[THE EFFECTS OF HORMONAL REPLACEMENT THERAPY (HRT) ON MAMMOGRAPHIC BREAST DENSITY AND ABNORMAL MAMMOGRAMS PROMPTING FURTHER INVESTIGATION].

AIMS: The purpose of this study was to portray and analyze the inter-relationship between the use of HRT, mammographic breast density and the finding of any mammographic abnormality that prompted further investigation such as core needle biopsy or additional imaging testing, while controlling for obstetric and relevant demographic data. BACKGROUND: Mammographic breast density has been associated with higher risk of breast cancer and decrease in its sensitivity, while hormonal replacement therapy (HRT) in turn, has been implicated in increasing mammographic density and is considered a risk factor for breast cancer by itself. The inter-relationship between HRT, breast density and any mammographic or sonographic finding requiring further investigation has not been fully investigated. METHODS: A total of 2,758 consecutive, screening mammograms performed during one year in a single academic medical center in Israel were analyzed. Each mammogram was supplemented by high resolution ultrasound. Density was measured by a visual, semi-quantitative, 5-grade scale, based on Boyd's classification and grouped into low density mammograms (LDM) (1-3) and high density mammograms (HDM) (4-5). Demographic and obstetric data, personal and family history of breast cancer, and the use of HRT were entered into the database. These parameters were correlated with breast density and any detected abnormality that prompted further investigation. Univariate and multivariate analyses as well as multivariate logistic regression were performed using SAS 9.2. RESULTS: A significant difference in density was observed between pre- and post-menopausal women (p = 0.0001). However, the use of HRT in post-menopausal women was not associated with higher incidence of HDM (18.6%, n=110/592) compared to post-menopausal women without HRT (15.4%, n=211/1370) (p=n.s). Mammographic abnormality was more likely to occur in post-menopausal women without HRT (52%, n=711/1370) compared with women on HRT (38.7% n=229/592) (p = 0.0001). This held true for solid lump (p=0.0001), tissue irregularity (p=0.016) and calcifications (p=0.0005). Menopause was associated with higher likelihood (48%) of any mammographic finding compared with 41.6% in pre-menopausal women (p = 0.0017). A total of 266 women with mammographic findings prompting histological assessment were identified, revealing 105 malignant lesions. HRT in post-menopausal women was associated with lower incidence (28%) of malignancy compared to post-menopausal women without HRT (50%). CONCLUSIONS: The present study, portraying the inter-relationship between mammographic breast density, any abnormal finding in screening mammograms, and the use of HRT has not found such treatment to be associated neither with increased density, nor with higher probability of finding malignancy. Furthermore, a lower incidence of mammographic abnormality was noted in HRT users. Albeit, further and larger studies are required to substantiate these findings. The results of this study do not support the notion that HRT increases the likelihood of malignancy or affects breast density.

The chemokine CCL5 as a potential prognostic factor predicting disease progression in stage II breast cancer patients.

PURPOSE: The aim of this study was to determine the prognostic value of the chemokine CCL5, considered as a promalignancy factor in breast cancer, in predicting breast cancer progression and to evaluate its ability to strengthen the prognostic significance of other biomarkers. EXPERIMENTAL DESIGN: The expression of CCL5, alone and in conjunction with estrogen receptor (ER)-alpha, ER-beta, progesterone receptor (PR), and HER-2/neu (ErbB2), was determined in breast tumor cells by immunohistochemistry. The study included 142 breast cancer patients, including individuals in whom disease has progressed. RESULTS: Using Cox proportional hazard models, univariate analysis suggested that, in stage I breast cancer patients, CCL5 was not a significant predictor of disease progression. In contrast, in stage II patients, the expression of CCL5 (CCL5(+)), the absence of ER-alpha (ER-alpha(-)), and the lack of PR expression (PR(-)) increased significantly the risk for disease progression (P = 0.0045, 0.0041, and 0.0107, respectively). The prognostic strength of CCL5, as well as of ER-alpha(-), improved by combining them together (CCL5(+)/ER-alpha(-): P = 0.0001), being highly evident in the stage IIA subgroup [CCL5(+)/ER-alpha(-) (P = 0.0003); ER-alpha(-) (P = 0.0315)]. In the stage II group as a whole, the combinations of CCL5(-)/ER-alpha(+) and CCL5(-)/PR(+) were highly correlated with an improved prognosis. Multivariate analysis indicated that, in stage II patients, ER-alpha and CCL5 were independent predictors of disease progression. CONCLUSIONS: CCL5 could be considered as a biomarker for disease progression in stage II breast cancer patients, with the CCL5(+)/ER-alpha(-) combination providing improved prediction of disease progression, primarily in the stage IIA subgroup.

[Laparoscopic colon and rectal surgery--after ten years and 350 operations].

BACKGROUND: Within a decade since laparoscopy was used in cholecystectomy it has become the preferred approach in many abdominal procedures. Laparoscopic colon and rectal surgery has not yet been adopted by the majority of surgeons, due to technical complexity and reservation regarding its oncological safety. As data and experience accumulate, this attitude is gradually changing. We present our experience with laparoscopic surgery of the large bowel over the last ten years. AIM: To assess the short and intermediate term results after laparoscopic colon and rectal surgery, and to summarize the long term results after curative colectomy for malignancy. METHODS: Data regarding all patients undergoing laparoscopic colon and rectal surgery was prospectively entered into a computerized database, including demographics, surgical technique and perioperative course. Follow-up information was gathered at outpatient clinic visits, and using telephone interviews in selected cases. Data analysis was performed using a statistical software package. RESULTS: Over a period of ten years, 350 various laparoscopic colon and rectal procedures were performed, for both benign and malignant conditions. Sixty percent of the operations were for treatment of colorectal cancer. In 14.5% of cases conversion to open laparotomy was required. Post-operative complications included surgical site infection in 17.4%, anastomotic leak in 6.9%, and a mortality rate of 2.8%. Long term follow-up revealed cancer recurrence locally in 2.3% and systemically in 8.2%. Five year survival was 56% after resection of colorectal cancer regardless of the stage, and 63% after resection with curative intent. CONCLUSIONS: The laparoscopic approach to large bowel surgery enables short and long term results comparable with those achieved by open technique, regarding perioperative complication rate and long term oncologic outcome. The advantages of laparoscopy, related to reduced abdominal wall trauma, justify the adoption of this technique as a legitimate alternative to the open approach.

Cortical activity of children with dyslexia during natural speech processing: evidence of auditory processing deficiency.

Children with dyslexia have difficulties with phonological processing. It is assumed that deficits in auditory temporal processing underlie the phonological difficulties of dyslectic subjects (i.e. the processing of rapid acoustic changes that occur in speech). In this study we assessed behavioral and electrophysiological evoked brain responses of dyslectic and skilled reading children while performing a set of hierarchically structured auditory tasks. Stimuli consisted of auditory natural unmodified speech that was controlled for the parameter of changing rate of main acoustic cues: vowels (slowly changing speech cues: /i/ versus /u/) and consonant-vowel (CV) syllables (rapidly changing speech cues: /da/ versus /ga/). Brain auditory processing differed significantly between groups: reaction time of dyslectic readers was prolonged in identifying speech stimuli and increased with increased phonological demand. Latencies of auditory evoked responses (auditory event related potentials [AERPs]) recorded during syllable identification of the dyslectic group were prolonged relative to those of skilled readers. Moreover, N1 amplitudes during vowel processing were larger for the dyslectic children and P3 amplitudes during CV processing were smaller for the dyslectic children. From the results of this study it is evident that the latency and amplitude of AERPs are sensitive measures of the complexity of phonological processing in skilled and dyslectic readers. These results may be signs of deficient auditory processing of natural speech under normal listening conditions as a contributing factor to reading difficulties in dyslexia. Detecting a dysfunction in the central auditory processing pathway might lead to early detection of children who may benefit from phonetic-acoustic training methods.

Bilateral superior cervical sympathectomy and noise-induced, permanent threshold shift in guinea pigs.

The rich sympathetic innervation to the cochlea suggests its potential control of cochlear blood flow and activity during noise exposure, as part of the general and local stress sympathetic reaction evoked by noise. In a previous study, superior cervical sympathectomy prior to sound exposure in guinea pigs in an awake state, resulted in reduced temporary threshold shift. The present study was conducted to explore whether this potential protection would also be manifested in conditions producing permanent threshold shift (PTS). Thirty-six guinea pigs, divided into four groups of nine guinea pigs each, were sound exposed for 2 h in an awake state. Eighteen guinea pigs underwent superior cervical sympathectomy prior to sound exposure. Auditory brainstem thresholds were recorded prior to sound exposure, and then at 24 h, 1 and 6 weeks post-exposure. Results indicated a reduced PTS at 122 dB sound pressure level (SPL) exposure, suggesting a protective effect of the sympathectomy. However, at 125 dB SPL exposure, the protective effect was reduced.

Social and utilitarian considerations for allocating organs within a national organ sharing system: a computerized simulation model for policy decision-making.

BACKGROUND: An organ-sharing system should achieve fairness and optimal graft longevity. Balancing between social and utilitarian considerations is a sensitive ethical, public and medical issue that requires a means to examine the consequences of any allocation policy or planned changes thereof. OBJECTIVE: To evaluate the performance and applicability of a computerized simulation model by examining the impact of two opposing organ allocation policies (social or utilitarian) on predicted organ distribution regarding age, waiting time, recipient sensitization measured by panel reactive antibody level, and overall donor-recipient tissue matching (measured by the number of HLA antigen mismatches). METHODS: Using a computerized simulation model, virtual donors and recipients were emulated and organs were allocated according to either social algorithms or utilitarian policies. The resulting number of HLA mismatches, PRA, age, and waiting time distributions were compared between allocation strategies. RESULTS: Simulating allocation of 7,000 organs to 17,000 candidate recipients and implementing social policies yielded donor-recipient compatibility comparable to utilitarian policies (0-1 mm: 19.4% vs. 28%) while allocating 66.7% of organs to long waiters (>48 months). CONCLUSION: This computerized simulation model is a valuable tool for decision-makers establishing or modifying organ allocation policies.

Kidney transplantation from living donors: comparison of results between related and unrelated donor transplants under new immunosuppressive protocols.

BACKGROUND: Recent advances in immunosuppressive therapy have led to a substantial improvement in the outcome of kidney transplantation. Living unrelated donors may become a source of additional organs for patients on the kidney waiting list. OBJECTIVES: To study the impact of the combination of calcineurin inhibitors and mycophenolate-mofetile, together with steroids, on outcomes of living related and unrelated transplants. METHODS: Between September 1997 and January 2000, 129 patients underwent living related (n = 80) or unrelated (n = 49) kidney transplant. The mean follow-up was 28.2 months. Immunosuppressive protocols consisted of MMF with cyclosporine (41%) or tacrolimus (59%), plus steroids. Patient and graft survival data, rejection rate, and graft functional parameters were compared between the groups. RESULTS: LUD recipients were older (47.8 vs. 33.6 years) with a higher number of re-transplants (24.5% vs. 11.2% in LRD recipients, P < 0.05). Human leukocyte antigen matching was higher in LRD recipients (P < 0.001). Acute rejection developed in 28.6% of LUD and 27.5% of LRD transplants (P = NS). Creatinine levels at 1, 2 and 3 years post-transplant were 1.6, 1.7 and 1.7 mg/dl for LRD patients and 1.5, 1.5 and 1.3 mg/dl for LUD recipients (P = NS). There was no difference in patient survival rates between the groups. One, 2 and 3 years graft survival rates were similar in LRD (91.3%, 90% and 87.5%) and LUD (89.8%, 87.8% and 87.8%) recipients. CONCLUSIONS: Despite HLA disparity, rejection and survival rates of living unrelated transplants under current immunosuppressive protocols are comparable to those of living related transplants.

Focused, minimally invasive radio-guided parathyroidectomy: a feasible and safe option for elderly patients with primary hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism in elderly patients is usually associated with additional co-morbidity that increases operative risk, and thus many geriatric patients are denied the benefit of surgery for a single parathyroid adenoma. OBJECTIVES: To evaluate the safety and efficacy of accurate single photon emission computed tomography sestamibi scintigraphy, enabling precise localization of a single adenoma, in the geriatric population. METHODS: Twenty-two patients aged 70 years and over with biochemically proven PHPT and with a single parathyroid adenoma identified by localization studies (sestamibi SPECT scan and ultrasonography) underwent 23 operations over 29 months (out of a total of 140 patients operated upon during the same period). Immediate preoperative sestamibi scintigraphy and marking of focal adenoma uptake followed by intraoperative hand-held gamma probe were used for the removal of the parathyroid adenoma by unilateral minimal access surgery. Associated major co-morbid conditions and pre- and postoperative calcium, phosphorus and parathormone levels were recorded. Indications for surgery were listed and operative and postoperative complications were noted. The patients were followed for a mean period of 17.7 months using the same parameters. RESULTS: The 22 patients with PHPT had a mean age of 76.3 +/- 5.9 years (range 70-88 years) and a female to male ratio of 13:9. Associated co-morbidity included ischemic heart disease (n = 15), hypertension (n = 22), non-insulin-dependent diabetes mellitus (n = 9), chronic obstructive pulmonary disease (n = 3), and previous neck surgery (n = 3). Mean preoperative serum calcium, phosphorous and PTH were 11.7 +/- 1.3 mg/dl, 2.5 +/- 0.5 mg/dl and 160.9 +/- 75.4 pg/ml respectively. In 20 of the 22 patients, surgery was successful in curing PHPT (91%). One patient had persistent hypercalcemia due to a missed adenoma, and repeat operation (by focused minimal accesss surgery) was successfully performed 2 weeks later. There were no complications and no morbidity postoperatively. Mean postoperative serum calcium, phosphorous and PTH were 9.6 +/- 1.2 mg/dl, 3.0 +/- 0.5 mg/dl and 35.2 +/- 24 pg/ml respectively. In all patients, serum calcium levels remained normal (9.7 +/- 1.3 mg/ml) after long-term follow-up (mean 17.7 +/- 9.6 months). CONCLUSIONS: Minimally invasive, radio-guided focused parathyroidectomy for a single adenoma is a safe and effective method to cure hyperparathyroidism in the elderly. Success of surgery is directly related to the surgeon's experience and to the precise localization marking provided by sestamibi scintigraphic SPECT localization and concurrent sonographic findings.

Detrimental effects of cyclosporin A on long-term graft survival in familial Mediterranean fever renal allograft recipients: experience of two transplantation centers.

BACKGROUND: Cyclosporin A has been associated with severe toxic side effects in patients with familial Mediterranean fever who underwent renal transplantation. Nevertheless, the impact on graft function and survival is not well documented. OBJECTIVE: To compare long-term graft function and survival, between CsA-based vs. CsA free immunosuppressive protocols in FMF recipients of renal allograft. METHODS: Data of FMF recipients were analyzed retrospectively. Graft survival and function and the incidence of acute rejection were correlated to graft source (living donor vs. cadaveric donor), colchicine dose, presence of proteinuria, and immunosuppression protocol (CsA-based triple drug therapy vs. azathioprine-prednisone alone). RESULTS: There were 35 FMF patients with primary renal grafts (13 from living donors and 22 from cadaveric donors). Mean follow-up was 10.6 +/- 6.05 years. Sixteen patients were on CsA-based triple drug therapy and 19 patients on AZA-Pred alone. Mean overall graft survival was 11.2 +/- 0.6 years and 9.4 +/- 1.36 vs. 11.6 +/- 0.4 years for CsA-treated and AZA-Pred groups respectively (P = 0.05). One-year survival was 94% and 96.6% for CsA-treated vs. non-CsA patients (not significant), but 5 and 10 years survival were 76% and 46%, compared to 94.5% and 86% respectively (P = 0.05 at 5 years and 0.001 at 10 years). Mean serum creatinine at time of data collection was 2.3 +/- 1.5 mg/dl in the CsA group vs. 1.6 +/- 0.7 mg/dl in the AZA-Pred group (P = 0.02). There were 14 and 13 reversible rejection episodes in the AZA-Pred and CsA groups respectively (not significant). CONCLUSION: It is suggested that CsA exerts detrimental effects on long-term renal graft function and survival in FMF patients.

Correlation between visual acuity and cognitive functions.

A possible association between visual acuity (VA) and dementia was investigated in 2716 subjects who were aged between 53 and 102 at first visit and had varying degrees of dementia. Better VA was found to be significantly correlated with a lower dementia level (person coefficient range 0.146-0.261 over 10 years of follow-up, all correlations are significant, p<0.0001) as well as with a higher global cognitive score (person coefficient range -0.254 to -0.318 over 10 years of follow-up, all correlations are significant, p<0.0001), a grade encompassing 19 different cognitive tests. This correlation remained significant after adjustment for age, years of education, gender, use of ophthalmic drugs and years of follow-up.

Children undergoing repeated exposures for radiation therapy do not develop tolerance to propofol: clinical and bispectral index data.

BACKGROUND: The purpose of this study was to apply clinical criteria and Bispectral Index monitor data for evaluating the development of tolerance to propofol in children undergoing repeated drug exposure. METHODS: Children undergoing multiple sessions of radiation therapy during anesthesia for various malignancies were given a predetermined dose of propofol at each session. Heart rate, blood pressure, oxygen saturation, respiratory rate, requirement of additional propofol, and time to emergence and discharge were recorded. The Bispectral Index was monitored continuously, and parameters were extracted and averaged for each week of therapy. RESULTS: Fifteen children (aged 2.5-10 yr) were treated for an average of 5 weeks (24 +/- 6 sessions). There were no significant differences in physiologic parameters or requirements of additional propofol between the weeks of treatment. Bispectral Index data analysis showed that although a nonlinear change with time for each parameter could not be rejected, the differences between the first and last intervals were nonsignificant. CONCLUSIONS: Overall changes with time resulted from random fluctuations without a consistent trend. Combined with clinical data, Bispectral Index parameters showed that tolerance to propofol does not develop in children undergoing repeated exposures to the drug during radiation therapy.

Reduced medial olivocochlear bundle system function in children with auditory processing disorders.

A common complaint of children with auditory processing disorders (APD) is difficulty in understanding speech in the presence of background noise. Evidence from animal and human studies has suggested that the medial olivocochlear bundle (MOCB) may play a role in hearing in noise. The MOCB function can be evaluated by the suppression effect of the transient evoked otoacoustic emissions (TEOAE) in response to contralateral acoustic stimulation (CAS). The present study was conducted to investigate the suppression effect of TEOAE in APD children. The study groups comprised 15 APD children aged 8-13 years associated with learning disabilities and 15 controls matched for gender and age. The suppression effect of TEOAE was evaluated by comparing the TEOAE levels with and without CAS. A significantly reduced suppression effect of TEOAE was demonstrated in the APD group, when compared to the controls. In addition, higher TEOAE levels were found in the APD group, suggesting inherent reduced MOCB activity on the outer hair cells in APD children. These results imply that some APD children present low activity of the MOCB system, which may indicate a reduced auditory inhibitory function and affect their ability to hear in the presence of background noise.

Recovery of neurologic function after spinal cord injury in Israel.

STUDY DESIGN: A retrospective cohort study was conducted. OBJECTIVE: To assess neurologic recovery and the manner in which it is affected by the severity of the neurologic damage after spinal cord injury. SUMMARY OF BACKGROUND DATA: Studies from various countries, but not from Israel, have shown considerable potential for recovery of the damaged human spinal cord. METHODS: The study sample included 250 patients with a traumatic spinal cord lesion treated between 1962 and 1992 at the major referral hospital for rehabilitation in Israel. Demographic and clinical data were collected from the hospital charts. The degree of neurologic recovery in each patient was determined by comparing the Frankel grade of neurologic deficit at first admission for rehabilitation with the grade at discharge from that hospitalization. RESULTS: There was median delay of 36 days between injury and admission for rehabilitation. During rehabilitation, full or substantial neurologic recovery (upgrade to Frankel Grade D or E) occurred in 27% of all the patients who were Grade A, B, or C on admission, and in 54% of those who were Grade C. The neurologic recovery was negatively associated with severity of the neurologic deficit. CONCLUSIONS: The outcome findings are similar to those reported from spinal rehabilitation units in other countries. The study is a further demonstration of the considerable potential for neurologic recovery after spinal cord injury, when posttraumatic or postsurgical management is focused on prevention of complications and maximal use of functional ability.