Israel Medical Association Journal

Background: In recent years several reports have been published describing dogs’ ability to detect, by scent, patients with cancer. This ability is based on the sniffing of volatile organic elements that are secreted by malignant cells, react to them. 

Objectives: To evaluate the ability of trained dogs to detect (i) breast cancer cell cultures (MCF7) compared to the control pseudo-normal keratinocyte cell line (HaCaT), and then (ii) melanoma (BG) and (iii) type 2 epithelial lung carcinoma (A549) malignant cell cultures to which they were not previously exposed in the course of their training.

Methods: Cell cultures were prepared in a standard manner. Two Belgian Shepherd dogs were trained and then tested in a single-blind test (for dogs and trainers) on their ability to detect the "target specimen," a MCF7 breast cancer cell culture. Following this, the ability of the dogs to detect cancer cell cultures that they were not previously exposed to (i.e., A549, BG) was tested. In each test round, four specimens placed in identical blocks were arranged in a line with one meter between them: one target specimen (MCF7, A549, BG), two control specimens (HaCaT), and a sample containing cell culture medium only.

Results: The two dogs picked out all the target specimens of MCF7 breast cancer cell cultures that they were trained to detect (10/10) as well as all the target specimens that they were not previously exposed to [A549 (5/5) and BG (5/5)], but did not pick out the control specimens or the cell culture medium. Thus, the sensitivity, specificity, and positive and negative predictive values for both dogs were 100%.

Conclusions: The results of this study support the assumption that cancer cells have a unique odor pattern, and that this odor pattern is common to different types of cancer.

 

Abstract

Background: Heart rate variability (HRV) analysis has been shown to be a predictor of sudden cardiac death and all-cause mortality in patients with cardiac disease.

Objectives: To examine whether newer HRV analysis algorithms, as used by the HeartTrends device, are superior to exercise stress testing (EST) for the detection of myocardial ischemia in patients without known coronary artery disease (CAD).

Methods: We present pilot data of the first 100 subjects enrolled in a clinical trial designed to evaluate the yield of short-term (1 hour) HRV testing for the detection of myocardial ischemia. The study population comprised subjects without known CAD referred to a tertiary medical center for EST with single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). All patients underwent a 1 hour electrocardiographic acquisition for HRV analysis with a HeartTrends device prior to EST with MPI. Sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively) were calculated for EST and HRV analysis, using MPI as the gold standard for the non-invasive detection of myocardial ischemia.

Results: In this cohort 15% had a pathologic MPI result. HRV analysis showed superior sensitivity (85%), PPV (50%) and NPV (97%) as compared to standard EST (53%, 42%, 90%, respectively), while the specificity of the two tests was similar (86% and 85%, respectively). The close agreement between HRV and MPI was even more pronounced among patients > 65 years of age.

Conclusions: Our pilot data suggest that the diagnostic yield of the novel HeartTrends HRV algorithm is superior to conventional EST for the non-invasive detection of myocardial ischemia.

Objectives: To determine the properties of HAM as an antigenic substrate for the detection of autoantibodies in pemphigus vulgaris and bullous pemphigoid.

Methods: Immunomapping and tandem liquid chromatography mass spectrometry were used to delineate the antigenic structure of HAM in 25 pemphigus patients, 41 pemphigoid patients, and 36 controls. Immunoblotting and indirect immunofluorescence were used to study the diagnostic utility of HAM, and the results were compared to those of indirect immunofluorescence on monkey esophagus, immunoblotting using normal human skin, and enzyme-linked immunosorbent assay (ELISA).

Results: Immunomapping demonstrated the presence of all the antigens known to be targeted in autoimmune bullous skin diseases, in both normal human skin and HAM, except for the absence of BP230, and low threshold levels of Dsg1, Dsg3 and Dsc3 in HAM. HAM indirect immunofluorescence demonstrated anti-basement membrane zone antibodies in 48.7% of the pemphigoid patients, and anti-intercellular space antibodies in 72.0% of the pemphigus patients. HAM immunoblotting did not demonstrate anti-BP230 antibodies, but detected anti-BP180 antibodies in 53.6% of the pemphigoid patients. It did not demonstrate anti-Dsg1 and/or anti-Dsg3 antibodies in any of the pemphigus patients. These results were inferior to those of ELISA and monkey esophagus indirect immunofluorescence.

Conclusions: Compared to other studied methods, HAM does not offer advantages in detecting autoantibodies in bullous pemphigoid and pemphigus vulgaris. 

Objectives: To evaluate the performance of the C. DIFF QUIK CHEK COMPLETE^® assay, designed to simultaneously detect C. difficile-produced glutamate dehydrogenase (GHD) and toxins A and B.

Methods: Using the C. DIFF QUIK CHEK COMPLETE assay, the Tox A/B EIA, and polymerase chain reaction (PCR), we tested 223 stool specimens from hospitalized patients with antibiotics-associated diarrhea. Sensitivity and specificity, and positive and negative predictive values (PPV, NPV) were calculated for the C. DIFF QUIK CHEK COMPLETE test and the Tox A/B EIA against PCR

Results: The C. DIFF QUIK CHEK COMPLETE test had a sensitivity of 83.5% and specificity of 94.3% compared to PCR for Tox A/B, with 93.7% correlation (PPV 98.5%, NPV 91.7%). The Tox A/B EIA yielded corresponding values of 72.1% and 93.1%, with 85.6% correlation (PPV 85.1%, NPV 85.8%).

Conclusions: Given the importance of an early and appropriate diagnosis of Clostridium difficile-associated infection, the C. DIFF QUIK CHEK COMPLETE test may be of huge benefit to practitioners.

Background: Delayed diagnosis of choroidal neovascularization (CNV) in age-related macular degeneration (AMD) adversely affects visual outcome.

Objectives: To identify factors associated with early detection of CNV in the clinic setting.

Methods: Demographic and clinical data and lesion characteristics were retrospectively collected from 76 consecutive AMD patients who had a history of CNV in one eye and presented with CNV in the second eye. These data were evaluated for association with visual acuity (VA) at the time of presentation.

Results: Better VA was associated with a history of CNV in the fellow eye (P < 0.0001), adherence to follow-up every 4 months (P = 0.015), younger age (P = 0.03), smaller lesion (P < 0.0001), and non-subfoveal location (P = 0.048). VA of the fellow eye did not correlate with VA at presentation with CNV.

Conclusions: These data suggest that patients’ experience of CNV, regardless of VA, facilitates early diagnosis in the fellow eye. Adherence to follow-up in the routine clinic setting also facilitates early detection of CNV.

There are major dilemmas regarding the optimal modalities for breast cancer screening. This is of particular relevance to Israel because of its high-risk population. It was suggested that an avenue for further research would be to incorporate advances in signal processing through the fast Padé transform (FPT) to magnetic resonance spectroscopy (MRS). We have now applied the FPT[1] to time signals that were generated according to in vitro MRS[2] data as encoded from extracted breast specimens from normal, non-infiltrated breast tissue, fibroadenoma and cancerous breast tissue. The FPT is shown to resolve and precisely quantify the physical resonances as encountered in normal versus benign versus malignant breast. The FPT unambiguously delineated and quantified diagnostically important metabolites such as lactate, as well as phosphocholine, which very closely overlaps with glycerophosphocholine and phosphoethanolamine, and may represent a magnetic resonance-visible molecular marker of breast cancer. These advantages of the FPT could clearly be of benefit for breast cancer diagnostics via MRS. This line of investigation should continue with encoded data from benign and malignant breast tissue, in vitro and in vivo. We anticipate that Padé-optimized MRS will reduce the false positive rates of MR-based modalities and further improve their sensitivity. Once this is achieved, and given that MR entails no exposure to ionizing radiation, new possibilities for screening and early detection emerge, especially for risk groups. For example, Padé-optimized MRS together with MR imaging could be used with greater surveillance frequency among younger women with high risk of breast cancer.

Background: Many patients in the internal medicine ward have anemia. The etiology for the anemia may be multifactorial and, in the setting of inflammatory process when the ferritin is increased, it is difficult to diagnose iron deficiency anemia. Soluble transferrin receptor (sTfR) had been suggested as an indicator for iron deficiency. No study has investigated the meaning of high sTfR as the only positive marker of iron deficiency anemia (IDA) caused by gastrointestinal tract (GIT) bleeding in hospitalized patients.

Objectives: To demonstrate the importance of high levels of sTfR as a marker for further GIT investigation in cases of anemia where the level of ferritin was normal or increased

Methods: We retrospectively assessed all patients in an internal medicine ward in our facility with anemia, high sTfR[1] levels (> 5.0 mg/L) and normal or high ferritin levels who underwent esophagogastroduodenoscopy and colonoscopy.

Results: Of 32 patients with anemia and normal or high ferritin levels and high sTfR, 22 patients (68%) had findings that explained IDA[2] (in some patients more than one finding). Those findings were colonic polyps (n=9), carcinoma of colon (n=4), duodenal ulcer (n=4), carcinoma of stomach (n=3), colitis (n=3), atrophic gastritis (n=1), erosive gastritis (n=1) and angiodysplasia (n=1).

Conclusions: High sTfR may be a good indicator of IDA caused by GIT[3] bleeding when the ferritin level is normal or high. GIT investigation is warranted in such cases.

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: 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: Early detection of malignant melanoma of the skin is the most important factor in patient survival. Naked-eye diagnostic sensitivity and specificity are low. Patients with multiple nevi are at high risk to develop melanomas and the clinical follow-up of such patients is difficult, resulting in missed melanomas on the one hand and unnecessary biopsies on the other.

Objectives: To describe the set-up of a special clinic aimed at early detection of melanoma and follow-up of high risk patients and preliminary results from 20 months of operation.

Methods: We established a pigmented lesions clinic based on a digital photography studio enabling documentation and comparison over time of full body photography and dermoscopy.

Results: In the first 20 months of work, 895 patients were seen, 206 of them for follow-up visits. A total of 29,254 photos were taken. Altogether, 236 lesions were suspicious (either clinically or dermoscopically) and the patients were advised to excise them. Seven melanomas were found in this initial examination (which did not include long-term follow-up).

Conclusions: With multimode photographic cutaneous surveillance, early detection of melanoma in high risk patients has been reported. Our clinic utilizes the same techniques and diagnostic algorithm as other leading clinics throughout the world, thus enabling us to deliver better follow-up for those patients.
 

Background: Electrocardiography has a very low sensitivity in detecting dobutamine-induced myocardial ischemia.

Objectives: To assess the added diagnostic value of a new cardiac performance index (dP/dt^ejc) measurement, based on brachial artery flow changes, as compared to standard 12-lead ECG, for detecting dobutamine-nduced myocardial ischemia, using Tc99m-Sestamibi single-photon emission computed tomography as the gold standard of comparison to assess the presence or absence of ischemia.

Methods: The study group comprised 40 patients undergoing Sestamibi-SPECT[1]/dobutamine stress test. Simultaneous measurements of ECG and brachial artery dP/dt^ejc were performed at each dobutamine level. In 19 of the 40 patients perfusion defects compatible with ischemia were detected on SPECT. The increase in dP/dt^ejc during infusion of dobutamine in this group was severely impaired as compared to the non-ischemic group. dP/dt^ejc outcome was combined with the ECG results, giving an ECG-enhanced value, and compared to ECG alone.

Results: The sensitivity improved dramatically from 16% to 79%, positive predictive value increased from 60% to 68% and negative predictive value from 54% to 78%, and specificity decreased from 90% to 67%.
Conclusions: If ECG alone is used for specificity, the combination with dP/dt^ejc improved the sensitivity of the test and could be a cost-savings alternative to cardiac imaging or perfusion studies to detect myocardial ischemia, especially in patients unable to exercise

Background: Syndromic surveillance systems have been developed for early detection of bioterrorist attacks, but few validation studies exist for these systems and their efficacy has been questioned.

Objectives: To assess the capabilities of a syndromic surveillance system based on community clinics in conjunction with the WSARE[1] algorithm in identifying early signals of a localized unusual influenza outbreak.

Methods: This retrospective study used data on a documented influenza B outbreak in an elementary school in central Israel. The WSARE algorithm for anomalous pattern detection was applied to individual records of daily patient visits to clinics of one of the four health management organizations in the country.

Results: Two successive significant anomalies were detected in the HMO’s[2] data set that could signal the influenza outbreak. If data were available for analysis in real time, the first anomaly could be detected on day 3 of the outbreak, 1 day after the school principal reported the outbreak to the public health authorities.

Conclusions: Early detection is difficult in this type of fast-developing institutionalized outbreak. However, the information derived from WSARE could help define the outbreak in terms of time, place and the population at risk.