In Vitro Interferon-Gamma Release in Diagnosis of Cutaneous Adverse Drug Reactions

S. Halevy, A. D. Cohen, N. Grossman

Dermatology Dept, Skin Bank and Investigative Dermatology Laboratory, Soroka University Medical Center and Faculty of Health Sciences; Ben-Gurion University of the Negev, Beer Sheba

Diagnosis of cutaneous adverse drug reactions is an accepted terminology. Is a challenge. Drug-specific T-cell clones (CD4+ or CD8+), with a Th1- or a Th2-type cytokine-release pattern, may be generated from the peripheral blood in CADRs. In vitro drug-induced cytokine-release suggests a drug-specific immune response, and may implicate the drug as a possible inducer of the skin reaction.

We evaluated the diagnostic role of in vitro drug-induced interferon-gamma (IFN-γ) release from peripheral blood lymphocytes in patients with CADRs. We studied 22 patients with CADRs following intake of 45 drugs (1-4 drugs per patient). Drugs were classified into 3 categories of suspicion. 17 patients who took 39 drugs of the same type (1-4 drugs per patient) without developing adverse reactions, served as controls. In vitro drug-induced release of IFN-γ from peripheral blood lymphocytes, following in vitro challenge with the unmodified drugs, was evaluated.

The mean IFN-γ increase following 45 drug tests (60.8±85.2%) was higher (p<0.05) than in controls after 39 drug tests (30.1±27.7%). Significance was greater (p<0.005) when the mean IFN-γ increase for the 24 highly suspected drugs (75.1±93.4%) and that for the controls were compared.

This study suggests that the in vitro drug-induced IFN-γ release test may serve as a diagnostic tool in CADRs.

שי שרוט¹, יואב צפמן¹, יהודה שינפלד²

¹המח' למחלות עצבים, המרכז הרפואית תל-אביב, ²מח' לרפואה פנימית ב' והמרכז למחלות אוטואימוניות, בי"ח שיבא, תל-השומר

תיסמונת האנטיפוספוליפידיים, antiphospholipid syndrome (APS) היא מחלה רב-מערכתית שבה מעורבים נוגדנים ואנטיגנים שונים. הפרעה האוטואימונית מתבטאת קלינית באירועים פקקתיים-תסחיפיים נשנים (עורקיים וורידיים), בהפלות עצמוניות נשנות, בתרומבוציטופניה ובכייל גבוה של נוגדנים כנגד פוספוליפידים ((antiphospholipid-antibodies - aPL וכן של נוגד קרישה זאבתי (lupus anticoagulant - LA). התיסמונת יכולה להתרחש משנית למחלות אוטואימוניות אחרות (כמו זאבת אדמנתית מערכתית systemic-lupus-erythematosus (SLE), לממאירויות או לזיהומים וכן כתגובה לתרופות. כשלא נמצאת סיבה ראשונית מעין אלו להתהוות התיסמונת, היא מוגדרת כראשונית (primary APS).

הנוגדנים הנמנים עם משפחת ה- aPL מאותרים בבדיקה שבה נמדדת תגובתיות (reactivity) חיסונית כלפי קרדיוליפין (aCL) ופוספוליפידים למיניהם הטעונים שלילית, בנוכחות או ללא נוכחות  ביתא 2 – גליקופרוטאין או קופקטורים חלבוניים אחרים, או ע"י תגובתיות חיסונית כלפי ביתא 2 – גליקופרוטאין (הידוע כקופקטור חיוני לקישור ה- aPL) או קופקטורים חלבוניים אחרים לבד, או על ידי יכולתם לעכב את מנגנון הקרישה בתבחיני קרישה התלויים בפוספוליפידים (LA=).

לא כל בני-האדם עם aPL יהיו תסמיניים. בסקר פרוספקטיבי של בנק הדם התגלה, שב- 6.5% מהאוכלוסייה הכללית אובחנו בתבחין ELISA נוגדנים מסוג IgP-aPL. לעתים קרובות, יורד כיל-ה- aPLלטווח התקין עם הזמן, ללא אירועים פקקתיים.

בחולים הלוקים ב- APS, דווח על ביטויים קליניים שונים, הכוללים סיבוכים המאטולוגיים, סיבוכים בעור, מחלת מסתמי הלב והיפגעות הכליות. בנוסף, דווח על ביטויים נירולוגיים שונים המערבים בעיקר את מערכת העצבים המרכזית. בסקירה זו, נדונים ההיבטים הנירולוגיים של תיסמונת הנוגדנים האנטיפוספוליפידיים.
 

Photodynamic Therapy of Nasal Basal Cell Carcinoma

R. Haddad, M. Cohen, O. Kaplan, R. Greenberg, H. Kashtan

Dept. of Surgery, Tel Aviv-Sourasky Medical Center

Photodynamic therapy (PDT) is a noninvasive modality used topically for several skin cancers. We evaluated the effects of PDT on basal cell carcinoma (BCC) of the nose, using aminolevulinic acid (ALA) as a photosensitizer and a non-laser light source (Versa-LightTM). The advantages of this light source are synergistic, hyperthermia and fewer side effects.

A paste of 20% ALA was applied topically to biopsy-proven BCC of the nose. Lesions were covered with occlusive light-shielding dressing and after 18 hours they were submitted to 10 minutes of exposure to the light. Initial evaluation was made after 21 days and every 3 months thereafter. Patients who did not respond after 2 treatments were referred for surgery.

Mean follow-up in 31 patients was 19 months (range 6-36). There were no significant side-effects. There was complete response in 24/27 (88.9%), in whom there was recurrence in 2/27 (7.4%).
 

Dermatitis from Contact with Agave Americana

Haim Golan, Marina Landau, Ilan Goldberg, Sara Brenner

Dermatology Dept., Tel Aviv-Sourasky Medical Center

Various plants induce dermatitis in man. There have been only a few published cases of contact dermatitis caused by Agave americana (AA).

We report intentional exposure to AA in a soldier seeking sick leave, and review our previously reported cases. Treatment with oral antihistamines and topical saline compresses resulted in subsidence of the systemic symptoms within 24h and regression of cutaneous manifestations in 7-10 days.

Physicians should be alert to the possibility of self-inflicted contact dermatitis induced by exposure to plants, especially to A. americana. Systemic signs may accompany the cutaneous lesions.

Combined Approach in Management of Penetrating Injury of Vertebral Artery

Y. Kluger, B. Sagie, D. Soffer, N. Hai, D. Oron

Rabin Trauma Center and Division of Invasive Radiology, Tel Aviv Medical Center

Penetrating injuries of the vertebral artery are not common. Although surgical control of this type of injury is well- documented, the combined approach (surgery and packing for temporary control of bleeding, followed by angiography and embolization for permanent control) is now recognized and practiced.

We describe a 40-year-old man who was stabbed in the neck. He was rushed to the operating theater in hemorrhagic shock. A vertebral artery injury was identified and packed. Angiography and embolization permanently controlled the bleeding.

The combined approach is safe and we recommend it in those in whom bleeding from the vertebral artery is initially well controlled with packing.

Ent of Femoral Artery Pseudo-Aneurysms 

G. Szendro, A. Klimov, A. Lennox, B. Jonathan, L. Avrahami, B. Yechieli, M. Griffin, S. Yurfest, Y. Charach, L. Golcman, A.N. Nicolaides

Vascular Surgery Dept., Soroka Medical Center, Beer Sheba; Irvine Laboratory for Cardiovascular Investigation and Research, St. Mary's  Hospital, Imperial College Medical  School, London; Vascular Laboratory, Soroka Medical Center, Beer Sheba; and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheba

The femoral artery remains the most used peripheral site for radiological catheter access. With a greater number of both diagnostic and therapeutic procedures being performed by interventional radiologists and cardiologists, and with larger catheters being used for stenting and endovascular grafting, the incidence of iatrogenic pseudo-aneurysms reported has reached as high as 0.5-2%. Ideally, they should thrombose spontaneously. However, when this does not occur, management options include: observation, ultrasound-guided obliterative compression, direct thrombin injection, embolization, stent graft insertion, and very rarely- surgery.

During a 7-year period (1992-1999) we treated 131 cases of femoral artery false aneurysms. Until 1998 ultrasound-guided compression-obliteration, with a 95% success rate, was our method of choice. Since 1998, direct thrombin injection, with 100% success in 24 cases, has become our preferred method. It is pain-free, fully successful even in anticoagulated patients, and is currently our treatment of choice.

Diphtheria in a Highly Immunized Population 

Rivka Sheffer, Esther Marva, Rachel Mimon, Paul Slater, Avital Cohen, Tamat Shohat

Tel Aviv District Health Office, Central Laboratory and Epidemiology Dept., Public Health Services, Jerusalem

Although diphtheria vaccination is routine world-wide, outbreaks of the disease continue to occur in supposedly vaccinated populations. The incidence of diphtheria in Israel is very low, with only 3 cases reported in the past 24 years (all in unvaccinated children). In 2 of the 3 an asymptomatic carrier was identified among the patients' close contacts, presumable the source of the infection.

We describe a recent case of diphtheria. It is important for physicians to be aware of the possibility of diphtheria occurrimg despite the high rate of vaccination in our population.

רונית חיימוב-קוכמן¹, ראובן ברומיקר², אריאל מילויצקי¹

¹מחלקת נשים ויולדות ²והמחלקה לטיפול נמרץ בילוד, בי"ח הדסה הר הצופים, הפקולטה לרפואה, האוניברסיטה העברית, ירושלים

Physicians' Reminders Promote Annual Fecal Occult Bloodtesting Compliance

Shlomo Vinker, Vardina Shumla, Eliezer Kitai

Family Medicine Dept., Sackler Faculty of Medicine, Tel Aviv University

Screening for the early detection of colorectal cancer using the fecal occult blood test has been shown to be effective in reducing mortality. In Israel family physicians recommend that their patients, aged 50-75, have the test performed annually. But compliance with testing in the general population has been poor.

We therefore studied this issue in 3 primary care facilities, in 384 patients, average age 62.7‏6.9 years; 81 (21.1%) performed the fecal occult blood test. Performance rates were significantly lower (13.9%) in those aged 50-59 (p = 0.0003), as compared wh those aged 60-69 and 70-75 (24.3% and 24.7%, respectively). Compliance rates of the patients of different physicians varied as well.

Recommendation of family physicians led to overall compliance of 21.1%. Additional efforts are needed to increase compliance in order to decrease colorectal cancer morbidity and mortality in Israel.

Color Doppler Imaging of Central Retinal Artery in Retinopathy of Prematurity

Alon Harris, Hanna J. Garzozi, Mira Harris-Izhak, Nir Shoham, Daniel R. Holland

Depts. of Ophthalmology, Indiana University School of Medicine, Indianapolis and of HaEmek Medical Center, Afula; and Eye Health Northwest, Portland, Oregon

Color Doppler imaging (CDI) is a noninvasive technique, combining 2-dimensional brightness-modulated (B-mode) ultrasound evaluation of eye and orbital structures, with simultaneous color-coded Doppler imaging of orbital blood flow. It has been used to characterize various ophthalmic disorders in adults. Currently there is no data describing orbital blood flow parameters in either normal children or in those with ophthalmic disease, such as the retinopathy of prematurity (ROP).

We evaluated blood flow in the central retinal artery of preterm infants undergoing examination for ROP. We also investigated whether useful readings could be obtained on a consistent basis, and the reproducibility of differences in central retinal artery blood flow between subjects with and without ROP (including the influence of "plus" disease).

We obtained hemodynamic readings in 43 of 46 eyes of preterm infants. 13 eyes had no signs of ROP; 18 had ROP (at least stage 1) without "plus" disease, and 12 had ROP with "plus" disease. There were no statistically significant differences in systolic blood flow velocity within the 3 groups. However the average velocity was slower in the "plus" disease group, correlating with the clinical finding of dilated and tortuous blood vessels which characterize the posterior retina of ROP eyes with "plus" disease.

Pulmonary Involvement in Osler- Weber-Rendu Syndrome 

Efrat Bron-Harlev, Benjamin Zeevi, Ben-Zion Garty

Dept. of Medicine B and Cardiac Catheterization Unit, Schneider Children's Medical Center, Petah Tikva

Hereditary hemorrhagic telangiectasia (Osler-Weber-Ren-du syndrome) is a group of autosomal dominant diseases with variable penetration, characterized by vascular malformations. Recently hereditary hemorrhagic telangiectasia has been found to be a phenotypic expression of mutations in genes located on chromosomes 9 and 12, and possibly of other genes located on other chromosomes.

We describe 2 patients with hereditary hemorrhagic telangiectasia and pulmonary involvement who presented with repeated complaints of dyspnea and cyanosis and were diagnosed as having long-standing asthma. Both were treated with therapeutic catheterization and embolization with good clinical outcomes.

Causes of Blindness in Israel 

Y. Hod, Y. Corcia, Y. Yassur, O. Geyer

Depts. of Ophthalmology, Carmel Medical Center, Haifa and Rabin Medical Center, Petah Tikva; Israel Ministry of Labor and Social Affairs, Jerusalem; and Rehabilitation Services Administration, Services for the Blind

Of the world population, 38 million are blind and another 110 million are visually impaired. Even in the developed countries there are 3.5 million who are blind.

This study of blindness in Israel is based on the National Blind Registry. At the end of 1998, 15,937 were registered as blind, 0.3% of the total population; 776 (5%) of them were 18 years old or younger; 6,426 (40%) 18-65 years old; and 8,735 (55%) 65 years or older.

The leading causes of blindness in Israel are glaucoma (2,074, 13%), macular degeneration (1,954, 12%) and diabetes mellitus (1,680, 11%). Since glaucoma and diabetes, and to a lesser extent glaucoma, respond to treatment, blindness could have been avoided in most cases. National screening programs for early diagnosis and treatment of these diseases would reduce prevalence of the newly blind.

Brief Preoperative Radiotherapy reduces Local Recurrences and Improves Survival in Rectal Cancer

T. Peretz, Z. Weshler,* Y. Goldberg, A.L. Durst, H.R. Freund

Depts. of Surgery and Oncology, Hadassah University Hospitals, and Hebrew University-Hadassah Medical School, Ein Kerem and Mt. Scopus, Jerusalem

Locoregional recurrence of rectal cancer ranges between 20%-50% following apparently radical surgery. Radiation has the potential of reducing this high rate of recurrence and residual disease. A retrospective analysis of 78 patients with locally advanced, biopsy proven, adenocarcinoma of the rectum treated between 1980-1987 was conducted. 28 (36%) were treated by surgery alone (surgery); 29 (37%) by surgery and postoperative radiotherapy (post-op); and 21 (27%) by surgery and preoperative radiotherapy (pre-op). 41 were females and 37 males. The median age was 62 years (range 25-90).

All tumors were resectable. 42 patients (54%) underwent abdomino-perineal resection and 36 (46%) anterior resection patients [8 Dukes B₁ (10%); 37 B₂ (47%); 2 C₁ (3%); 31 C₂ (40%]. Local recurrences were verified by transanal or ultrasound guided needle biopsy.

The 5-year actuarial survival rates by the Kaplan-Meier method for 75 evaluated patients was 55%. Overall 5-year actuarial survival was significantly higher (p=0.001) in pre-op radiotherapy (95%) compared to surgery alone (45%), or surgery with postoperative radiotherapy (32%). The data were significant (p=0.006) for patients with stage B tumors, but not stage C. This trend of improved survival held also at 8-year follow-up (80% pre-op; 32% post-op; 27% surgery). The 5-year actuarial local control was significantly better (p=0.03) for the pre-op irradiated patients (22%), compared with surgery only (56%) and post-op radiotherapy (38%). Local control was better (p=0.02) for Dukes B tumors in the preoperative group, but not Dukes C tumors.

Actuarial 5-year survival of those without distant metastases was 87% for pre-op patients, 62% for surgery alone and 48% for post-op radiotherapy. As all patients were clinically classified as advanced rectal tumors, tumor downstaging by preoperative radiotherapy seems to be paramount for local control. Improved local control translates into a siginificant advantage in overall actuarial survival.

*DECEASED.

Transarterial Oil Chemoembolization for Hepatocellular Carcinoma 

Izhar Levy, Anthony Verstandig, Talia Sasson, Dana Wolf, Ilia Krichon, Eugin Libson, Pinchas Levensart, Orit Papo, Oded Yurim, Ahmed Id, Daniel Shouval

Division of Medicine, Liver Unit and Invasive Radiology, Radiology, Pathology and Surgery Depts., Hadassah University Hospital, Ein Kerem, Jerusalem

Hepatocellular carcinoma (HCC) is a common malignancy with a grave prognosis. Most patients have both the malignant tumor as well as hepatic cirrhosis. Liver transplantation or hepatectomy are considered the only curative procedures, but can be applied in fewer than 10% of patients. In recent decades the most common treatments of HCC are transarterial chemoembolization with oil (TOCE) and percutaneous ethanol injection (PEI). We summarize our retrospective study of 100 patients (mean age 64) 3‏ treated by TE.

In 271 procedures between 1989-1998, in 16 patients hepatectomy was combined with TOCE and in 8 PEI was combined with TOCE, while the rest were treated by TOCE alone. Tumor mass was reduced in 36% of those treated by TOCE (tumor volume reduced 24-75%). Alpha-feto protein (AFP) was reduced 25-90% in 20/32 of those with elevated AFP levels. Median survival for the 100 in the entire group was 19 months (10.9 months in those with conservative treatment). Median survival in the 57 in Okuda stage 1 and the 43 in stages 2 or 3 was 30.1 months and 10.9 months, respectively (p<0.0001). Of the 57 in stage 1, 16 underwent hepatectomy in addition to TOCE and 41 were treated only by TOCE (median survival 15 and 26 months, respectively, p not significant).

Comparing Okuda 1 patients treated by TOCE only with the natural history of the disease and historical controls (Okuda 1 patients treated conservatively in 1984) median survival was 26 and 10 months respectively (p<0.001). The side effects of TOCE were relatively mild. There was 1 fatality (3 days after treatment), and quality of life was maintained. Despite progress in the treatment of HCC by TOCE, PEI, and liver transplantation, long-term survival has remained unsatisfactory.

Multiple Organ Damage due to Cholesterol Embolization

Ido Wolf, Meir Mouallem

Dept. of Medicine E, Sheba Medical Center, Tel Hashomer, and Sackler Faculty of Medicine, Tel Aviv University

Cholesterol crystal embolization can affect multiple organ systems and mimic other systemic diseases. We describe a 65-year-old woman who had renal failure, diarrhea, transient ischemic attacks and purple toes due to spontaneous cholesterol crystal embolization.