Israel Medical Association Journal

Background: Patients with multiple (< 100) colorectal adenomatous polyps are at increased risk for colorectal cancer. Genetic evaluation of those patients who test negative for APC gene mutation is both a clinical and economic burden but is critical for counseling and surveillance. In Israel, this is confounded by the fact that national health insurance does not fully cover genetic evaluation of APC gene exon 16.

Objectives: To perform a comprehensive genetic evaluation of APC gene mutation-negative polyposis patients with the aim of developing a future evaluation protocol.

Methods: Genetic analyses were performed in 29 APC gene mutation-negative Jewish individuals with 5 to ≥ 40 colonic adenomas who did not fulfill Amsterdam (clinical) criteria for Lynch syndrome. Analyses included completion of APC gene exon 16 sequencing, analysis for APC gene copy number variations (deletions or duplications), MUTYH gene sequencing, and microsatellite instability in CRC[1] patients fulfilling “Bethesda” (laboratory investigation) criteria for Lynch syndrome.

Results: Completion of APC gene exon 16 sequencing revealed one patient with the E1317Q polymorphism. All were normal by APC multiplex ligation-dependent probe amplification analysis. Pathogenic MUTYH mutations were found in three patients, all of North African origin; two additional patients had variants of unknown significance. One of six patients with Bethesda-positive criteria was MSI²-High with immunohistology consistent with MLH1 mutation.

Conclusions: Based on this small but well-characterized cohort with multiple colorectal adenomas, Lynch syndrome needs to be excluded if there are compatible criteria; otherwise MUTYH sequencing is probably the first step in evaluating APC-negative patients, especially for Jews of North African descent. Completing APC exon 16 sequencing and copy number variations analysis should probably be the last evaluations.

The laparoscopic approach to the treatment of colon and rectal cancer was controversial long after it was accepted for benign conditions. Laparoscopic cancer resection should meet appropriate oncologic standards and achieve a long-term oncologic outcome at least equivalent to that of open resection. Several international randomized controlled trials have provided adequate data to ascertain the oncologic quality of laparoscopic colon resection, showing a benefit in short-term outcome over open resection. The use of laparoscopic resection for rectal cancer is awaiting further investigation.

Background: The prevalence of aortic stenosis increases with advancing age. Once symptoms occur the prognosis in patients with severe aortic stenosis is poor. The current and recommended treatment of choice for these patients is surgical aortic valve replacement. However, many patients, mainly the very elderly and those with major comorbidities, are considered to be at high surgical risk and are therefore denied treatment. Recently, a transcatheter alternative to surgical AVR[1] has emerged.

Objectives: To describe the first year experience and 30 day outcome of transcatheter aortic self-expandable CoreValve implantation in Israel.

Methods: Transcatheter aortic valve implantation using the CoreValve system has been performed in Israel since September 2008. In the following year 55 patients underwent CoreValve TAVI[2] in four Israeli centers.

Results: Patients' mean age was 81.7 ± 7.1 years; there were 35 females and 20 males. The mean valve area by echocardiogram was 0.63 ± 0.16 cm². The calculated mean logistic Euroscore was 19.3 ± 8%. Following TAVI, mean transvalvular gradient decreased from baseline levels of 51 ± 13 to 9 ± 3 mmHg. The rate of procedural success was 98%. One patient died on the first day post-procedure (1.8%) and all-cause 30 day mortality was 5.5% (3 of 55 patients). One patient had a significant post-procedural aortic regurgitation of > grade 2. Symptomatic improvement was evident in most patients, with reduction in functional capacity grade from 3.2 ± 0.6 at baseline to 1.4 ± 0.7. The most common post-procedural complication was complete heart block, which necessitated permanent pacemaker implantation in 37% of patients.

Conclusions: The Israeli first year experience of transcatheter aortic valve implantation using the CoreValve self-expandable system demonstrates an effective and safe procedure for the treatment of severe aortic stenosis in patients at high surgical risk.

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: While family presence during resuscination has been researched extensively in the international and especially American medical literature, in Israel this subject has rarely been researched. Because such policies have become common practice in many countries, it is important to investigate the attitudes of health care staff in Israeli emergency departments to better understand the potential implication of adopting such policies.

Objectives: To examine the attitudes of the physicians and nurses in the ED of Soroka Medical Center to FPDR[1]. 

Methods: The methods we used were both qualitative (partly structured open interviews of 10 ED staff members from various medical professions) and quantitative (an anonymous questionnaire that collected sociodemographic, professional, and attitude data).

Results: The qualitative and quantitative results showed that most staff members opposed FPDR. The main reasons for objecting to FPDR were concern about family criticism, the added pressure that would be put on the staff members, fear of lawsuits, fear of hurting the feelings of the families, and the danger of losing one’s objectivity while treating patients. Physicians objected more strongly to FPDR than did nurses.  

Conclusions: More research is needed on FPDR in Israel, including an examination of its medical, ethical, legal and logistic aspects. In addition to the views of the medical staff, the attitudes of patients and their families should also be examined.

[1] FPDR = family presence during resuscitation

 

Background: Autoimmune neutropenia of infancy is caused by neutrophil-specific autoantibodies. Primary AIN[1] is characterized by neutrophil count < 500 ml and a benign self-limiting course. Detecting specific antibodies against the polymorphic human neutrophil antigen usually confirms the diagnosis. Current available tests, however, are expensive and inapplicable in many laboratories as they require the use of isolated and fixed granulocytes obtained from donors pretyped for their distinct HNA[2] alloform.

Objectives: To assess the performance of a modified test to identify by FACS-analysis granulocyte-specific antibodies in the sera of neutropenic children.

Methods: We evaluated 120 children with a clinical suspicion of AIN, whose sera were analyzed by flow cytometry for the presence of autoantibodies using the indirect granulocyte immunofluorescence test. In contrast to the traditional tests, the sera were tested against randomly selected untyped neutrophils derived from a batch of 10 anonymous healthy subjects, presumably including the common HNA alloforms. Control sera samples were from patients with chemotherapy-induced, familial or congenital neutropenias. To further assure the quality of the new test, we retested six samples previously tested by the gold standard method. All medical files were screened and clinical outcomes were recorded.

Results: Our method showed specificity of 85%, sensitivity of 62.5%, and a positive predictive value of 91.8%, values quite similar to those obtained by more traditional methods.

Conclusions: The new method showed high specificity for detection of anti-neutrophil antibodies in the appropriate clinical setting and could be an effective aiding tool for clinical decision making.

Background: According to the Israeli immunization schedule 1 year old babies should receive two concomitant vaccinations: MMR (measles-mumps-rubella), and DTap-Hib-IPV (diphtheria tetanus acellular pertussis-Haemophilus influenzae type b-poliomyelitis). However, about one-third of infants in Israel receive these vaccinations separately. Nurses at a primary care prevention clinic in Israel observed that the separate mode of vaccination is associated with a lower rate of side effects.

Objectives: To validate this observation and determine whether it represents an exception or the rule.

Methods: A nested prospective follow-up study was conducted in a primary care clinic in Israel. The survey included 191 mothers and their offspring born during 2004/2005. The mothers were interviewed over the telephone 2 weeks after the day of vaccination.

Results: The rate of adverse effects in children who received the injections separately was significantly lower than among those who were vaccinated simultaneously (40% vs. 57%).

Conclusions: It may be necessary to reconsider the current vaccination policy regarding concomitant injections.

Background: The incidence of stroke varies among ethnically and culturally diverse groups.

Objectives: To examine the ethnic-geographic patterns of stroke incidence in men and women with coronary heart disease in Israel, focusing on the extent to which this variability can be explained by known differences in risk factors for stroke.

Methods: Patients with documented coronary heart disease were followed for 6–8 years for incident cerebrovascular events. Baseline medical evaluation included assessment of vascular risk factors and measures of blood lipids. Among 15,052 patients, a total of 1110 were identified with any incident ischemic cerebrovascular event by ICD-9 codes, of whom 613 had confirmed ischemic stroke or transient ischemic attack.

Results: A major excess of ischemic cerebrovascular events among Israeli Arab women as compared to males, and an inverse finding among Israeli born Jews, were noted. The high risk in the Arab population in Israel reflected an unfavorable risk profile, since predicted rates by multivariate analysis and observed rates were 69 and 68 per 1000, respectively. High ischemic cerebrovascular event rates were identified among patients born in the Balkan countries and North Africa (89 and 90 per 1000) but unfavorable risk factor levels of these individuals did not explain them. Most trends appeared similar in male and female patients. A comparison of observed and accepted-according-to-risk-profile rates of ischemic cerebrovascular events yielded significant differences (P = 0.04), consistent with an additional role of geographic/ethnic origin, resulting from factors that remain unrecognized,or with variables unassessed in this study.

Conclusions: We identified an ethnic diversity in stroke risk among Israeli born in different parts of the world beyond what could be expected on the basis of differences in known risk factors. These findings call for detailed research aimed at identifying additional differences in the risk profile of patients with atherothrombotic disease exposed to an increased risk of stroke.