The possible association between IVF and breast cancer incidence.

BACKGROUND: The possible association between ovulation-inducing drugs and breast cancer development has been debated. Our aim was to evaluate the incidence of breast cancer in a cohort of women exposed to in vitro fertilization (IVF). METHODS: A retrospective cohort analysis was performed by linkage of the computerized database of all women treated at the IVF Unit at Assaf Harofeh Medical Center between 1986 and 2003, and the Israeli National Cancer Registry. The standardized incidence ratio (SIR) was computed as the ratio between the observed number of breast cancer cases and the expected cases, adjusted for age and continent of birth, in the general population. Tumor characteristics of the IVF patients were studied by reviewing original medical records. RESULTS: 35 breast carcinomas were diagnosed among 3,375 IVF-treated women, compared to 24.8 cases expected (SIR = 1.4; 95% CI 0.98-1.96). Age >or=40 years at IVF treatment (SIR = 1.9; 95% CI 0.97-3.30), hormonal infertility (SIR = 3.1; 95% CI 0.99-7.22), and >or=4 IVF cycles (SIR = 2.0; 95% CI 1.15-3.27) were found to be risk factors to develop breast cancer compared to the general population. Multivariate analysis revealed that women who underwent >or=4 IVF cycles compared to those with one to three cycles were at risk to develop breast cancer, although not significantly (SIR = 1.9; 95% CI 0.95-3.81). Of IVF-treated women 85% had ER(+) tumors and 29% had positive family history. CONCLUSIONS: A possible association between IVF therapy and breast cancer development was demonstrated, especially in women >or=40 years of age. These preliminary findings need to be replicated in other cohort studies.

Breast cancer in the elderly: histological, hormonal and surgical characteristics.

The characteristics, menstrual risk factors and surgical therapy of 187 consecutive patients more than 70 years of age (mean: 75.9) were investigated and compared with those of 609 patients less than 70 years of age (mean: 53.9). There was no difference in stage, size, state of axillary nodes, grade, histological types, Ki-67, vascular invasion, estrogen receptor rate, and HER-2/neu (+) rate. Positive progesterone receptor rate was higher in older patients (54.7% vs. 63.1%). Tumors were larger (p=0.01) and their stage higher (p=0.014) in patients more than 80 years of age. All menstrual risk factors were similar in the two groups. Positive familial history was more frequent in patients <60 years. Significantly more young patients used hormone replacement therapy (HRT) (21.8 vs. 8.6%). Older patients underwent less breast-conserving surgery (36.1 vs. 55.1%), and less axillary lymph node dissection (ALND) (69.7 vs. 84.9%). We conclude that breast cancer characteristics and menstrual risk factors are similar in the two age groups.

Fibroblasts genetically engineered to secrete interleukin 12 can suppress tumor growth and induce antitumor immunity to a murine melanoma in vivo.

Interleukin 12 (IL-12), a disulfide-linked heterodimeric cytokine produced primarily by macrophages, is composed of light (p35) and heavy (p40) chains. It binds to a receptor on T-cells and natural killer cells, promoting the induction of primarily a TH1 response in vitro and in vivo. To determine whether paracrine IL-12 secretion can alter tumor cell growth or promote antitumor immunity, we have developed a delivery system using genetically engineered fibroblasts in murine tumor models. NIH3T3 cells were stably transfected to express 100-240 units/10(6) cells/48 h of IL-12 using expression plasmids carrying both the murine p35 and p40 genes of murine IL-12. The effects of paracrine secretion of IL-12 on tumor establishment and vaccination models were examined using the poorly immunogenic murine melanoma cell line (BL-6) in C57BL/6 mice. To determine the effects of IL-12 on tumor formation, nonirradiated BL-6 cells were inoculated s.c. into C57BL/6 mice admixed with NIH3T3 cells transfected with both subunits of mIL-12 (3T3-IL-12) or with cells transfected with only the neomycin phosphotransferase gene (3T3-Neo). Compared to mice given injections of BL-6 alone, the day of emergence of detectable tumors was significantly delayed in mice given injections of BL-6 admixed with 3T3-IL-12, but not in mice with BL-6 admixed with 3T3-Neo. Effectiveness in this system was related to the amount of IL-12 expressed by the 3T3-IL-12. To determine the ability of locally secreted IL-12 at the tumor site to induce antitumor immunity, 10(6) irradiated tumor cells mixed with 3T3-IL-12 or 3T3-Neo were injected as a vaccine, and the response to a tumor challenge was subsequently examined. With a tumor challenge of less than 1 x 10(5) nonirradiated BL-6 cells, significant delay of establishment of tumor was noted with a relatively small amount of IL-12 secretion (1.2 units/5 x 10(5) cells/48 h). Larger amounts of secreted IL-12 provided no additional therapeutic benefit. Histological examination of tumor inoculum with 3T3-IL-12 secreting a high level of IL-12 showed peritumoral accumulation of macrophages, a characteristic capsule around the tumor composed of palisades of fibroblasts, and decreased numbers of CD4+ cells in the tumor. These results suggest that local delivery of IL-12 inhibits tumor growth in a dose dependent manner but leads to the development of an antitumor immune response when IL-12 is expressed at the tumor site at the relatively small amount indicated above.(ABSTRACT TRUNCATED AT 400 WORDS)

Altered gut barrier function to Candida during parenteral nutrition.

We hypothesize that catheter-related sepsis with Candida during total parenteral nutrition (TPN) is caused by Candida translocation from the gut. Fifty male Sabra rats weighing 330 +/- 40 g were randomized into four groups and put into metabolic cages: group 1 (n = 16), nonoperated free-feeding controls; group 2 (n = 10), infused with normal saline and free feeding; group 3 (n = 14), infused with TPN solution for a total of 36 kcal and 1.5 g g protein.100 g-1 body wt.day-1;group 4 (n = 10), same TPN regimen as group 3 but also receiving oral and intravenous antibiotics. On day 7, all animals received 1.5 x 10(10) viable Candida albicans CBS 562 cells by gavage, and 24 h later, the number of Candida colony-forming units in blood, mesenteric lymph nodes, and kidneys was determined. No growth of Candida was detected in group 1 or group 2. Positive Candida cultures were found in the blood, mesenteric lymph nodes, and kidneys of groups 3 and 4, although levels reached statistical significance only for mesenteric lymph nodes in group 3. Because Candida growth occurred exclusively in groups receiving TPN and bowel rest, we conclude that altered gut-barrier function to Candida occurs during TPN and speculate that Candida sepsis during TPN might be the result of Candida translocation from the gut due to the combination of high-density Candida colonization and favorable local conditions in the gut induced by TPN and bowel rest.

Polymyxin B reduces total parenteral nutrition-associated hepatic steatosis by its antibacterial activity and by blocking deleterious effects of lipopolysaccharide.

Overgrowth of Gram-negative bacteria as a result of total parenteral nutrition (TPN) and bowel rest could be responsible for the release of a variety of hepatotoxic substances such as endotoxin or tumor necrosis factor (TNF) and the ensuing TPN-associated liver function derangements. Polymyxin B is an effective antimicrobial agent as well as a blocking agent for endotoxin (lipopolysaccharide) activity and TNF production. In the present study we compared the oral and intravenous effects of polymyxin in rats receiving TPN in an attempt to define these two possible mechanisms of action of polymyxin on TPN-associated hepatic steatosis. Both oral, as well as intravenous polymyxin B, significantly reduced total hepatic fat and triglyceride accumulation in TPN rats, more so in the intravenous group exhibiting close to control levels. Both polymyxin-treated groups exhibited significantly lower Gram-negative bacterial counts in the cecum, with the oral group exhibiting a lower count than the IV group. The spontaneous production of TNF by peritoneal macrophages was markedly increased in rats receiving TPN and very close to being undetected in both groups receiving TPN and polymyxin. We believe polymyxin B protects the liver during TPN by both its antimicrobial effect which prevents overgrowth of gut Gram-negative bacteria and the subsequent translocation of endotoxin, and by its specific antilipopolysaccharide activity which, in the present study, completely abolished hepatic steatosis and TNF production during TPN.

Antitumor necrosis factor antibodies reduce hepatic steatosis during total parenteral nutrition and bowel rest in the rat.

BACKGROUND: In previous studies, we demonstrated the overgrowth of gram-negative bacteria in the gut and an enhanced release of tumor necrosis factor (TNF) by peritoneal macrophages, suggesting that endotoxin, TNF, or both, may act as hepatotoxins to produce hepatic steatosis during total parenteral nutrition (TPN) and bowel rest. The present study attempts to better define the role of each of these two mediators. The first part examines the LD50 for various doses of endotoxin in TPN-treated rats compared with free-feeding and free-feeding saline-infused rats. In the second part we repeatedly administered anti-TNF monoclonal antibodies to rats subjected to TPN and bowel rest. METHODS: In the first set of experiments, 87 male Sabra rats were randomized into three groups: free-feeding, infused with normal saline, and infused with TPN. On day 7 of the experiment, all rats received an IV injection of endotoxin at various doses (1.5, 2.5, 5.0, 7.5, and 10 mg/kg). The LD50 in the three groups and at the various doses of lipopolysaccharide tested was determined at 24 hours postinjection. In the second set of experiments, 38 male Sabra rats were randomized into three groups: infused with normal saline and fed rat food ad libitum, infused with TPN, and infused with TPN but also receiving monoclonal antibodies against TNF. RESULTS: Lower endotoxin doses were required to achieve LD50 in the two IV-infused groups (2.5 to 5.0 mg/kg) compared with the free-feeding group (7.5 mg/kg) (p < .03). These findings suggest a moderate increase in susceptibility to the lethal effect of endotoxin in IV-treated rats. The total hepatic fat and triglyceride levels, which were markedly increased in TPN rats, were significantly reduced by using anti-TNF antibodies. Enhanced TNF production by peritoneal macrophages during TPN was completely eliminated by anti-TNF antibodies, probably the result of suppressed TNF production. CONCLUSIONS: The continuous translocation of endotoxin from gram-negative bacterial overgrowth in the gut during TPN and bowel rest results in enhanced release of TNF by macrophages. TNF causes hepatic dysfunction, portrayed in the present experimental model as hepatic steatosis. TPN-induced hepatic steatosis was significantly reduced by the administration of monoclonal antibodies against TNF-alpha.

99Tc(m)-tetrofosmin scintimammography for detecting breast cancer: a comparative study with 99Tc(m)-MIBI.

Scintimammography using 99Tc(m)-MIBI (99Tc(m)-sestamibi) has demonstrated promising results in the detection of breast cancer. Recently scintimammography using 99Tc(m)-tetrofosmin has been suggested as a better diagnostic tool and a more convenient agent to use in this condition. In this study we compared both agents in 35 consecutive women with abnormal mammographic or physical findings. Thirty-four of them underwent MIBI scan, followed by tetrofosmin scan 2 days later (performed on all 35 women). Within 2 weeks, a pathological diagnosis was obtained either by needle or open biopsy. In both scans the uptake ratio between the lesion and the background uptake was calculated. Twenty patients who underwent tetrofosmin scan and 19 patients with MIBI scan had malignant breast tumours, while 15 women had benign lesions. The sensitivity, specificity, positive and negative predictive values and total accuracy of the MIBI scan were 89.4%, 80%, 85%, 85.7% and 85.3%, respectively; almost identical values were obtained with tetrofosmin (90%, 80%, 85.6%, 85.7% and 85.7%, respectively). The uptake ratios in the MIBI and tetrofosmin scans were 1.68 +/- 0.52 and 1.7 +/- 0.47, respectively. No differences were found between the two scintimammographies in all the parameters examined. In conclusion, MIBI and tetrofosmin breast scans are accurate and equally efficient for the detection of breast malignancies.

99Tcm-MIBI scintimammography for the detection of breast malignancies: the contribution of the count ratio to specificity.

We evaluated the efficacy of 99Tcm-sestamibi (MIBI) scintimammography for the detection of breast cancer in 332 patients. Two hundred and seven scans were confirmed by histological or cytological results; the other patients were examined because they belonged to high-risk groups or had dense fibroglandular breasts. Of 207 patients with histological confirmation, 112 positive studies were obtained: 86 true-positive and 26 false-positive. Scintimammography was negative in 95 patients: 88 true-negative and seven false-negative. Six of seven false-negative results were obtained in patients with impalpable tumours. The sensitivity, specificity, positive and negative predictive values were 92.5%, 77.2%, 76.8% and 92.6% respectively. The overall accuracy was 84.1%. To identify false-positive results, the count ratio of the target lesion to the contralateral normal area on 38 true-positive scans and in 26 false-positive examinations was calculated from the region of interest drawn on the 99Tcm-MIBI scan (L/N ratio). A significantly higher ratio was found for the true-positive scans (1.583 +/- 0.501 vs 1.246 +/- 0.213; P = 0.0002). In conclusion, 99Tcm-MIBI scintimammography is a sensitive and accurate method for the detection of breast malignancies.

Bolus high dose interleukin-2 for the treatment of malignant melanoma.

BACKGROUND: High dose interleukin-2 therapy, administered in bolus, is considered to be a reasonable treatment option in a selected group of patients with metastatic malignant melanoma. OBJECTIVES: To present our experience using this mode of therapy in 21 patients with metastatic melanoma. MATERIALS AND METHODS: The 21 patients in our study group comprised 13 men and 8 women with a mean age of 46 years (range 29-63). Their metastatic disease was present in all extracranial sites, dermal and sub-dermal metastases being the most common (15 patients had at least one site, in addition to other locations of metastases). Patients with intracranial disease were excluded due to the poor effectivity of IL-2 at this site. Treatment comprised a course of 2 weeks of therapy with a 1 week rest interval between. Radiological and physical evaluation was performed 6-8 weeks after the first course. If a response was achieved a second course of therapy was given. Patients received up to 14 planned doses of IL-2 in each week, 720,000 IU/kg of IL-2 per dose i.v. in 15 minutes. All treatments were given in the surgical ward, and only one patient was hospitalized in the intensive care unit. RESULTS: Of the 21 patients, one had a complete response that has lasted for 17 months and 5 patients had a partial response (range 3 months to 3 years). One patient died during treatment, and one patient who refused further treatment because of no response died a few days after completion of treatment. Prior to therapy three of the responders had received autologous vaccines with good immunological response (P = 0.115). Toxic side effects were significant, but they were treated successfully with no residual damage. CONCLUSIONS: High dose IL-2 can be administered safely in a surgical department. The response rates achieved in this series justify the use of high dose IL-2 in a selected group of patients. To improve response rates, a combination of autologous vaccines prior to high dose IL-2 may be recommended.

[Sutureless bowel anastomosis with a biofragmentable ring in Crohn's disease].

A biofragmentable anastomosis ring has recently been developed and is used in end-to-end intestinal anastomosis. It is composed of 2 circular polyglycolic acid (Dexon) components which are interdigitated to form a sutureless anastomosis. We used it in an ileo-ileal and 2 ileo-colic end-to-end anastomoses in 3 patients with Crohn's disease in the past 6 months. Postoperative recovery of bowel function and oral feeding were comparable to that in patients after conventional anastomoses with sutures or staplers. Experience accumulated in 2 large multicentric comparative studies proved that the ring is a safe, fast and effective method for bowel anastomosis. We found it to be safe even in Crohn's disease.

[Primary breast tumor and malignant phyllodes tumor of the breast-- two rare cases demonstrated by technetium 99m scintimammography].

Breast cancer can be detected by scintimammography using Tc-99m sestamibi (MIBI). The method is highly accurate, sensitive and specific. Histologically, most of the tumors have been adenocarcinomas. We present 2 women with rare breast tumors, primary squamous cell carcinoma and malignant phyllodes tumor. In both, mammography and cytological biopsy were not diagnostic, but MIBI scintimammography demonstrated focal uptake in the diseased breast.

[Is Crohn's disease different in the elderly?].

We reviewed the records of 22 patients hospitalized at onset or first presentation of Crohn's disease after age 50. There were 12 females and 10 males, and the mean age was 64.5 years. The most common presenting symptoms were: abdominal pain, fever, diarrhea and weight loss. The disease was located in the small bowel in 14, in the ileo-colic region in 3 and in the colon in 5. The median interval from onset of symptoms until diagnosis was 42 months. 12 (54%) underwent surgery. All 5 patients with colonic disease were operated. 6 patients underwent small bowel resections, mostly terminal ileum, while 1 had resection of both terminal ileum and left colon. The recurrence rate was 70% in the medically treated and 50% in those operated. 1 patient died after surgery for Crohn's disease (4.5%), and 3 others died of unrelated causes. Compared to younger patients, the symptomatology, clinical course, need for and response to surgery, and its complications, did not differ in these older patients, but the recurrence rate seemed to be higher.

[Spontaneous splenic rupture associated with facial erysipelas].

Spontaneous rupture of the spleen is rare Although over 100 cases have been reported, only a few were of true spontaneous rupture. Most cases were associated with diseases which directly involved the spleen. We report a 53-year-old woman with facial erysipelas and true spontaneous rupture of the spleen.

Mammary arteritis mimicking cancer. Case report.

Giant cell arteritis and polyarteritis nodosa are systemic diseases which rarely involve the breasts. Two cases are reported in which breast masses, clinically suspected to be malignant, were found to be isolated vasculitis--bilateral giant cell mammary arteritis in a 67-year-old woman and isolated mammary polyarteritis nodosa in a 45-year-old woman. Vasculitis should be considered in the differential diagnosis of breast masses.

Biliary and pancreatic metastases of breast carcinoma: is surgical palliation indicated?

Obstructive jaundice developed in a patient concomitantly with the diagnosis of breast carcinoma. Abdominal exploration disclosed a metastatic tumor in the head of the pancreas, the distal bile duct, and the gallbladder. A cholecystectomy and choledochojejunostomy were performed and later, because of intestinal obstruction, the patient underwent gastrojejunostomy. Pathological examination demonstrated metastatic lobular carcinoma of breast with strongly positive staining for estradiol. Additional hormonal therapy has been given to the patient since the operation. The patient is alive 16 months after the diagnosis of her disease. This case suggests that a vigorous diagnostic approach should be adopted in every jaundiced patient with metastatic breast cancer in order to exclude causes of jaundice other than diffuse metastatic involvement of the liver. Patients with extrahepatic biliary metastasis should be treated by aggressive surgical treatment, combined with systemic therapy which can offer them significant palliation and better survival.

Cecal diverticulitis: a diagnostic challenge.

BACKGROUND: Cecal diverticulitis is frequently indistinguishable from acute appendicitis preoperatively and is sometimes mistaken for carcinoma at laparotomy. The surgeon must be aware of the possibility of diverticulitis of the cecum in the operating room and choose the appropriate treatment. PURPOSE: Because there is no universal therapeutic approach to these patients, we decided to assess the presenting symptoms, clinical findings, preoperative diagnosis, operative findings determining the proper management of these patients. METHODS: A retrospective chart review of 13 patients with pathologically confirmed cecal diverticulitis, who underwent surgery in our department from 1984 to 1998, was undertaken. RESULTS: The mean age of patients was 43.5 years. Right lower quadrant pain and local tenderness were the only clinical findings in 92.3%, with preoperative diagnosis of acute appendicitis in 84.6% of patients. The operative finding in most cases was inflammatory mass of the cecum; in 6 cases it was indistinguishable from perforated cecal carcinoma. Six patients underwent right hemicolectomy, 5 had ileocecectomy, 1 patient was treated by tube cecostomy, and 1 had diverticulectomy. There were three minor postoperative complications: pneumonia, wound infection and lower limb superficial thrombophlebitis. CONCLUSIONS: Cecal diverticulitis needs a high index of suspicion for achieving a preoperative diagnosis. We suggest that the operative therapy should be ileocecectomy. The surgical specimen should be examined during surgery and only if carcinoma is found should the patient have a formal colectomy.

Treatment of faecal incontinence in children with spina bifida by biofeedback and behavioural modification.

Faecal incontinence may lead to serious social and physiological disturbances. Over 90% of patients with spina bifida have varying degrees of neurogenic bowel with disturbances of faecal control. This is a serious habilitation problem in these patients. Three encopretic children with myelomeningocele were treated by Biofeedback operant conditioning and behavioural modification to self-initiate bowel movements. Their neurological levels were T-10; T-11; T-12. Each child had a mean of 10 Biofeedback sessions each of 30-45 minutes, combined with daily behavioural modification. Two patients improved and have voluntary bowel movements. Therapy failed in one patient. We conclude that Biofeedback operant conditioning combined with specific behavioural modification may become a simple technique to treat encopretic patients with meningomyelocele.