. p53 was also overexpressed in the metastatic group compared with the nonmetastasizing CRC, but this difference was not significant. The frequency of expression of all these markers was similar in the metastasizing primary CRC and the liver secondaries from the same patients. There was no correlation between the expression of the individual markers and histological grade, DNA ploidy, and subsequent local recurrence and lung metastasis and survival. However, when both groups were assessed together, positive expression of c-myc was more likely to occur in poorly differentiated tumors, whereas PCNA expression increased with more advanced Dukes stages. Conclusion: These results suggest that the overexpression of c-myc, c-neu, PCNA, and p53 may occur in CRC that are likely to metastasise to the liver.     

ESOT - Novartis Study Grant: Call for Application,Guidelines and Application Form

The effect of the Prandtl number (Pr) and the Reynolds number (Re) on the behaviour of weak laminar axisymmetric and plane fountains has been studied using dimensional and scaling analyses and direct numerical simulation. For Fr 1.0 and assuming viscous effects are important, the analysis shows that for both the axisymmetric and plane fountains, y_mFrRe^–1/2, where Fr is the Froude number defined at the fountain source and y_m is the non-dimensionalized fountain height. These scalings are also valid for the non-dimensionalized fountain width. The analyses also shows _msFr², where _ms is the non-dimensionalized time scale for the fountain flow in the fountain core to reach steady state, and using this time scale y_TFr(RePr)^–1/2, where y_T is the non-dimensionalized thickness of the temperature layer on the symmetry axis over which the fountain fluid temperature changes from the inlet value to that of the ambient fluid. All these scalings have been quantified by the direct numerical simulations, hence confirming in certain ranges the phenomenological scaling obtained in this paper. The financial supports from the National Natural Science Foundation (grant numbers 19872059 and 10262003) and Yunnan Province of the People's Republic of China to W. Lin and the Australian Research Council are gratefully acknowledged.     

Regulation of mineral-to-matrix ratio of lumbar trabecular bone in ovariectomized rats treated with risedronate in combination with or without vitamin K<Subscript>2</Subscript>

The relationship between bone turnover and bone tissue and material properties was examined in ovariectomized (OVX) rats treated with risedronate in combination with or without vitamin K₂. Seventy female rats, 18 weeks of age, were assigned to 7 groups (n = 10): sham-operated + vehicle control; OVX + vehicle control; OVX + risedronate 0.1, 0.5, or 2.5mg/kg/day po; OVX + vitamin K₂ 30mg/kg/day po; OVX + vitamin K₂ (30mg/kg/day) and risedronate (0.5mg/kg/day). Treatments were given daily for 9 months. To assess bone turnover, we measured serum osteocalcin and urinary deoxypyridinoline at 0, 3, and 9 months. To assess vertebral and femoral tissue and material properties, bone mass, bone mineral density (BMD by DXA), trabecular bone structure (vertebra: 3D-CT), cortical bone structure (femur: histomorphometry), biomechanical properties, and mineral properties (mineral-to-matrix and carbonate-to-phosphate ratios by Fourier transform infrared microspectroscopy) were measured ex vivo at 9 months. Ovariectomy increased bone turnover and induced significant loss of bone mass/density, structure, mineral properties (mineral-to-matrix ratio), and strength. Risedronate produced dose-dependent inhibition of the ovariectomy-induced increase in turnover and loss of bone mass/density, structure, mineral-to-matrix ratio, and strength, with a lowest effective dose of 0.1–0.5mg/kg/day. High-dose risedronate (2.5mg/kg/day) did not induce increases in any parameter above that of sham control. Vitamin K₂ had no effects. In the OVX groups, urinary deoxypyridinoline at 3 and 9 months correlated significantly with vertebral BMD, trabecular bone volume, ultimate load, stiffness, and mineral-to-matrix ratio, and with femoral BMD, cortical area, and ultimate load. These results support the concept that changes in bone tissue and material properties can result directly from changes in bone turnover. Different effects among different drugs on material properties, including mineral-to-matrix ratio, may reflect differences in the relative rate and magnitude of osteoclastic bone resorption and osteoblastic primary bone mineralization.     

The Finding of Invasive Cancer After a Preoperative Diagnosis of Ductal Carcinoma-In-Situ: Causes of Ductal Carcinoma-In-Situ Underestimates With Stereotactic 14-Gauge Needle Biopsy

Background: For the evaluation of nonpalpable lesions of the breast, image-guided 14-gauge automated needle biopsy is increasingly replacing wire-localized excision. When ductal carcinoma-in-situ (DCIS) is diagnosed at core biopsy, invasive cancer is found in approximately 17% of excision specimens. These so-called DCIS underestimates pose a problem for patients and surgeons, because they generally cause extension of treatment. We evaluated DCIS underestimates in detail to assess reasons for missing the invasive component at core biopsy. This evaluation also included a histological comparison with true DCIS (DCIS at core biopsy and excision).Methods: Between 1997 and 2000, DCIS was diagnosed at 14-gauge needle biopsy in 255 patients. In 41 cases (16%), invasive cancer was found at excision. We performed a thorough histopathological and radiological review of all these DCIS underestimates, including a histological comparison with core biopsy specimens of 32 true DCIS cases. We assessed the main reason for missing the invasive component at core biopsy.Results: Causes for DCIS underestimates were categorized into mainly radiological (n = 20), mainly histopathological (n = 15), and histological disagreements (n = 6). High-grade DCIS and periductal inflammation in core biopsies made a DCIS underestimate 2.9 and 3.3 times more likely, respectively.Conclusions: A variety of radiological and histopathological reasons contribute to the DCIS underestimate rate. Approximately half of these are potentially avoidable.     

Overexpression ofbax enhances the radiation sensitivity in human breast cancer cells

Bax-a, a splice variant ofbax which promotes apoptosis, is expressed in many kinds of untransformed cell lines and breast tissue, whereas only weak or no expression could be detected in breast cancer cell lines and malignant breast tissue. Human breast cancer MCF-7 cells, which have a weakbax gene expression, were stably transfected with pCX2neobax encoding humanbax and neomycin-resistant genes, and two unique clones (MCF-7/bax-1 and MCF-7/bax-2) were thus generated which expressed different levels ofbax-. Sensitivity to ionizing radiation (IR) was examined and each was more sensitive to IR than the parental MCF-7 cells. The degree of enhancement in radiosensitivity was dependent on the expression level ofbax, and IR was found to induce intranucleosomal DNA fragmentation in stable transfectant but not in parent cells, thus suggesting that this sensitization is due to apoptosis. We suggest that exogenousbax- expression might therefore be one of the factors determining cellular radiosensitivity in MCF-7 breast cancer cells and may potentially have a therapeutic application by enhancing radiation sensitivity in breast cancer cells.     

The effect of verapamil on halothane-epinephrine or digitalis-induced ventricular dysrhythmias in dogs

The effect of verapamil on ventricular dysrhythmias was evaluated using two canine models. In one model, ventricular dysrhythmias were induced by 1% halothane-epinephrine (1.5 30µg/kg/min.) in 20 dogs (Group I). In the other model, ventricular dysrhythmias were induced by digoxin (0.1 0.2mg/kg) in 27 dogs (Group II). Verapamil (0.2 0.5mg/kg) was given to treat these ventricular dysrhythmias. When verapamil was ineffective, lidocaine (1 2mg/kg) was given following the administration of verapamil. In 7 dogs of group II, lidocaine alone was given. Verapamil was effective in 16 animals of group I, and in 10 animals of group II. Lidocaine was ineffective in the remaining 4 of group I, whereas effective in the remaining 17, including those given lidocaine alone of group II. From these findings, it was inferred that Ca²⁺ dependent abnormal automaticity and/or re-entry may be more closely related to the genesis of halothane-epinephrine-induced ventricular dysrhythmias refractory to lidocaine, whereas triggered activity may be more closely related to that of digitalis-induced ventricular dysrhythmias. In conclusion, verapamil was more effective against halothane-epinephrine-induced ventricular dysrhythmias than against digitalis-induced ventricular dysrhythmias.(Yoshizawa Y, Shimizu R, Kasuda H et al.: The effect of verapamil on halothan-epinephrine or digitalis-induced ventricular dysrhythmia in dogs. J Anesth 2: 28–35, 1988)     

Enamel matrix protein turnover during amelogenesis: Basic biochemical properties of short-lived sulfated enamel proteins

The formation and turnover of sulfated enamel proteins was investigated by SDS-PAGE, fluorography, and TCA-precipitations using freeze-dried incisors of rats injected intravenously with ³⁵S-sulfate (³⁵SO₄) and processed at various intervals from 1.6 minutes to 4 hours thereafter. Some rats were injected first with ³⁵SO₄ followed 5 minutes later by 0.3 mg of cycloheximide. This was done to terminate protein translation and allow events related to extracellular processing and degradation of the sulfated enamel proteins to be visualized more distinctly. Other rats were injected with cycloheximide followed at 0 minutes (simultaneous injection) to 30 minutes later by ³⁵SO₄. This was done to characterize the time required for proteins to travel from endoplasmic reticuium to Golgi apparatus, where they became sulfated. The results indicated that enamel organ cells (ameloblasts) rapidly incorporated ³⁵SO₄ into a major 65 kDa protein that was secreted into the enamel within 6–7.5 minutes. This parent protein appeared to be processed extracellularly within 15 minutes into major 49 kDa and 25 kDa fragments which themselves had apparent half-lives of about 1 and 2 hours, respectively. There were also many minor sulfated fragments varying in molecular weight (Mr) from 13–42 kDa, which appeared to originate from extracellular processing and/or degradation of the parent 65 kDa sulfated enamel protein or its major 49 kDa and 25 kDa fragments. Experiments with glycosidases further suggested that the majority of sulfate groups were attached to sugars N-linked by asparagine to the core of the 65 kDa sulfated enamel protein. The sulfated enamel proteins resemble acidic glycoproteins previously classified as enamelins. Unlike the enamelins, however, they are short-lived and do not appear to survive in enamel as it matures.     

Accompanying DCIS in breast cancer patients with invasive ductal carcinoma is predictive of improved local recurrence-free survival

BackgroundDuctal carcinoma in situ (DCIS) often accompanies invasive ductal carcinoma (IDC). The presence of co-existing DCIS is postulated to present as a less aggressive phenotype than IDC alone.Patients and methodsPatients diagnosed with hormone receptor-positive breast cancer receiving mastectomy were evaluated. Only patients without adjuvant radio- and chemotherapy were included to decrease treatment bias on local recurrence (LR).ResultsOf 2239 breast cancer patients, 198 fulfilled the inclusion criteria. The overall LR rate was 11.6%. Tumor stage (p = 0.002), nodal status (pN2 vs. pN0, p = 0.023) and pure IDC compared with IDC-DCIS (p = 0.029) were multivariate independent factors for increased LR risk. Patients with IDC-DCIS were significantly younger (p < 0.001), had smaller tumors (p = 0.001), less lymph node involvement (p = 0.012). The LR rate was significantly increased in patients with pure IDC (p = 0.012). The time to distant metastases was decreased in patients with pure IDC compared with that observed in patients with IDC-DCIS (log rank = 0.030).ConclusionInvasive ductal carcinoma accompanied by DCIS is associated with lower LR. The prognostic value of co-existing DCIS in the adjuvant decision-making process may be considered a new independent prognostic marker. This finding needs further studies to evaluate its usefulness in premenopausal women.     

Synchronous colon carcinomas: Molecular-genetic evidence for multicentricity

Background: The synchronous presentation of multiple colonic adenocarcinomas is an unusual, but well-recognized event accounting for 2–11% of these neoplasms. Synchronous tumors may have a different biology and prognosis than solitary tumors. Evidence based on measurement of DNA ploidy suggests that a significant percentage of synchronous tumors have a common clonal origin, probably resulting from translumenal metastasis. Methods: Fifteen synchronous colorectal cancers (30 tumors) were examined for histologic differences as well as genetic mutations. p53 gene abnormalities were detected by polymerase chain reaction (PCR) followed by single-strand conformation polymorphism analysis. Ki-ras mutations were detected by PCR followed by oligonucleotide-specific hybridization. Results: p53 gene mutations were detected in 12 of 30 tumors. In only one case was the same p53 mutation present in both tumors from one patient. Similarly, Ki-ras mutations were observed in 9 of 30 tumors. Concordant Ki-ras mutations were observed in only one case, which was also concordant for p53 mutation. Conclusion: Because p53 and Ki-ras mutations tend to occur fairly early in tumor development, it seems likely that cases discordant for p53 and Ki-ras mutations represent independently developing tumor foci. Taken together, these findings strongly suggest that the great majority of synchronous colonic adenocarcinomas arise as independent neoplasms and their worsened prognosis is not a result of unusually early metastatic spread.Results of this study were presented in part at the 48th Annual Cancer Symposium of The Society of Surgical Oncology, Boston, Massachusetts, March 23–26, 1995.     

Cytologic evaluation of lumpectomy margins in patients with ductal carcinoma in situ: Clinical outcome

Backround: Breast conservation therapy is controversial for ductal carcinoma in situ (DCIS) due to recently reported high recurrence rates. We believe that cytologic evaluation of lumpectomy margins improves efficiency and leads to a lower recurrence rate following lumpectomy for DCIS. Methods: A prospectively accrued database of 1255 breast cancer patients at the H. Lee Moffitt Cancer Center and Research Institute was found to have 218 patients with DCIS (17.4%). Of those 218 cases, 114 were treated with lumpectomy, axillary dissection, and radiation therapy; the remaining 104 patients were treated with mastectomy with or without reconstruction. Imprint cytology was used to evaluate all lumpectomy margins. Permanent sections and imprint cytology were reviewed by the same pathologist. Results: All lumpectomy specimens (116 tumors in 114 patients) were evaluated. The median follow up was 57.5 months (range 2–110 months). One hundred and three patients with 104 tumors were selected on the basis of pure DCIS (with or without microinvasion), and treated with lumpectomy, axillary dissection and radiation therapy. Of the 104 tumors utilizing attempted breast conservation therapy, 7 (6.6%) required mastectomy. There were 6 recurrences (6.1%) with a median time for recurrence of 47.5 months (range 27–85 months); four recurrences were comedo and two were noncomedo at original diagnosis. Conclusions: The determination of lumpectomy margins in DCIS patients using imprint cytology leads to an overall recurrence rate of 6.1% with reduction in operative time, and re-excision rate. Significant recurrence rates were associated with microinvasion and multifocal tumors (28%) versus simple DCIS at 5 years. Breast conservation therapy and surgical margin determination with imprint cytology for DCIS is a cost-effective and reliable method of treatment for simple DCIS.     

Loss of Heterozygosity and DNA Aneuploidy in Colorectal Adenocarcinoma

Background: This study evaluated the relationship between DNA aneuploidy and loss of heterozygosity (LOH) at different genetic loci in colorectal adenocarcinoma.Methods: A total of 112 patients with surgically removed colorectal adenocarcinoma in Taipei Veterans General Hospital from January 1999 to July 2001 were included in this study. The pattern of DNA ploidy was determined with DNA flow cytometry, and the LOH of various genetic loci was determined with fluorescence polymerase chain reaction and denaturing gradient gel electrophoresis. The relationship between DNA ploidy, LOH of various genetic loci, and clinicopathologic variables was analyzed with the ² test with Yates correction as well as by multivariate binary logistic regression analysis.Results: Seventy-one (63.4%) of the 112 carcinomas had DNA aneuploidy. The DNA aneuploidy was not associated with any clinicopathologic variable. Ninety-one tumors (81.3%) exhibited LOH in at least one genetic locus. In the univariate analysis, the DNA aneuploidy was associated with LOH of Tp53-penta, D8S254, D5S346, and high-frequency LOH (P = .001, P = .016, P = .041, and P < .001, respectively). In the multivariate analysis, the most significant factor influencing DNA aneuploidy was D8S254, followed by Tp53-penta, high-frequency LOH, and D5S346.Conclusions: DNA aneuploidy is strongly associated with LOH at specific genetic loci.     

Altered osteoblast gluconeogenesis in X-linked hypophosphatemic mice is associated with a depressed intracellular pH

We have studied gluconeogenesis and intracellular pH levels in normal (+/Y) and X-linked hypophosphatemic (Hyp/Y) mice. Compared with +/Y littermates, Hyp/Y mouse osteoblasts showed a higher rate of glucose production from fructose (10-fold), glutamine, and malate, but no significant difference when -ketoglutarate was used as substrate. The activities of the pentose cycle enzymes, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase, were not different in the two osteoblast preparations. Examination of intracellular pH (pH_i) using the double excitation of the pH-sensitive dye 2,7-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester (BCECF-AM) revealed a significantly lower pHi in Hyp/Y mouse osteoblasts compared with +/Y mouse osteoblasts (7.01±0.03 n=10 versus 7.15±0.04 n=8, respectively; P<0.05). These results show for the first time that osteoblasts are capable of glucose production and that glucose production is altered in the Hyp/Y mouse osteoblast. As altered gluconeogenesis has been associated with reduced intracellular pH in other systems, a similar mechanism may be operative in the Hyp/Y mouse osteoblast. The observed defects may be intrinsic to the Hyp phenotype as the alterations in intracellular pH and gluconeogenesis persisted in vitro, or they may represent impressed memory from the in vivo state and the presumed circulating factor that influences phosphate transport.     

Extensive pure ductal carcinoma in situ of the breast: Identification of predictors of associated infiltrating carcinoma and lymph node metastasis before immediate reconstructive surgery

AimTo identify predictors for infiltrating carcinoma and lymph node involvement, before immediate breast reconstructive surgery, in patients with an initial diagnosis of extensive pure ductal carcinoma in situ of the breast (DCIS).Patients and methodsBetween January 2000 and December 2009, 241 patients with pure extensive DCIS in preoperative biopsy had underwent mastectomy. Axillary staging (sentinel node and/or axillary dissection) was performed in 92% (n = 221) of patients. Patients with micro-invasive lesions at initial diagnosis, recurrence or contralateral breast cancer were excluded.ResultsRespectively 14% and 21% of patients had a final diagnosis of micro-invasive carcinoma (MIC) and invasive ductal carcinoma (IDC). Univariate analysis showed that the following variables at diagnosis were significantly correlated with the presence of either MIC or IDC in the mastectomy specimen: palpable tumor (p = 0.002), high grade DCIS (p = 0.002) and detection of an opacity by mammography (p = 0.019). Axillary lymph node (ALN) involvement was reported in 9% of patients. Univariate analysis suggested that a body mass index higher than 25 (p = 0.007), a palpable tumor (p = 0.012) and the detection of an opacity by mammography (p = 0.044) were associated with an increased rate of ALN involvement.ConclusionSkin-sparing mastectomy and immediate breast reconstruction (IBRS) has become increasingly popular, especially for patients with extended DCIS of the breast. This study confirmed that extended DCIS is associated with a substantial risk of finding MIC or IDC on the surgical specimen but also ALN involvement. Adjuvant systemic treatment and/or radiotherapy could be indicated for some of these patients after the surgery. Patients should be informed of the rate of 1) complications associated to IBRS that will potentially delay the introduction of systemic or local therapy 2) complications associated to radiotherapy after IBRS.     

Distal Margin Requirements After Preoperative Chemoradiotherapy for Distal Rectal Carcinomas: Are ≤ 1 cm Distal Margins Sufficient?

Background:Sphincter-sparing alternatives to abdominoperineal resection (APR) in the treatment of rectal cancer often are underused out of concern for inadequate distal margins and local failure. The present study addresses whether sphincter-sparing techniques with distal margins 1 cm adversely influence oncological outcome in patients given preoperative chemoradiotherapy.Methods:Thirty-seven patients with rectal cancer 8 cm from the anal verge were enrolled in the study. Preoperative external beam radiotherapy (5400 Gy) was administered together with continuous infusion of 5-fluorouracil (300 mg/m²/day). Surgical resection was performed in 36 patients with pathological assessment of tumor response and margins. Patients with sphincter-sparing resection and distal margins > 1 cm or 1 cm and those who underwent APR were compared.Results:Thirty-six patients completed preoperative chemoradiotherapy, with successful sphincter-preservation in 28 patients. At a median follow-up of 33 months, there were 12 recurrences overall, which included 11 distant failures and four pelvic failures. Disease-free survival (DFS) was not different between those who had an APR compared with sphincter-sparing resection with distal margins 1 cm. DFS was worse (P < .02) when radial margins were 3 mm compared with > 3 mm.Conclusions:Sphincter preservation is feasible in more than 75% of patients with tumors 8 cm from the anal verge after preoperative chemoradiotherapy. Sphincter-sparing surgery with distal margins 1 cm can be used without adversely influencing local recurrence or DFS. Limited radial margins ( 3 mm), however, are associated with increased disease recurrence.Presented at the 1998 Annual Meeting of the Society for Surgery of the Alimentary Tract, New Orleans, Louisiana, May 18, 1998