Israel Medical Association Journal

Background: HER2 is an important prognostic and predictive marker in invasive breast cancer. It is currently assessed by immunohistochemistry for protein over-expression and by fluorescence in situ hybridization for gene amplification. The immunohistochemistry-equivocal cases (2+) are currently retested by FISH[1] to determine eligibility for trastuzumab treatment. Retesting by FISH significantly raises the cost of patient management and sometimes delays treatment. The 4B5 is a new, FDA-approved, rabbit monoclonal antibody for HER2 testing.

Objectives: To examine the reliability of 4B5 IHC[2] HER2 testing in cases found to be HER2 status equivocal by CB11 IHC.

Methods: Twenty-eight invasive breast cancer cases, with an equivocal HER2 status by CB11 IHC, were retested by the 4B5 antibody as well as by FISH analysis. The scoring was performed using the same guidelines as HercepTest and was correlated with the FISH ratio. Results: Of the original 28 CB11 clone designated equivocal cases, 14 (50%) showed negative HER2 staining using the 4B5 clone (HercepTest score 0 and 1+). Five cases (18%) proved to be positive (HercepTest score 3+) and 9 cases (32%) remained equivocal (HercepTest score 2+). The corresponding FISH ratio results showed that all 4B5 negative cases were negative by FISH testing, with a negative predictive value of 100% 4 of 5 of the 4B5-positive cases were positive by FISH testing, with a positive predictive value of 80%. One 4B5-positive case was borderline-high (2.2 ratio) by FISH. The correlation between 4B5 IHC and FISH was statistically significant (P = 0.0013) by chi-square test.

Conclusions: Sequential testing by 4B5 IHC could greatly reduce the need for FISH testing in cases considered HER2 equivocal by CB11 IHC.
 

 
[1] FISH = fluorescence in situ hybridization

[2] IHC = immunohistochemistry

Background: Obstruction of urine outflow can result from mechanical blockade as well as from functional defects. In adults, urinary tract obstruction is due mainly to acquired defects, such as pelvic tumors, calculi, and urethral stricture. In childhood it is mostly due to congenital malformations. In this article we present two rare cases of acute obstructive renal failure that presented with hydronephrosis. These cases underline the wide range of causes that may lead to this clinical feature. 

Background: Epidemiological data show significant associations of vitamin D deficiency and autoimmune diseases. Vitamin D may prevent autoimmunity by stimulating naturally occurring regulatory T cells.

Objectives: To elucidate whether vitamin D supplementation increases Tregs[1] frequency (%Tregs) of circulating CD4+ T cells.

Methods: We performed an uncontrolled vitamin D supplementation trial among 50 apparently healthy subjects including supplementation of 140,000 IU at baseline and after 4 weeks (visit 1). The final follow-up visit was performed 8 weeks after the baseline examination (visit 2). Blood was drawn at each study visit to determine 25-hydroxyvitamin D levels and %Tregs. Tregs were characterized as CD4+CD25++ T cells with expression of the transcription factor forkhead box P3 and low or absent expression of CD127.

Results: Forty-six study participants (65% females, mean age ± SD 31 ± 8 years) completed the trial. 25(OH)D[2] levels increased from 23.9 ± 12.9 ng/ml at baseline to 45.9 ± 14.0 ng/ml at visit 1 and 58.0 ± 15.1 ng/ml at visit 2. %Tregs at baseline were 4.8 ± 1.4. Compared to baseline levels we noticed a significant increase of %Tregs at study visit 1 (5.9 ± 1.7, P < 0.001) and 2 (5.6 ± 1.6, P < 0.001).

Conclusions: Vitamin D supplementation was associated with significantly increased %Tregs in apparently healthy individuals. This immunomodulatory effect of vitamin D might underlie the associations of vitamin D deficiency and autoimmune diseases. Hence, our finding provides a rationale for further studies to investigate vitamin D effects on autoimmunological processes.

Background: High frequency oscillatory ventilation based on optimal lung volume strategy is one of the accepted modes of ventilatory support for respiratory distress syndrome in very low birth weight infants. In 1999 it was introduced in our unit as the primary ventilation modality for RDS[1].

Objectives: To evaluate if the shift to HFOV[2] influenced the outcome of ventilated VLBW[3] infants in the neonatal intensive care unit of Carmel Medical Center.

Methods: Data were obtained from the medical charts of VLBW infants born at Carmel Medical Center, and late mortality data were taken from the Israel Ministry of Internal Affairs records. A retrospective analysis and a comparison with a historical control group ventilated by the conventional method were performed.

Results: A total of 232 VLBW infants with RDS were mechanically ventilated, from 1995 to 2003: 120 were ventilated using HFOV during the period 1999–2003 and 102 infants using CV[4] during 1995–1999. The mean gestational age of survivors was 27.4 ± 2 weeks in the HFOV group and 28.4 ± 2 in the conventional ventilation group (P = 0.03). The sub-sample of infants with birth weights <1000 g ventilated with HFOV showed higher survival rates than the infants in the conventional ventilation group, 53 vs. 25 (64.6% vs. 44.6%) respectively (P < 0.05). A trend for lower incidence of pulmonary interstitial emphysema was observed in the HFOV group.

Conclusions: The introduction of HFOV based on optimal lung volume strategy proved to be an efficient and safe method of ventilation support for VLBW infants in our unit.

Background: Vitamin A and its derivative retinoic acid regulate various aspects of cell behavior as growth, differentiation, and proliferation. Retinoic acid derivatives have been suggested to play a role in processes such as hepatic regeneration and fibrosis.

Objectives: To evaluate the influence of vitamin A on rat liver epithelial cell proliferation.

Methods: We performed common bile duct ligation in rats that had been subjected to differing vitamin A diets and compared their livers to control rats. Proliferation, apoptosis, and retinoic acid receptors were evaluated by histology and immunohistochemistry in bile duct cells and hepatocytes.

Results: Vitamin A deficiency was found to be associated with enhanced proliferation of bile duct epithelial cells following CBD[1] ligation. The proliferation was manifested by increased numbers of ducts, by aberrant extended ductal morphology, and by elevated numbers of nuclei expressing the proliferation marker Ki67. The amount of vitamin A in the rat diet did not affect detectably ductal cell apoptosis. We observed up-regulated expression of the retinoid X receptor-alpha in the biliary epithelium of vitamin A-deficient rats that had undergone CBD ligation, but not in vitamin A-sufficient rats.

Conclusions: We speculate that the mechanism underlying the ductal proliferation response involves differential expression of RXR[2]-alpha. Our observations suggest that deficiency of vitamin A may exacerbate cholestasis, due to excessive intrahepatic bile duct proliferation.

Background: Parallel to increased life expectancy, the number of very elderly patients hospitalized in internal medicine departments is growing rapidly, although clinical data on hospital care are lacking.

Objectives: To investigate the sociodemographic data, hospitalization characteristics and outcomes of nonagenarian patients, as these measures are necessary for evaluating prognostic information and predictors of mortality.

Methods: We reviewed the medical records of all patients aged ≥ 90 hospitalized in our institute's Department of Internal Medicine. The data comprised 482 admissions of 333 patients hospitalized over a one year period.

Results: Half of the study patients were residents of nursing institutions. A high rate of atrial fibrillation was documented (106 patients, 32%). Acute infectious diseases constituted the leading diagnosis (276/482 admissions, 57%), followed by acute coronary syndrome (17% of admissions). In-hospital mortality occurred in 74 patients (22%). Chronic therapy with statins or acetylsalicylic acid was inversely related to mortality (P < 0.05). The main predictors for in-hospital death of nonagenarians were pressure sores, older age, atrial fibrillation, malignant disease, and admission due to an acute infection, especially Clostridium difficile-associated diseases. In addition, mental decline, permanent urinary catheter, leukocytosis, renal failure and hypoalbuminemia predicted post-discharge mortality. Admission due to an infectious disease but not acute coronary syndrome was significantly correlated to in-hospital and post-discharge mortality (P < 0.001).

Conclusions: Hospitalized nonagenarians comprise a growing group with distinct characteristics and increasing significance in the daily practice of internal medicine departments. Comprehensive assessment of the elderly at admission together with identification of the above clinical and laboratory risk factors for mortality will help determine in-hospital management, discharge planning and rehabilitation programs.

Background: Diabetes mellitus is a multi-organ disorder affecting many types of connective tissues, including bone and cartilage. Certain skeletal changes are more prevalent in diabetic patients than in non-diabetic individuals. A possible association of diabetes mellitus and lumbar spinal stenosis has been raised.

Objectives: To compare the prevalence of diabetes mellitus in patients with spinal stenosis, degenerative disk disease or osteoporotic vertebral fractures.

Methods: A cross-sectional analysis was performed of 395 consecutive patients diagnosed with spinal stenosis, degenerative disk disease or osteoporotic vertebral fractures. All the patients were examined by one senior author in the outpatient orthopedic clinic of a large general hospital between June 2004 and January 2006 and diagnosed as having either lumbar spinal stenosis (n=225), degenerative disk disease (n=124) or osteoporotic vertebral fractures (n=46).

Results: The prevalence of diabetes mellitus in the three groups (spinal stenosis, osteoporotic fracture, degenerative disk disease) was 28%, 6.5% and 12.1%, respectively, revealing a significantly higher prevalence in the spinal stenosis group compared with the others (P = 0.001). The higher prevalence of diabetes in the stenotic patients was unrelated to the presence of degenerative spondylolisthesis.

Conclusions: There is an association between diabetes and lumbar spinal stenosis. Diabetes mellitus may be a predisposing factor for the development of lumbar spinal stenosis.

Background: Cancer is a leading cause of mortality worldwide. The most effective way to combat cancer is by prevention and early detection.

Objectives: To evaluate the outcome of screening an asymptomatic population for the presence of benign and neoplastic lesions.

Methods: Routine screening tests for prevention and/or early detection of 11 common cancers were conducted in 300 consecutive asymptomatic, apparently healthy adults, aged 25–77 years. Other tests were performed as indicated.

Results: Malignant and benign lesions were found in 3.3% and 5% of the screenees, respectively, compared to 1.7% in the general population. The most common lesions were in the gastrointestinal tract followed by skin, urogenital tract and breast. Advanced age and a family history of a malignancy were associated with increased risk for cancer with an odds ratio of 9 and 3.5, respectively (95% confidence interval 1.1–71 and 0.9–13, respectively). Moreover, high serum C-reactive protein levels and polymorphisms in the APC and CD24 genes indicated high cancer risk. When two of the polymorphisms existed in an individual, the risk for a malignant lesion was extremely high (23.1%; OR[1] 14, 95% CI[2] 2.5–78).

Conclusions: Screening asymptomatic subjects identifies a significant number of neoplastic lesions at an early stage. Incorporating data on genetic polymorphisms in the APC and CD24 genes can further identify individuals who are at increased risk for cancer. Cancer can be prevented and/or diagnosed at an early stage using the screening facilities of a multidisciplinary outpatient clinic.

Pancreatic cancer is not a common malignancy in Israel, but it is the third most common cause of cancer mortality, attributable to a lack of screening tests, inaccessibility of the pancreas, and late cancer stage at diagnosis. We reviewed the epidemiology, known risk factors and screening methods available in Israel and describe the Israeli national consortium that was established to identify persons at risk and decide on screening methods to detect and treat their early-stage pancreatic cancer. In collaboration with the Israel National Cancer Registry, we evaluated the incidence and trends of the disease in the Jewish and non-Jewish populations. The consortium reviewed known lifestyle risk habits and genetic causes, screening methodologies used and available in Israel. Overall, there are about 600 new patients per year, with the highest incidence occurring in Jewish men of European birth (age-standardized rate 8.11/10⁵ for 2003–06). The 5 year survival is about 5%. The consortium concluded that screening will be based on endoscopic ultrasonography. Pancreatic cancer patients and families at risk will be enrolled, demographic and lifestyle data collected and a cancer pedigree generated. Risk factors will be identified and genetic tests performed as required. This concerted national program to identify persons at risk, recommend which environmental risk factors to avoid and treat, and perform endoscopic ultrasound and genetic screening where appropriate, might reduce their incidence of invasive pancreatic cancer and/or improve its prognosis

Background: Current treatment options for acute calculous cholecystitis include either early cholecystectomy, or conservative treatment consisting of intravenous antibiotics and an interval cholecystectomy several weeks later. Percutaneous drainage is reserved for patients in whom conservative therapy failed or as a salvage procedure for high risk patients.

Objective: To identify clinical and radiographic factors leading to failure of conservative treatment.

Methods: We prospectively collected data on consecutive patients admitted with the diagnosis of acute cholecystitis. Parameters were compared between patients who were successfully treated conservatively and those who required percutaneous cholecystostomy. Logistic regression analysis was performed to identify predictors for failure of conservative treatment. 

Results: The study population comprised 103 patients with a median age of 60 who were treated for acute cholecystitis. Twenty-seven patients (26.2%) required PC[1]. On univariate analysis, age above 70 years, diabetes, elevated white blood cell count, tachycardia (> 100 beats/min) at admission, and a distended gallbladder (> 5 cm transverse diameter) were found to be significantly more common in the PC group (P < 0.001). WBC[2] was higher in the PC group throughout the initial 48 hours. On multivariate analysis, age above 70 (odds ratio 3.6), diabetes (OR[3] 9.4), tachycardia at admission (OR 5.6), and a distended gallbladder (OR 8.5) were predictors for cholecystostomy (P < 0.001). Age above 70 (OR 5.2) and WBC > 15,000 (OR 13.7) were predictors for failure of conservative treatment after 24 and 48 hours (P < 0.001). 

Conclusions: Age above 70, diabetes, and a distended gallbladder are predictors for failure of conservative treatment and such patients should be considered for early cholecystostomy. Persistently elevated WBC (> 15,000) suggests refractory disease and should play a central role in the clinical follow-up and decision-making process for elderly patients with acute cholecystitis.

Background: Fetal alcohol spectrum disorder is a range of disabilities caused by gestational exposure to alcohol. FASD[1] is the leading cause of preventable mental retardation and developmental disability in the United States, with an incidence of 1–10 per 1000 live births. FASD in Israel has yet to be examined systematically.

Objectives: To evaluate professionals’ experience, awareness and knowledge of FASD in Israel and their awareness of maternal consumption of alcohol, and to collect epidemiological data on the syndrome in Israel.

Methods: A short questionnaire was sent to all 43 program directors of genetic institutes (n=14) and child developmental centers in Israel (n=29). Four questions related to their experience and knowledge of FASD. The epidemiological survey included data from all 17 hospitals in Israel and from the two main health management organizations within the public health care system.

Results: The response rate was 98% (n=42). A total of 38.1% of respondents reported having diagnosed at least one case of FASD and fewer than 10% of respondents stated that the knowledge regarding FASD among physicians in Israel was adequate. Developmental pediatricians were more likely to have diagnosed at least one case as compared to geneticists. During the period 1998–2007 the diagnosis of FASD appeared in the records of only 4 patients from the total number of 17 hospitals in Israel. During the same period only six patients were diagnosed at the HMO[2] within the public health care system.

Conclusions: Despite the accumulated knowledge on FASD in many countries and the increase in alcohol consumption in Israel, professionals' awareness of its potential damage is limited. Educational programs to increase physician awareness should accompany publicity campaigns warning the public of the dangers associated with alcohol consumption during pregnancy.