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Breast augmentation with implants is a popular cosmetic procedure which has been performed for nearly six decades. As the number of breast augmentation procedures continually rises, we increasingly encounter breast cancer patients who have silicone implants. A significant portion of these patients includes candidates suited for lumpectomy. In these cases, a major concern is the potential exposure of the implant during lumpectomy while an additional consideration is the need to replace the implants due to their age or condition. The purpose of this study is to present an original surgical approach to patients with breast implants requiring breast conservative resection due to breast carcinoma. Over the course of 10 years, breast-augmented candidates for a lumpectomy who underwent a technique that combines lumpectomy with the replacement of the old implant through an incision from the previous scar in the inframammary fold (IMF) were reviewed. With this approach, after removal of the implant through the IMF incision, the tumor is resected with appropriate surgical margins from inside the implant pocket, leaving the overlying skin intact. Data on demographic characteristics, implants, oncologic information, intraoperative surgical findings, and complication were collected. The implant information included brand, size, age, plan of dissection, and condition of the implant as assessed preoperatively. Oncologic information included tumor type, number of tumors, size, and location. Surgical information included the size of the tissue excised, condition of the implant removed, as well as characteristics of the new implants, plane of augmentation, and intraoperative and postoperative complications. All breast specimens were marked and weighed, and the patients were followed-up postoperatively for at least 6 months by the plastic and breast surgeons and by the oncologists. This technique has been employed in 21 patients with previous breast augmentation and a recent diagnosis of breast carcinoma. The average implant age was 13.3 years. The average tumor size was 2.1 cm × 2.8 cm. All patients had clear surgical margins. No significant complications were reported. This technique enables the performing of a lumpectomy procedure without adding additional scars to the breast, the exchange of the implant in a simultaneous procedure, and the decrease of the risk of implant exposure due to additional scars on the breast parenchyma. It minimizes postoperative complications and provides excellent results both therapeutically and aesthetically.

Background Low back pain (LBP) is one of the most common health complaints, with lifetime prevalence rates as high as 84%. The Oswestry Disability Index (ODI) is often the measure of choice for LBP in both research and clinical settings and, as such, has been translated into 29 languages and dialects. Currently, however, there is no validated version of Hebrew-translated ODI (ODI-H). Objective To examine the psychometric properties of the ODI-H. Methods Cross-culturally appropriate translation into Hebrew was conducted. A convenience sample of 115 participants (Case Group) with LBP and 68 without LBP (Control Group) completed the ODI-H, SF-36 Health Survey, and two Visual Analog Scales (VAS). Results Internal consistency was α = 0.94 and test-retest reliability for 18 participants repeating the ODI-H was 0.97. No floor or ceiling effects were noted for Cases, although there was a floor effect for the Control Group. Scores were significantly different for the two groups, indicating discriminant validity. Concurrent validity was reflected by significant correlations with SF-36 scores, particularly the Physical Functioning and Bodily Pain subscales (-0.83 and -0.79, respectively) and with the VAS (0.84 and 0.79). Conclusions The ODI-H is a valid and reliable measure of low back pain-related disability for the Hebrew-speaking public.

The purpose of this study was to assess pathological complete response and whether it serves a surrogate for survival among patients receiving neo-adjuvant doxorubicin–cyclophosphamide followed by paclitaxel for triple-negative breast cancer with respect to BRCA1 mutation status. From a neo-adjuvant systemic therapy database of 588 breast cancer cases, 80 triple-negative cases who had undergone BRCA genotyping were identified. Logistic regression model was fitted to examine the association between BRCA1 status and pathological complete response. Survival outcomes were evaluated using Kaplan–Meier method, differences between study groups calculated by log-rank test. Thirty-four BRCA1 carriers and 43 non-carriers were identified. The BRCA1 carriers had pathological complete response rate of 68 % compared with 37 % among non-carriers, p = 0.01. Yet this did not translate into superior survival for BRCA1 carriers compared with non-carriers. No difference in relapse-free survival were noted among those with or without pathological complete response in BRCA1 carriers regardless of pathological complete response status (Log-rank p = 0.25), whereas in the non-carrier cohort, relapse-free survival was superior for those achieving pathological complete response (Log-rank p < 0.0001). Response to neo-adjuvant systemic therapy differed in BRCA1-associated triple-negative breast cancer compared with triple-negative non-carriers, with a higher rate of pathological complete response. However, compared with non-carrier triple-negative breast cancer, pathological complete response was not a surrogate for superior relapse-free survival in BRCA1 patients. Future studies using specific chemotherapy regimens may provide further improvements in outcomes.

Background and Objectives One of the major unmet needs in Breast Conserving Surgery (BCS) is a rapid and accurate margin assessment of the lumpectomy specimen. This study evaluates the ability of a novel MRI system (prototype of the ClearSight™ system; Clear-Cut Medical Ltd., Rehovot, Israel) to distinguish malignant and non-malignant tissues in freshly excised breast specimen by comparing MR measurements to histopathology results. Methods Seventy-seven samples were obtained from 22 patients undergoing BCS enrolled in the study. A T2* (T2 Star) value in milliseconds (ms) was calculated for each sample and correlated with histopathology results. Results Of the 77 samples, 35 samples were classified by histopathology as malignant and 42 as non-malignant. T2* values were significantly higher in malignant samples compared to non-malignant samples (15.3 ± 2.72 ms and 10.6 ± 1.47 ms, respectively [P

Laparoscopic sleeve gastrectomy (LSG) is an accepted bariatric procedure. Swallow studies (SS) after LSG are not uniform and display different patterns with regard to contrast passage through the gastric sleeve. The impact of immediate postoperative contrast transit time on weight loss has not been studied. The influence of immediate fluid tolerance on weight loss after LSG is herein reported.Ninety-nine patients after LSG were included. There were 67 females, mean age 41 (range 17-67), mean BMI 44.4 (range 37-75). A routine SS was performed on postoperative day (POD) 1. Pattern of contrast transit was noted. Patients were followed-up in our bariatric clinic.Percent excess weight loss was significantly lower in the patients with rapid contrast passage (Group 1, n = 50) than those with delayed passage (Group 2, n = 49). Group 1 achieved 62, 58, and 53 % at 1, 2, and 3 years, respectively, while Group 2 attained 69, 74, and 75 % at the same time points (p = 0.05, 0.001, and 0.04, respectively). Group 1 patients displayed a negative weight loss trend after 1 year whereas Group 2 patients plateaued after 2 years.Tolerance of fluid intake after LSG is crucial for patient recovery and discharge. Distinct radiologic appearance on POD 1 helps predict this behavior. Mid-term weight loss after LSG appears to be dependent on immediate postoperative contrast transit time, whereas patients with slow contrast passage tend to lose more weight. Long-term follow-up will reveal whether this finding will hold true.

Up to 4% of breast cancer cases occur in women younger than 35 years. Studies have suggested an association between breast cancer at a young age, poorer outcome, and adverse clinical and pathologic characteristics. It is unclear whether age is an independent prognostic factor.To characterize the prognostic significance of young age at diagnosis through comparison of disease characteristics of "less-young" (born between 1958-1962 and aged 37-44 years) and "very-young" (born after 1967 and aged ≤35 years) premenopausal patients.Consecutive patients with breast cancer born after 1967 treated at Sheba Medical Centre between January, 1999 and October, 2002 were identified and their files reviewed. This cohort was identified as "very-young" and was compared with a group of "less-young" patients. The clinico-pathologic characteristics and survival data were compared.Sixty-one very young and 94 less-young patients were identified. The mean age at diagnosis was 29.9 (range, 23-34 years) and 40.5 years (range, 37-44 years) for the very young and less young patients, respectively (P0.0001). Significantly more very young patients had metastatic disease at presentation (20% vs. 3%, respectively, P = 0.0007). The very young patients were more likely to have high grade, endocrine nonresponsive tumors than the less young patients. After controlling for stage and tumor grade, very-young age was not shown to be an independent risk factor for reduced survival.Very young age among Israeli women with breast cancer is associated with higher stage at diagnosis, adverse pathologic characteristics and adverse outcome but is not an independent prognostic factor for survival.

Background Appendiceal carcinoid tumor is the most common type of primary appendiceal malignant lesion. Nonetheless; it is an exceedingly rare diagnosis; found in only about .3% to .9% of appendectomy specimens. We report the clinical and pathologic characteristics of carcinoids found with long-term follow-up evaluation. Methods Data of patients who were histologically reported to have carcinoid tumor of the appendix; in a single center; during a 16-year period were collected retrospectively. In addition; patients were contacted for current follow-up information. Results A total of 44 patients were diagnosed with appendiceal carcinoid during the study period. The median follow-up period for the cohort was 7 years. No evidence of any recurrent disease or other noncarcinoid neoplasm was found. Conclusions Our data confirm the good prognosis as seen in earlier reports. The long-term significance of having a carcinoid; and whether this poses a risk for future neoplasms; need even longer-term studies.

Germline mutations in the BRCA1 and BRCA2 genes are associated with a significantly increased lifetime risk for developing breast and/or ovarian cancer. However, incomplete penetrance and substantial variability in age of disease onset among carriers of the same mutation suggests the involvement of additional modifier genes and/or environmental factors. Somatic inactivating mutations in the p53 gene and genes of the p53 pathway often accompany BRCA1/2-associated tumors. Therefore, we assessed whether these genes are modifiers of penetrance. We genotyped Jewish-Ashkenazi women for functional single-nucleotide polymorphisms (SNPs) in the AKT1 (C>T rs3730358) and the PERP (C>T rs2484067) genes that affect p53-mediated apoptosis, as well as two tag-SNPs in the CHEK2 (C>T rs743184) and the ZBRK1/ZNF350 (G>A rs2278414) genes that encode for proteins involved in growth arrest following DNA damage. The study population included 138 healthy women, 148 breast/ovarian cancer BRCA1/2 mutation carriers, 121 asymptomatic BRCA1/2 mutation carriers, and 210 sporadic noncarrier breast cancer patients. Utilizing lambda(2) and Kaplan-Meier analysis revealed a hazard ratio (HR) of 3.23 (95% CI: 1.44-54, P = 0.0184) for the TT genotype of AKT (rs3730358), HR = 2.105 (95% CI: 1.049-7.434, P = 0.039) for CHEK2 CC genotype (rs743184), and HR = 2.4743 (95% CI: 1.205-11.53, P = 0.022) for the AG genotype of ZBRK1/ZNF350 (rs2278414). No significant association between PERP variants and cancer was identified HR = 0.662 (95% CI: 0.289-1.324, P = 0.261). Our results suggest that genes that act upstream of p53, or participate in the DNA damage response, may modify the risk of cancer in women with mutant BRCA1/2 alleles.

Prevention of blood loss in liver resections is essential for reducing postoperative morbidity. The main method to control bleeding during surgery of the left hemiliver is occlusion of the left portal pedicle. This may be accomplished by hilar, fissural or posterior intrahepatic techniques. However, these techniques may injure transposed vessels or bile ducts from the right portal pedicle to the left. The purpose of this study was to describe the anatomical aspects of the posterior intrahepatic ligamentum venosum approach to the left portal pedicle. Anatomical study was carried out on 215 isolated adult livers. In 57 specimens, sections of the extra- and intrahepatic portions of the left portal pedicle were prepared under stereoscopic microscopy. The ligamentum venosum is the anatomical landmark between the medial and lateral portions of the left portal vein. The convergence of the ligamentum venosum along the left portal pedicle is where the left portal sheath reaches its maximal thickness and these connections are tight. In 8–12%, the medial portion of the left portal pedicle includes a transposed right paramedian vein or right-sided bile ducts. According to our anatomical study, we believe that it is possible to use the ligamentum venosum as an anatomical guide to achieve a controlled approach of the left portal pedicle during left-sided hepatectomies. Moreover, ligation of the left portal pedicle at its convergence with the ligamentum venosum may prevent erroneous injury of transposed right paramedian vessels or bile ducts.

The p53 tumor suppressor serves as a crucial barrier against cancer development. In tumor cells and their progenitors, p53 suppresses cancer in a cell-autonomous manner. However, p53 also possesses non-cell-autonomous activities. For example, p53 of stromal fibroblasts can modulate the spectrum of proteins secreted by these cells, rendering their microenvironment less supportive of the survival and spread of adjacent tumor cells. We now report that epithelial tumor cells can suppress p53 induction in neighboring fibroblasts, an effect reproducible by tumor cell-conditioned medium. The ability to suppress fibroblast p53 activation is acquired by epithelial cells in the course of neoplastic transformation. Specifically, stable transduction of immortalized epithelial cells by mutant H-Ras and p53-specific short inhibitory RNA endows them with the ability to quench fibroblast p53 induction. Importantly, human cancer-associated fibroblasts are more susceptible to this suppression than normal fibroblasts. These findings underscore a mechanism whereby epithelial cancer cells may overcome the non-cell-autonomous tumor suppressor function of p53 in stromal fibroblasts.

Trastuzumab in combination with adjuvant chemotherapy improves disease free survival and overall survival in HER2 over-expressing breast cancer patients. Data concerning the use of trastuzumab in the neo-adjuvant setting is limited. We aimed to compare outcome of HER2 over-expressing breast cancer patients treated with either standard chemotherapy, consisting of doxorubicin, cyclophosphamide and a taxane to outcome of patients treated with the same chemotherapy regimen with the addition of trastuzumab in concurrence with paclitaxel.We conducted a retrospective review of all consecutive HER2 over-expressing breast cancer patients treated at the participating institutions during the study period and received neo-adjuvant therapy. Allocation to trastuzumab was not based on clinical parameters and was approved only by part of the insurers. Clinical and pathological characteristics, as well as response rate and type of surgery were analyzed.Thirty seven patients received chemotherapy alone and 24 patients received chemotherapy and trastuzumab. A similar distribution of age, clinical stage and histology was noted in both groups. The rate of pathological complete response (pCR) was significantly higher among the trastuzumab-treated group compared to chemotherapy-alone group (75 vs. 24% respectively, p=0.0002). pCR in the breast was noted in 18 of 24 (75%) compared to 10 of 36 (28%, p=0.0005) and pCR in the axillary lymph nodes was noted in 19 of 20 (95%) compared to 8 of 28 (29%, p=0.0001), in the trastuzumab group compared to the chemotherapy-alone group respectively. The safety profile was similar between both groups and no clinical cardiotoxicity were noted.The addition of trastuzumab to standard chemotherapy in the neo-adjuvant setting improves pathological complete response rates in HER2 over-expressing breast cancer patients.

This article reviews and discusses the up-to-date data on and feasibility of focused ultrasound surgery. This technique uses high-energy ultrasound beams that can be directed to penetrate through the skin and various soft tissues, focus on the target, and destroy tumors by increasing the temperature at the targeted tissue volume. The boundaries of the treatment area are sharply demarcated (focused) without causing damage to the surrounding organs. Although the idea of using sound waves to ablate tumors was first demonstrated in the 1940 s, only recent developments have enabled this technology to become more controlled and, hence, more feasible. The major breakthrough toward its clinical use came with coupling the thermal ablative process to advanced imaging. The development of magnetic resonance as the foundation to guide and evaluate the end results of focused ultrasound surgery treatment, the image guidance of the ultrasound beam, and the development of a reliable method for tissue temperature measurement and real-time feedback of the extent of tissue destruction have pushed this novel technology forward in oncological practice.

Liver surgery is technically demanding and is considered a major procedure with relatively high morbidity rates. Magnetic resonance-guided focused ultrasound surgery (MRgFUS) uses focused ultrasonic energy to create a heat coagulation lesion, which can be achieved in a totally controlled, very accurate manner (1 mm). The aim of this study was to evaluate the safety and accuracy of non-invasive focal ablation of liver tissue achieved by consecutive MRgFUS sonications.Six MRgFUS procedures were performed in five pigs under general anesthesia, with the ExAblate 2000 system (InSightec, Israel). Real-time imaging and temperature mapping (Signa Twinspeed 1.5T, GEHC, USA) enabled the immediate evaluation of the results of each sonication. Different foci were chosen within the liver. These mock lesions were ablated by several sonications, each of them performed during 20-30 s of apnea. Between sonications, the pigs were normally ventilated. The pigs were sacrificed 3-21 days after the procedure and their livers were examined.The MRgFUS created complete tissue destruction of mock lesions in different areas of the pig's liver. The lesion sizes in each animal varied according to the number of sonications used and the extent of overlap between adjacent sonications. The lesion ranged in size from 1.5 cm x 1.5 cm x 2.0 cm to 5.5 cm x 4.5 cm x 2.0 cm. There was no morbidity.MRgFUS under general anesthesia is a safe, completely non-invasive technology for the ablation of liver tissue. Liver tissue can be ablated in a very accurate manner, based on the pre-treatment planning on the MR images. The MR imaging characteristics, including real-time temperature mapping, enable real-time control of every step of the ablation process. Mechanical ventilation with intermittent periods of apnea is a technique that overcomes the problem of the respiratory movements of the liver.

Background. Canine hepatocellular adenomas are benign, well-differentiated, primary hepatic tumors. Surgical resection is technically demanding and is considered a major procedure with relatively high morbidity rates. Magnetic resonance-guided focused ultrasound surgery (MRgFUS) uses focused ultrasonic energy to non-invasively create a heat-coagulated lesion deep within the body. This effect can be achieved in a controlled, accurate manner. The aim of this study was to evaluate the safety, accuracy and efficacy of non-invasive focal ablation of tissue volumes of a canine benign liver tumour by consecutive MRgFUS sonications. Materials and methods. Four MRgFUS procedures were performed in a 10-year-old, male, mixed large breed dog (45 kg) under general anaesthesia. The exact location and volume of the ablated areas were planned on the MR images. Real-time MR imaging and temperature mapping enabled the immediate evaluation of the effect of each sonication. Different areas were chosen within the tumour. These volumes of tumoral tissue were ablated by multiple sonications. To allow accurate targeting and quality imaging, sonications were performed during 20–30s of apnoea. Between the sonications the dog was normally ventilated. The dog was operated 21 days after the fourth ablative procedure. The tumour was resected and histopathologically examined. Results. The MRgFUS created necrosis with contiguous areas of complete tissue destruction within the liver tumour, in full accordance with the planning. A focal thermal injury to the cartilage of the right lower ribs was noted after the fourth treatment. This lesion became infected and was treated surgically. Ten months after the last treatment the dog is well and healthy. Conclusions. Focused ultrasound ablation of liver tumoral tissue with MR guidance under general anaesthesia and controlled apnoea is a safe and accurate treatment modality. Its main advantage is that it is a completely non-invasive image-guided treatment. The ablation of significant volumes of a highly vascular liver tumoral tissue was achieved. Such tissue can be ablated in a very accurate manner, exactly according to the pretreatment planning on the MR images. The MR imaging characteristics, including real-time temperature mapping, enable real-time control of every step of the ablation process. Mechanical ventilation with intermittent apnoea periods overcomes the problem of the respiratory movements of the liver. Care must be taken to avoid the passage of the ultrasound beam through energy-absorbing calcified tissue.

Approximately 10% of the cases of breast cancer and invasive ovarian cancer are hereditary, occurring predominantly in women with germ-line mutations in the BRCA1 or BRCA2 genes. Low expression of these genes in sporadic tumors extends their significance to sporadic breast and ovarian cancers as well. For over a decade since its identification, extensive research has been directed toward understanding the function of the breast and ovarian tumor suppressor gene BRCA1. The long-term goal has been to identify the biochemical pathways reliant on BRCA1 that can be exploited for developing targeted therapies and benefit mutation carriers. To date, no one specific role has been identified, but rather it is clear that BRCA1 has significant roles in multiple fundamental cellular processes, including control of gene expression, chromatin remodeling, DNA repair, cell cycle checkpoint control, and ubiquitination, and overall is important for maintenance of genomic stability. Major findings and potential BRCA1-dependent therapies will be discussed. [Mol Cancer Ther 2006;5(6):1396–404]

BRCA1/BRCA2 mutations account for a substantial proportion of familial breast cancer, but clearly mutations in additional genes exist, one candidate being the p53 gene. To evaluate its putative involvement in inherited predisposition to breast/ovarian cancer in Jewish high-risk women, mutational analysis of the p53 gene (exons 4-9) was carried out using exon-specific polymerase chain reaction followed by denaturing gradient gel electrophoresis (DGGE) analysis, complemented by DNA sequencing of abnormally migrating fragments. Overall, 132 Jewish breast cancer patient non-BRCA1/2 mutation carriers and 167 average risk controls (Ashkenazi (n=60), non-Ashkenazi (n=107)) were genotyped, and no inactivating p53 germline mutations were detected. Consistent migration abnormalities were noted in 167 fragments, 134 of which were shown to be the Arg72Pro polymorphism, whereas migration abnormalities in fragments containing exons 4 (n=2) and 6 (n=23) and introns 3 (n=4) and 9 (n=4) corresponded to five previously described polymorphisms. Allele distribution of the R72P missense mutation between ethnically diverse Jewish breast cancer cases and average risk controls showed significant differences: among non-Ashkenazi breast cancer cases, 62.5%, 33.3% and 4.2% were homozygous, heterozygous and homozygous for the Arg72, Arg72Pro and the Pro72 polymorphism, respectively, whereas for controls, the distribution was 22.4%, 65.4% and 12.2%, respectively (P=0.00052), and among Ashkenazi breast cancer cases, allele distribution was 68.5%, 29.6% and 1.9%, whereas for controls, the distribution was 50%, 40% and 10%, respectively (P=0.0125). We conclude that arginine homozygosity at codon 72 of the p53 gene is associated with a significant increased breast cancer risk in Jewish high-risk population.

BRCA1/BRCA2 germline mutations are associated with an increased breast/ovarian cancer risk. Offspring gender ratios may be skewed against male births in BRCA1 mutation carriers. In addition, the lack of viable homozygous BRCA1/BRCA2-mutation carriers implies that recurrent miscarriages may be associated with homozygous fetuses. Jewish Israeli high-risk women who were tested for being carriers of the predominant BRCA1/BRCA2 mutations in Jewish high-risk families were analyzed for the sex of offspring and the rate of spontaneous miscarriages. Overall, 817 women participated: 393 BRCA1/BRCA2-mutation carriers (229 with breast/ovarian cancer) and 424 high-risk noncarriers (208 with breast/ovarian cancer). No differences between the male-to-female offspring ratios of all study groups were noted. Among mutation carriers, the offspring male-to-female ratio was 0.97 (444 : 460), and among mutation carriers with cancer it was 0.92 (262 : 284). Similarly, no offspring gender skewing was noted among high-risk noncarriers, regardless of health status. The rates of three or more spontaneous miscarriages among participants with at least one live birth were 4.37% (15/343) among mutation carriers and 3% (12/401) among high-risk women (P = not significant). In conclusion, the offspring gender ratio is similar in high-risk Jewish families and in the general population. The issue of the rate of recurrent miscarriages in high-risk Jewish women is unresolved.

Background Operative blood loss is among the most important factors determining the prognosis of patients undergoing hepatic resection. The best method for preventing bleeding is preliminary selective vascular occlusion of lobar, sectoral, or segmental portal triads, although not always technically feasible. Method Transportal occlusion of the portal triad with a balloon catheter was used in 35 hepatectomies for various tumors. Results In 27 out of 35 resections, there was absence or minimal bleeding from afferent vessels (portal vein, hepatic artery). In the remaining eight cases, there was significant bleeding from the hepatic artery. In these cases, transportal occlusion of portal triad was combined with a temporary interruption of the hepatic artery after the dissection of the hepatoduodenal ligament. The average intraoperative blood loss was 350–1,500 ml. Conclusion The use of a balloon catheter occlusion of the portal triad during liver resection is often technically feasible. It facilitates temporary occlusion of hardly accessible portal veins in the hepatic hilus without their prior exposure and minimizes bleeding. J. Surg. Oncol. 2005;89:39–42. © 2004 Wiley-Liss, Inc.

Objective: To evaluate the risk for developing second primary thyroid cancer (TC) following breast cancer (BC) and second primary BC following TC on a nationwide basis. Methods: All BC and TC Jewish females diagnosed in Israel during 1960–1998 were identified through the Israel Cancer Registry. The expected second primaries were calculated using cancer incidence rates stratified by age, country of birth and period of diagnosis among the Jewish population in Israel. Standardized incidence ratios (SIRs) were estimated using Poisson regression. Results: A total of 49,207 breast and 4911 thyroid neoplasms were identified. After the exclusion of concomitant disease (diagnosed within 1 year), 59 and 70 second primaries TC and BC yielded SIRs of 1.34 (95% CI: 1.03, 1.72) and 1.07 (95% CI: 0.84, 1.34), respectively. Younger age and earlier calendar year of first primary diagnosis and shorter follow-up period were associated with increased risk for developing second primary neoplasm. Conclusions: Considering the long latency required for carcinogenesis, excess risk of second primary diagnoses soon after the first cancer, argues against the hypothesis of first primary treatment as an initiator for the second cancer. A detection bias of meticulously followed cancer patients, early exposure to common risk factors or genetic susceptibility of certain subpopulations for both malignancies seem plausible.

Germline mutations in BRCA1 or BRCA2 account for the majority of inherited breast cancer cases. Yet, in up to 40% of familial breast cancer cases, no mutations can be detected in either gene. Germline mutations in PTEN underlie two inherited syndromes: Cowden disease (CD) and Bannayan-Riley-Ruvalcaba syndrome (BRRS). The known association of CD with breast cancer risk made it plausible that germline mutations within PTEN may play a role in inherited predisposition to breast cancer. The nine coding exons of the PTEN gene were screened for harboring germline mutations using denaturing gradient gel electrophoresis (DGGE) complemented by sequencing, in two subsets of Israeli patients: 12 patients clinically diagnosed with BRRS, and 89 women with an apparent inherited predisposition to breast cancer, some with salient features of CD. Two of three familial BRRS patients exhibited novel germline mutations in PTEN: a missense mutation changing methionine to arginine at codon 134, and insertion of two nucleotides (CA) at cDNA position 1215 resulting in a frameshift at codon 61 and a premature stop at codon 99. Among 89 high-risk women, two missense mutations were detected in exon 4: A to C change at cDNA position 1279 resulting in a change of aspargine to threonine at codon 82 (N82T), and a G to an A alteration in 1269 which alters threonine to alanine at codon 78 (T78A), a non-conservative missense mutation. This study suggests that PTEN does not play a major role in predisposing to hereditary breast cancer in Israeli women, and that detection of PTEN mutations in BRRS patients is more likely in familial cases.

Genetic counseling for individuals at high risk for developing breast and ovarian cancer (oncogenetic counseling) involves evaluation of cancer risk, psychological assessment, and genetic testing for germline mutations in BRCA1/BRCA2 genes. The long-term psychosocial impact of oncogenetic counseling on consultees and the retention of oncogenetic information are uncertain. We retrospectively interviewed 155 women who underwent oncogenetic counseling in a single medical center in Israel in 1996 (N = 50) and 1998 (N = 105). There were 29 (18.7%) BRCA1/BRCA2 mutation carriers and 126 non-carriers; 58 (37.4%) had a past or present history of cancer, and 97 (62.6%) were first-degree relatives within breast/ovarian cancer families. A questionnaire evaluating self-reported distress and anxiety symptoms before and after counseling, as well as the retention of relevant information (e.g., individual and offspring cancer risk, early detection schemes), one and three years after the initial consultation was administered. Overall, oncogenetic counseling had a minimal effect on anxiety-related symptoms. Mutation carriers reported anxiety-associated symptoms, such as sleeplessness and “bad mood”, more frequently than non-carriers following oncogenetic counseling. As expected, 61.8% of carriers and only 30% of non-carriers accurately remembered the personal and offspring cancer risk and preventive and early detection schemes. We conclude that although there seemed to be slight worsening of anxiety-related symptoms following oncogenetic counseling in BRCA1/BRCA2 mutation carriers, these symptoms were minimal and did not affect everyday life activities. In addition, there is an ongoing need to emphasize oncogenetic information to high-risk individuals. © 2002 Wiley-Liss, Inc.

Several studies have shown that extracellular matrix reduces chemotherapeutic drugs-induced apoptosis in small cell lung cancer cells, myelomas and gliomas. We have investigated the protective effect of defined extracellular matrix components and of extracellular matrix from different cell types (fibroblasts, hepatocytes and intestinal epithelial cells) on the toxicity of three types of chemotherapeutic drugs on colon cancer cells. Human colon cancer cell lines LS174T and LiM6 were plated on plastic, on hepatocyte-derived ECM or on stromal ECM and in the presence of the antimetabolite 5-fluorouracil (5-FU), the topoisomerase I inhibitor camptothecin and the topoisomerase II inhibitor etoposide. We determined IC50 for the drugs for each of these culture conditions. We also determined the expression of the anti-apoptotic proteins bcl-2 and bcl-x (L) under these culture conditions. We found that stromal ECM protected LiM6 cells from the toxicity of etoposide and LS174T, but not LiM6 cells, from the toxicity of camptothecin. Collagen I, fibronectin and fibroblast-derived ECM rendered LiM6 cells, but not LS174T, more sensitive to the harmful effect of 5-FU. Both colon cell lines had increased expression of anti-apoptotic proteins bcl-2 and bcl-x(L) when cultured on the various ECMs and with the drugs, but there was no correlation between a protective ECM effect and expression of the anti-apoptotic proteins. Stromal-derived ECM may protect colon cancer cells from etoposide and camptothecin-induced apotosis, through a mechanism that is not bcl-2 or bcl-x(L) dependant.

INTRODUCTION In patients receiving pre-operative anthracyclines for locally advanced breast cancer, early cardiotoxicity is a well-recognised complication that may interfere with surgery. The aim of this study was to assess the safety of breast surgery after neoadjuvant treatment with Doxorubicin. PATIENTS AND METHODS A retrospective study of breast cancer patients treated with Doxorubicin as part of their neoadjuvant protocol. All patients were subsequently operated in our institution. Intra-operative and postoperative haemodynamic, cardiac or respiratory events were collected. RESULTS A total of 83 patients were included. All patients had a normal left ventricular ejection fraction before starting on chemotherapy. Doxorubicin was given in conjunction with Cyclophosphamide and Paclitaxel. The cumulative dose of Doxorubicin was 240 mg/m2. All patients completed their chemotherapy less than a year before surgery and were clinically asymptomatic. Of the patients, 2.3% displayed a significant reduction in cardiac function to meet cardiotoxicity criteria, although not clinically apparent. No complications occurred intra-operatively or postoperatively. CONCLUSIONS Breast surgery can be safely performed after breast neoadjuvant chemotherapy with Doxorubicin. The risk of early cardiotoxicity does not mandate a cardiac function assessment after completion of treatment. Work-up should be individualised according to the anthracycline regimen, patient's cardiac risk factors and functional status before surgery.

Carriers of germline mutations in the BRCA1 gene have a significant increased lifetime risk for being diagnosed with breast cancer. The incomplete penetrance of BRCA1 suggests that environmental and/or genetic factors modify the risk and incidence among mutation carriers. Nutrition and particular micronutrients play a central role in modifying the phenotypic expression of a given genotype by regulating chromatin structure and gene expression. The active form of vitamin D, 1α,25-dihydroxyvitamin D3, is a potent inhibitor of breast cancer growth. Here we report that two non-calcemic analogues of 1α,25-dihydroxyvitamin D3, seocalcitol (EB1089) and QW-1624F2-2, collaborate with BRCA1 in mediating growth inhibition of breast cancer cells and breast cancer stem-like cells. EB1089 induces a G1/S phase growth arrest that coincides with induction of p21waf1 expression only in BRCA1-expressing cells. A complete knockdown of BRCA1 or p21waf1 renders the cells unresponsive to EB1089. Furthermore, we show that in the presence of ligand, BRCA1 associates with vitamin D receptor (VDR) and the complex co-occupies vitamin D responsive elements (VDRE) at the CDKN1A (p21waf1) promoter and enhances acetylation of histone H3 and H4 at these sites. Thus, BRCA1 expression is critical for mediating the biological impact of vitamin D3 in breast tumor cells.

We investigated the effect of hepatocyte-derived extracellular matrix (ECM) on the expression of erb-B2 and erb-B3 in colon cancer cell lines, as well as the role of erb-B2 and erb-B3 in colon cancer cell proliferation. Colon cancer cell lines plated on hepatocyte-derived ECM had increased protein levels of both erb-B2 and erb-B3. The addition of soluble recombinant proteoglycan syndecan-4 also resulted in higher expression of erb-B2 and erb-B3. We prepared hepatocyte-derived ECM from 1 to 7 days' cultures of hepatocytes, which contained different amounts of sulfated glycosaminoglycans. There was a direct correlation between the amounts of sulfated glycosaminoglycans in the ECM and the levels of erb-B2 and erb-B3 in the colon cell line KM12. The stimulatory effect of hepatocyte-derived ECM was abolished when the colon cancer cells were cultured in the presence of antibodies to erb-B2. These studies show that hepatocyte-derived ECM and the heparan sulfate proteoglycans present in it are responsible for inducing erb-B2 and erb-B3 in colon cancer cells. The growth stimulatory effect of extracellular matrix is mediated, at least in part, by increased expression of erb-B2 and erb-B3. © 2001 Wiley-Liss, Inc.

We present data acquired in our institution about the incidence of incidental appendiceal carcinoids over a period of 16 years. The possibility of occult carcinoids raises the question of appendectomy of a noninflamed appendix during diagnostic laparoscopy for suspected appendicitis. We performed a retrospective chart analysis of the surgical registry of a university-affiliated tertiary care center of a major population area for the past 16 years. Data were collected on all patients (n = 7592) who underwent appendectomy for the presumed diagnosis of acute appendicitis. Outcome measures were the incidence of incidental carcinoids of the appendix found during appendectomies and whether the introduction of laparoscopic appendectomy should alter the surgical management of a normal-appearing appendix. A total of 20 carcinoid appendices were resected by open surgery and 17 by laparoscopy. The diagnosis of a carcinoid tumor was not suspected in any patient before the operation, nor was a tumor identified at the time of the operation. In 6 (16%) patients the appendix appeared normal at the time of the operation. It has long been the standard of care to remove any appendix found in laparotomy for suspected appendicitis, but it is not clear what should be done during laparoscopy for suspected appendicitis when the appendix appears normal. Our data confirm the presence of occult carcinoids in normal-appearing appendices. Further studies are needed to determine the clinical significance of this finding.

In Ashkenazi (East European) Jews, three predominant mutations in BRCA1 (185delAG and 5382insC) and BRCA2 (6174-delT) account for the majority of germline mutations in high risk breast and/or ovarian cancer families. Among non-Ashkenazi Jews, the 185delAG, Tyr978Ter, and a handful of "private" mutations have been reported anecdotally within both genes. In this study we attempted to determine the spectrum of BRCA1 and BRCA2 mutations in high-risk Jewish individuals, non-carriers of any of the predominant Jewish mutations. We employed multiplex PCR and denaturing gradient gel electrophoresis (DGGE) analysis for BRCA2, and combined denaturing high performance liquid chromatography (DHPLC) and protein truncation rest (PTT) for BRCA1, complemented by DNA sequencing. We screened 47 high-risk Jewish individuals, 26 Ashkenazis, and 21 non-Ashkenazis. Overall, 13 sequence alterations in BRCA1 and eight in BRCA2 were detected: nine neutral polymorphisms and 12 missense mutations, including five novel ones. The novel missense mutations did not co-segregate with disease in BRCA1 and were detected at rates of 6.25% to 52.5% in the general population for BRCA2, Our findings suggest that except for the predominant mutations in BRCA1 and BRCA2 in Jewish individuals, there are only a handful of pathogenic mutations within these genes. It may imply novel genes may underlie inherited susceptibility to breast/ovarian cancer in Jewish individuals. Hum Mutat 16:491-501, 2000. (C) 2000 Wiley-Liss, Inc.

Relative to her risk of breast carcinoma, the woman with a BRCA1 or BRCA2 gene mutation can be managed either by intensive screening (with or without chemoprevention) or by prophylactic mastectomy. Although it would be preferable to avoid prophylactic surgery, the current level of screening technology and the rudimentary state of chemoprevention do not guarantee a good outcome with intensive surveillance. A review of the currently available data was undertaken to determine the efficacy of prophylactic surgery, intensive screening, and chemoprevention. An attempt then was made to extrapolate the efficacy of the various approaches to the management of women who carry BRCA1 or BRCA2 gene mutations. Intensive surveillance may not detect breast carcinoma at an early, curable stage in young women with BRCA1 or BRCA2 gene mutations because the growth rate of the tumors in these women most likely will be rapid and the density of the breast tissue may compromise detection. Chemoprevention is in its infancy, and its efficacy in this population is unknown. Conversely, prophylactic surgery may not be completely effective in preventing breast carcinoma. The authors are hopeful that sometime in the next decade advances in chemoprevention, screening technology, or breast carcinoma treatment will make mastectomy obsolete. However, for the time being prophylactic mastectomy has attributes that make it an alternative for this population that must be considered. Careful discussion of all options is essential in the management of these women.

Recent data from animal studies suggest thatinduced hypothyroidism inhibits the development of liverinjury in several animal models, including livercirrhosis and fulminant hepatic failure in rats, and immune-mediated acute liver injury in mice. Theaim of the present study was to determine whetherhypothyroidism would likewise preventacetaminophen-induced hepatic damage in rats. Liverdamage was induced by acetaminophen (2 g/kg) administered bygavage to fasting rats as a single dose. Hypothyroidismwas induced by methimazole, propylthiouracil, orsurgical thyroidectomy and confirmed by elevated serum levels of TSH. Hypothyroidism significantlyinhibited acetaminophen-induced liver damage asmanifested by the decreased serum levels of liverenzymes, malondialdehyde and blood ammonia, as well asby the higher hepatic glutathione content, in allthree groups of hypothyroid rats compared to euthyroidcontrols (P < 0.01). Histopathologic analysis showedsignificantly less liver necrosis and inflammation in the acetaminophen-treated hypothyroid rats.Oxygen extraction, measured in isolated perfused ratliver preparation, was also reduced in the hypothyroidlivers to 42 ± 8% compared to 81 ± 14% ofcontrols (P < 0.01). However, the expression ofCYP2E1 in the livers of hypothyroid rats, as measured bywestern blot analysis, was not decreased compared tocontrol rats. These results suggest that inducedhypothyroidism, regardless of the mode of induction, protectsrat liver from acetaminophen hepatotoxicity. This effectmay be related to hypometabolism of liver cells, but theexact mechanism needs further clarification.

Recent data from animal studies suggest that induced hypothyroidism prevents the hyperdynamic circulation in portal vein ligated rats, liver cirrhosis in rats chronically treated with thioacetamide (TAA), and immune-mediated acute liver injury induced in mice by concanavalin A. Therefore, the aim of this present study is to determine whether hypothyroidism would likewise prevent fulminant hepatic failure (FHF) in rats. FHF was induced by 3 consecutive ip injections of TAA (400 mg/kg) at 24-hour intervals. Hypothyroidism was induced in rats by either methimazole (MMI) or propylthiouracil (PTU) and surgical thyroidectomy and was confirmed by elevated serum thyroid stimulating hormone levels. Serum levels of liver enzymes, blood ammonia, and prothrombin time were significantly lower in all 3 groups of hypothyroid rats. The stage of hepatic encephalopathy (HE) and the survival rates were significantly improved in the hypothyroid rats (P < .01); the histologic examination of their livers showed less necrosis and inflammation (P < .01). In the hypothyroid rats, the serum levels of malondialdehyde 48 hours after thioacetamide (TAA) administration were lower than in control rats (P < .01). Exogenous supplementation of hypothyroid rats with L-thyroxine started 48 hours before TAA administration abrogated the protective effects of hypothyroidism. The serum levels of tumor necrosis factor alfa (TNF-alpha), interleukin (IL) 2 and IL-6 after 24 hours were slightly lower in the hypothyroid rats, but the administration of soluble receptor of TNF (10-1,000 microg/rat) did not prevent the induction of fulminant liver failure by TAA. Oxygen extraction, studied in isolated perfused liver preparation, was significantly lower in livers of hypothyroid rats (P < .01). These results suggest that induced hypothyroidism decreases the development of liver injury in a rat model of FHF. The mechanism may involve diminished oxidative cell injury caused by decreased oxygen utilization and hypometabolism associated with hypothyroidism.

The coexistence of hyperkinetic circulation, hypermetabolism, and hyperactivity of the sympathetic nervous system is encountered in both cirrhosis and hyperthyroidism. Several drugs, such as propylthiouracil and propranolol, that are beneficial for treating some patients with chronic liver diseases are also prescribed for the treatment of thyrotoxicosis. We investigated the effects of experimentally induced hypo- and hyperthyroidism on the development of cirrhosis induced in rats by thioacetamide (TAA). We specifically examined whether hypothyroidism could prevent and hyperthyroidism could aggravate liver damage. Hypothyroidism induced by methimazole (MMI, 0.04%), propylthiouracil (PTU 0.05%), and by thyroidectomy was confirmed by a significant elevation of thyroid-stimulating hormone (TSH) levels. Hyperthyroidism (decreased TSH levels) was induced by eltroxin (ELT:50 micrograms/kg). Thirteen groups of 10 rats each were studied: euthyroid controls (3 groups: water, TAA 1.5 months, and TAA 3 months), hypothyroid (6 groups: MMI, PTU, surgical, MMI-TAA, PTU-TAA, surgical-TAA), and hyperthyroid (4 groups:ELT 1.5 months and 3 months, and ELT-TAA for 1.5 months and 3 months). Hepatic fibrosis (scored from 0 to 3) was significantly reduced (P < .0001) in hypothyroid rats as compared with euthyroid controls, and was aggravated in TAA-treated hyperthyroid rats (P < .0001). Quantitative microscopic analysis of liver biopsy specimens from all groups confirmed the semiquantitative histopathological scores (P < .001). Direct intrasplenic pressure measurement revealed a significant portal pressure elevation in the TAA and the ELT-treated rats (from 4.7 +/- 0.1 in the euthyroid group to 8.1 +/- 2.3 and 10.2 +/- 2.1 and 12.5 +/- 1.6 in the TAA, ELT and ELT-TAA groups, respectively). However, in the hypothyroid-TAA groups, the portal pressure was found to be within the euthyroid normal range (4.6 +/- 1.2 and 5.8 +/- 0.6 in the PTU-TAA and surgical-TAA, respectively). After 12 weeks, the mean spleen weight of rats receiving only TAA was significantly higher than the TAA-treated hypothyroid rats (P < .0001), indicating that the hypothyroid TAA-treated rats were less portal hypertensive. These results suggest that induced hypothyroidism can inhibit, whereas hyperthyroidism can aggravate, the development of cirrhosis in a rat model.

Tumor necrosis factor-alpha (TNF) has been suggested to be the mediator of insulin resistance in infection, tumor cachexia, and obesity. We have previously shown that TNF diminishes insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1). The current work examines potential mechanisms that mediate this event. TNF effect on IRS-1 in Fao hepatoma cells was not associated with a significant reduction in insulin receptor tyrosine kinase activity as measured in vitro but impaired the association of IRS-1 with phosphatidylinositol 3-kinase, localizing TNF impact to IRS-1. TNF did not increase protein-tyrosine phosphatase activity and protein-tyrosine phosphatase inhibition by vanadate did not change TNF effect on IRS-1 tyrosine phosphorylation, suggesting that protein-tyrosine phosphatases are not involved in this TNF effect. In contrast, TNF increased IRS-1 phosphorylation on serine residues, leading to a decrease in its electrophoretic mobility. TNF effect on IRS-1 tyrosine phosphorylation was not abolished by inhibiting protein kinase C using staurosporine, while inactivation of Ser/Thr phosphatases by calyculin A and okadaic acid mimicked it. Our data suggest that TNF induces serine phosphorylation of IRS-1 through inhibition of serine phosphatases or activation of serine kinases other than protein kinase C. This increased serine phosphorylation interferes with insulin-induced tyrosine phosphorylation of IRS-1 and impairs insulin action.

OBJECTIVES: To investigate the ability of parametric diffusion tensor imaging (DTI), applied at 3 Tesla, to dissect breast tissue architecture and evaluate breast lesions. MATERIALS AND METHODS: All protocols were approved and a signed informed consent was obtained from all subjects. The study included 21 healthy women, 26 women with 33 malignant lesions, and 14 women with 20 benign lesions. Images were recorded at 3 Tesla with a protocol optimized for breast DTI at a spatial resolution of 1.9 × 1.9 × (2-2.5) mm3. Image processing algorithms and software, applied at pixel resolution, yielded vector maps of prime diffusion direction and parametric maps of the 3 orthogonal diffusion coefficients and of the fractional anisotropy and maximal anisotropy. RESULTS: The DTI-derived vector maps and parametric maps revealed the architecture of the entire mammary fibroglandular tissue and allowed a reliable detection of malignant lesions. Cancer lesions exhibited significantly lower values of the orthogonal diffusion coefficients, λ1, λ2, λ3, and of the maximal anisotropy index λ1-λ3 as compared with normal breast tissue (P < 0.0001) and to benign breast lesions (P < 0.0009 and 0.004, respectively). Maps of λ1 exhibited the highest contrast-to-noise ratio enabling delineation of the cancer lesions. These maps also provided high sensitivity/specificity of 95.6%/97.7% for differentiating cancers from benign lesions, which were similar to the sensitivity/specificity of dynamic contrast-enhanced magnetic resonance imaging of 94.8%/92.9%. Maps of λ1-λ3 provided a secondary independent diagnostic parameter with high sensitivity of 92.3%, but low specificity of 69.5% for differentiating cancers from benign lesions. CONCLUSION: Mapping the diffusion tensor parameters at high spatial resolution provides a potential novel means for dissecting breast architecture. Parametric maps of λ1 and λ1-λ3 facilitate the detection and diagnosis of breast cancer.

Tumor-infiltrating lymphocytes (TILs) are produced by resecting tumor tissue and growing and expanding ex vivo large quantities of autologous T cells. Once the TILs are ready for infusion, the patient undergoes a non-myeloablative lympho-depleting course of chemotherapy and subsequent TIL infusion with high-dose bolus IL-2. This study reviews the surgical experience of the TIL program at the Chaim Sheba Cancer Research Center in Israel. Eligible patients underwent surgical consultation to determine what tumorectomy would be beneficial for harvesting appropriate tissue. Factors involved in the decision included tumor mass size, location and morbidity of the procedure. Between January 2006 and May 2010, 44 patients underwent 47 procedures of adoptive transfer of TILs. Three patients underwent the procedure twice for recurrence after initial good responses, including an additional surgical procedure to produce fresh tumor. Thirty-seven excisions were with general anesthesia and 10 were with local anesthesia. Of the 37 general anesthesia procedures, 27 were open procedures involving a thoracotomy, a laparotomy or dissection of a major lymph node basin. Ten used minimally invasive techniques such as thorascopy or laparoscopy. Tumorectomy sites included 18 lymph node metastasis, 13 subcutaneous nodules, 11 lung specimens and 5 abdominal visceral metastasis including 2 liver lesions. Surgical mortality and major morbidity was 0%. Minor morbidity included only wound complications. Maximal number of TILs were derived from lymph node specimens, while liver metastasis procured the fewest TILs. Adoptive cell transfer technology affords a maximal tumor response with minimal surgical morbidity in metastatic patients.

Tumor necrosis factor-alpha (TNF) has recently been shown to induce insulin resistance. We have examined the possible effect of TNF on the early events in insulin transmembrane signaling. Incubation of the insulin-sensitive rat hepatoma Fao cells with 5 nM TNF for 1 h led to a 65% decrease in insulin-induced tyrosine phosphorylation of both the insulin receptor beta-subunit and IRS-1, its major cytosolic substrate. TNF-induced impairment of tyrosine phosphorylation was maximal at 0.5 nM and was not accompanied by any reduction in insulin binding. Sixteen hours of TNF incubation led to further impairment in insulin-induced tyrosine phosphorylation of these proteins. Our findings suggest that TNF may exert its anti-insulin effect by interrupting the early insulin-stimulated tyrosine phosphorylation events, which are crucial to insulin transmembrane signaling.

Laparoscopic adjustable gastric banding (LAGB) is an effective bariatric procedure with low morbidity and mortality. Unfortunately, it is fraught with high failure rates in long-term follow-up. Laparoscopic sleeve gastrectomy (LSG) is an emerging procedure, quickly gaining momentum in the arsenal of bariatric practice as a first step toward gastric bypass/biliopancreatic diversion or as a stand-alone operation. Recently, it has been described as a revisional option for previous bariatric surgery failures. We report our early experience with LSG as a revisional procedure for failed LAGB.From January 2007 to April 2010, 46 patients, who had undergone LAGB, underwent LSG. Patient demographics, reason for band removal, interval between removal and LSG, operative times, estimated blood loss, complications, length of hospital stay, and percent of excess weight loss were collected.Of the 46 patients, 20 (43%) had their bands removed before LSG (median time interval, 2 years; range, 2 months to 9 years); the rest had concomitant band removal and LSG. Twelve patients were men (26%). Mean age and BMI were 40 (range, 20-60) years and 43.1 kg/m(2) (range, 33-57), respectively. In two cases, surgery was converted to an open procedure due to extensive adhesions related to previous surgeries. Median operative time, estimated blood loss, and length of hospital stay were 118 (range, 70-250) minutes, 41 (range, 5-600) ml, and 3 (range, 1-100) days, respectively. Major morbidity was encountered in three patients (6%; leak in 2 and bleeding in 1). There were no mortalities. Mean follow-up time for our cohort is 17 (range, 1-39) months. Percent of excess weight loss at 2, 6, 12, 24, and 36 months was 24, 37, 53, 51, and 48%, respectively.Our results suggest that LSG is safe, feasible, and effective as a revisional procedure for failed LAGB and can be considered as an appealing option in these cases. Larger series and longer follow-up are needed to confirm this.

Laparoscopic sleeve gastrectomy (LSG) is gaining popularity as an additional bariatric procedure, either as a first step for biliopancreatic diversion or gastric bypass or as a stand-alone option for selected patients. Early postoperative fluid tolerance varies between patients and influences the length of hospital stay. Swallow studies after LSG are not uniform and display different patterns with regard to contrast passage through the gastric sleeve. The 55 patients (40 women) in this study underwent LSG during 18 months. These patients had a mean age of 38.2 years (range: 17–61 years) and a mean body mass index (BMI) of 44.8 kg/m2 (range: 39–75 kg/m2). The LSG procedure was performed using a four-port technique to resect the greater curvature of the stomach around a bougie. The mean operative time was 120 min (range: 45–240 min). A routine swallow study was performed on postoperative day 1, and clear fluids were initiated if no leak was detected. Patients were discharged when they could tolerate a daily fluid intake of 2 l. No mortalities, obstructions, or leaks occurred in the study cohort. Two main patterns of contrast passage were identified: type 1 (immediate unhindered flow through the sleeve to the antrum with a slight delay before continuation of the contrast to the duodenum) and type 2 (contrast filling of the proximal sleeve with delay of flow distally toward the duodenum). Patients with rapid contrast passage (group 1, n = 24) tolerated clear fluids better than those with delayed flow (group 2, n = 31) and were discharged earlier than their counterparts (mean length of hospital stay, 2.5 vs. 3.4 days; p

Objective To address optimal timing of sentinel lymph node biopsy (SLNB) in breast cancer patients undergoing neoadjuvant treatment. Methods The study population included 117 patients with locally advanced cancer with clinically negative nodes treated with primary chemotherapy. Group 1 underwent SLNB and completion axillary lymph node dissection (ALND) in conjunction with lumpectomy/mastectomy, after neoadjuvant treatment (n = 31). Group 2 underwent SLNB followed by neoadjuvant therapy and subsequently surgery and completion of ALNDs (n = 58). Group 3 was treated using the same sequence as group 2, however, completion ALND was performed only for patients with positive sentinel lymph nodes (SLNs) (n = 28). Results SLN identification was lowest in group 1 compared to groups 2 and 3 (87% and 98.8% respectively; P =

Advances in technology and the increase in screening for breast cancer that identifies tumors at earlier stages have made it possible to destroy tumors in situ without surgery. This can also be used to treat locally advanced tumors. These locoregional ablative techniques include minimally invasive surgical as well as noninvasive ablative modalities, new radiation technologies, and regional chemotherapy. New developments in imaging modalities such as MR make these treatment opportunities more precise and reliable. The regional minimally invasive technologies provide treatment options that are physiologically, cosmetically, and psychologically more acceptable to the patient. Many of these need further investigation before they become an accepted sound practice. This paper reviews and discusses the up-to-date data and feasibility of technologies for locoregional treatment of breast cancer

A functional single nucleotide polymorphism in the promoter of the MDM2 gene, SNP309 (T>G), was recently found to accelerate tumorigenesis in early onset cancer cases. The SNP309 G-allele, introduces an SP1 site in the MDM2 promoter, resulting in enhanced MDM2 expression and activity. Thus, the G-allele of MDM2 SNP309 may represent a cancer predisposing allele. In this report, we assessed the role of SNP309 as a modifier of mutant BRCA1/BRCA2 alleles in inherited breast and ovarian cancer cases among Ashkenazi-Jewish (AJ) women. We genotyped several subsets of AJ women: 138 healthy women, 140 affected BRCA1/2 mutation carriers, 120 asymptomatic BRCA1/2 mutation carriers and 187 sporadic breast cancer patients. The frequency of GG genotype of SNP309 was similar among the different groups. Interestingly, we found almost three times higher frequency of the GG genotype among BRCA1/2 carriers diagnosed with breast and/or ovarian cancer at or under the age of 51 years compared with carriers diagnosed with cancer above the age of 51 years (allele frequency, P = 0.019). The GG genotype was significantly associated with breast and ovarian cancer risk among BRCA1/2 carriers diagnosed before 51 years of age (OR, 3.93; 95% CI, 1.41-10.90, P = 0.009). No significant difference in frequency of the GG genotype was observed between early and late onset non-carrier cancer patients and no association with risk, OR, 1.30; 95% CI 0.69-2.47, P = 0.419). These data suggest that MDM2 SNP309 acts as a modifier of mutant BRCA1/2 mutant alleles in AJ and may accelerate breast and ovarian carcinogenesis in genetically predisposed individuals.

The insulin-like growth factors (IGFs) play a pivotal role in breast cancer. Inherited predisposition to breast and ovarian cancer is associated with germline BRCA1/BRCA2 mutations. To evaluate the impact of BRCA1 mutations on IGF-IR gene expression, we performed an immunohistochemical analysis of IGF-IR in primary breast tumors from BRCA1 mutation carriers and non-carriers. Results obtained revealed a significant elevation in IGF-IR levels in tumors from BRCA1 mutation carriers compared with non-carriers. To assess the potential inhibitory role of BRCA1 on IGF-IR levels, we infected the BRCA1-deficient HCC1937 cell line with a BRCA1-encoding adenoviral vector. Results of Western blots showed that BRCA1 induced a large reduction in endogenous IGF-IR levels. Furthermore, results of chromatin immunoprecipitation assays indicated that the mechanism of action of BRCA1 involves interaction with Sp1, a potent transactivator of the IGF-IR gene. In conclusion, our data suggests that the IGF-IR gene is a physiologically relevant downstream target for BRCA1 action.

The insulin-like growth factors, IGF-I and IGF-II are a familyof mitogenic polypeptides with important roles in growth and differentiation. The biological actions of the IGFs are mediated by the IGF-I receptor (IGF-IR), a cell-surface tyrosine kinase, whose activation by serum IGF-I seems to be a key step in breast cancer initiation. Evidence accumulated indicates that estrogens stimulate the expression and activity of IGF axis components. The aim of our study was to examine the transcriptional mechanisms involved in regulation of IGF-IR gene expression by the estrogen receptor (ER). For this purpose, transient transfections using an IGF-IR promoter-luciferase reporter plasmid were performed in breast cancer-c derived ER-positive MCF-7 cells and isogenic ER-negative C4 cells. To examine the potential involvement of zinc-finger nuclear proteins in the transactivating effect of estrogens, chromatin immunoprecipitation (ChIP) experiments were performed using an Sp1 antibody, along with the Sp1-family-binding inhibitor Mithramycin A. The results obtained indicate that basal IGF-IR promoter activity was 5.8-fold higher in MCF-7 than in C4 cells. Estradiol treatment significantly activated the IGF-IR promoter in MCF-7, but not in C4 cells. Furthermore, the estrogen responsive region in the IGF-IR promoter was mapped to a GC-rich sequence located between nucleotides −40 and −188 in the 5′ flanking region. ChIP experiments revealed that at least part of the estrogen effect on IGF-IR expression was mediated through activation of the Sp1 transcription factor. In summary, our studies demonstrate that IGF-IR gene transcription in breast cancer cells is controlled by interactions between ERα and Sp1. Dysregulated expression of the IGF-IR gene may have pathologic consequences with relevance in breast cancer etiology.

Type 2 diabetes mellitus is associated with increased incidence and inferior outcome of various malignancies. The aim of this study was to explore the impact of type 2 diabetes on breast cancer characteristics at presentation. The study population included 79 diabetic and 158 age-matched non-diabetic patients. Parity, country of birth, co-morbidity other than diabetes, and mode of diagnosis were similar in both groups. Mean body mass index (BMI) was higher among diabetic patients. Tumour stage and size were higher among diabetic patients and the differences remained significant after adjustment for BMI. Moreover, after adjustment for BMI, breast cancer among diabetic patients was more often hormone receptor negative. Our results show that diabetes mellitus is associated with negative prognostic factors at breast cancer presentation.

The aim of this study was to compare reproductive factors, use of oral contraceptives (OC) and hormone replacement therapy (HRT) in consecutive Jewish Ashkenazi breast cancer patients, with and without BRCA1/BRCA2 mutations. Jewish Israeli women with breast cancer (n = 385) were genotyped for the three predominant Jewish mutations in BRCA1 and BRCA2, and data on reproductive factors, OC and HRT use, were analyzed using logistic regression analyses. Overall, 28/385 (7.3%) of participants were mutation carriers, the majority of whom were Ashkenazi (n = 22; 78.6%) and were diagnosed with breast cancer at or under age 49 years (n = 18; 64.3%). Mutation carriers were more likely than non-carriers to ever use OC (39.3% vs. 20.2%; P = 0.053), HRT (35.7% vs. 13.7%; P = 0.007), and have first menarche at or below 12 years of age (71.4% vs. 40.6%; P = 0.03). Multivariate analysis showed that Ashkenazi women diagnosed with breast cancer under 40 years of age, with a family history of breast/ovarian cancer, who ever used HRT were more likely to be mutation carriers. This study has shown that HRT use is more prevalent among Jewish Ashkenazi mutation carriers, but its role in modifying breast cancer risk in mutation carriers remains unknown.

While the precise genes involved in determining familial breast cancer risk in addition to BRCA1/2 are mostly unknown, one strong candidate is RAD51 . Jewish non-Ashkenazi women at high-risk for breast/ovarian cancer and ethnically matched controls were genotyped using four single nucleotide polymorphisms spanning the RAD51 genomic region, and the resulting haplotypes were constructed using the GERBIL algorithm. A total of 314 individuals were genotyped: 184 non-Ashkenazi high-risk women (119 with breast cancer), and 130 unaffected, average-risk ethnically matched controls. Using GEBRIL, three frequent haplotypes were constructed. One of the haplotypes (TGTA – coined haplotype 3) was present in 7.3% (19/260 haplotypes) of controls ( n = 130) and in 16.8% (40/238 haplotypes) of high-risk breast cancer patients ( n = 119, P = 0.001). A specific RAD51 haplotype is more prevalent among non-Ashkenazi Jewish high-risk women than in average-risk population.

The use of high energy focused ultrasound (FUS) waves to destroy tumor tissue in breast cancer is explored. High energy FUS destroys cells by raising the temperature of the treated volume high enough to denature cell proteins and bring about cellular death. The absorbed energy results in extremely high tissue gradients between target cells and surrounding tissue, so the effect of the focused energy is concentrated only at the target, leaving the healthy tissue unscathed. This phase one trial has examined the possibility of ablating breast carcinoma using MRI Guided FUS (MRIgFUS) in place of lumpectomy. Ten female patients underwent the procedure at the Chaim Sheba Medical Center between September 2002 and August 2004, using the ExAblate 2000 (InSightec, Haifa Israel Ltd.). Seven to 10 days after the procedure, all patients underwent standard lumpectomy and axillary sampling to complete standard treatment and to allow pathological evaluation of the procedure. Two patients had a complete pathological response. The remaining 8 patients had varying amounts of residual tumor; 2 had microscopic foci of residual carcinoma, 3 had 10% residual tumor, and 3 had 10-30% of residual tumor. Although still in its infancy, the future role of this type of ablation in breast cancer and other tumors is discussed.

During a 2 year period (1992–1993), 149 patients with advanced abdominal cancer underwent total abdominal ischemic perfusion (TAP) and stop-flow infusion (SFI) 159 times in an attempt to achieve palliation. These procedures and aortic stop-flow infusion require insertion of balloon catheters into the abdominal aorta and inferior vena cava by a transfemoral approach. Flow is arrested for 15 minutes, during which time chemotherapeutic agents are infused into the aorta, distal to the balloon occlusion. Femoral access is by a surgical incision. The passage of the catheters is guided by fluoroscopy. Some tumor response was observed in 35% of the patients. Ten patients had major vascular complications; two iliac artery aneurysms were lacerated and required emergency repair. There were two femoral artery false aneurysms that required surgical correction, one early and one late. Aortic dissection was detected in four patients, but these did not require surgical intervention. Two patients had thrombosis distal to the occluded vessel, both required surgical intervention. To reduce the incidence of these vascular complications we recommend: (1) a clinical and vascular laboratory evaluation before the procedure, and (2) angiography of normal flow in patients with underlying vascular disease. © 1996 Wiley-Liss, Inc.