High-Dose Chemotherapy and Autologous Stem Cell Trans-Plantation for Refractory and Relapsing Hodgkin's Disease

A. Avigdor, I. Hardan, O. Shpilberg, P. Raanani, I. Grotto, I. Ben-Bassat

Hematology Institute and Hemato-oncology Unit, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University

High dose chemotherapy and autologous stem cell transplantation are widely used in relapsed and primary refractory Hodgkin's disease. We transplanted 42 patients with Hodgkin's disease between 1990-1998. Median follow-up was 31 months (range 1-102). 29 (69%) were transplanted after relapse and 13 (31%) were refractory to first line therapy. Median age at transplantation was 29 years (range 19-58) and 23 (55%) were males.

All were treated with the BEAM protocol (carmustine, etoposide, cytarabine and melphelan). 18 who were in remission received radiotherapy following transplantation. The source of the stem cells was bone marrow in 17% and peripheral blood in 83%. At initial diagnosis: 57% had stage III-IV disease and B symptoms were present in 52%. 75% were treated with MOPP, ABVD or with related versions. Radiotherapy followed in 52%. Prior to transplantation, 45% of the relapsed group were in the advanced stage. 33% and 12% of all patients had lung and bone involvement, respectively.

The complete remission rate was 86% for the 2 groups. 2 (5%) died from transplant-related complications and MDS/AML developed in 2 (5%) after transplantation. The 3-year overall survival (OS) and disease-free survival (DFS) were 68% and 60%, respectively. The 3-year OS for the relapsed group was 64% compared with 76% for the refractory group, and the 3-year DFS for the relapsed group was 60% vs. 42% for the refractory group (neither difference significant). Radiotherapy following transplantation did not have a beneficial effect on DFS. No prognostic factors for outcome of transplantation were found, most probably due to the limited number of patients and the high variability of disease characteristics.

We conclude that high dose chemotherapy and autologous stem cell transplantation are effective and relatively safe for relapsed or primary refractory Hodgkin's disease. The DFS at 3 years was longer for those transplanted after relapse than those with primary refractory disease, but not significantly. Patients with primary refractory disease can be salvaged with high dose chemotherapy.

Cells-Preliminary Report Immunohistochemical Identification of Testicular Germ

Batia Bar-Shira Maymon, Gedalia Paz, Leah Yogev, Ron Hauser, Letizia Schreiber, Amnon Botchan, Haim Yavetz

Institute for Fertility Study, Lis Maternity Hospital; Pathology Institute, Tel Aviv-Sourasky Medical Center; and Sackler Faculty of Medicine, Tel Aviv University

The use of testicular spermatozoa for intracytoplasmic sperm injection introduced a new treatment modality for management of male infertility.

Since testicular biopsies of non-obstructive azoospermic men are not homogenous in their histological patterns, identification with certainty of focal spermatogenesis might be difficult, particularly in those with small foci of spermatogenesis. We used an immunohistochemical marker of the male germ line, an antibody generated against RBM (RNA-binding-motif), to recognize with high precision the presence of germ cells in the biopsy. Biopsies of 30 men with azoospermia, most with non-obstructive azoospermia and a few with obstruction of the vas deferens, were evaluated.

Immunohistochemical staining for RBM protein contributed to the detection and accuracy of the identification of germ cells. Furthermore, this immunohistochemical technique aided the histopathologist to focus on even small foci of spermatogenesis. Absence of the protein expression confirmed the diagnosis of Sertoli-cell-only syndrome. The results indicate that expression of RBM can be a diagnostic marker for identifying the germ cells of small concentrations of spermatogenesis. This method can enhance the accuracy of histopathological evaluation of testicular biopsies that had formerly relied mainly on hematoxylin-and-eosin staining.

Etoposide and Cisplatin for Non-Small Cell Lung Cancer 

David B. Geffen, Sofia Man, Yoram Cohen*

Dept. of Oncology, Soroka-University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheba

Etoposide and cisplatin (EP) has been the standard therapy for non-small cell lung cancer (NSCLC) at many cancer centers for over a decade. We analyzed our experience with EP in NSCLC to provide a baseline for comparison with new drugs. From 1986 through 1994, 46 of our patients with NSCLC received EP as first-line chemotherapy. Radiation therapy was administered to 25 of them, including 20 who received it immediately before or concomitantly with chemotherapy. Toxicity was mild and included only 1 episode of neutropenic fever and 1 case of reversible renal failure.

Overall response was 22%. In 3, response was complete (pathologically documented in 2 of them) and in 7 partial. Median survival in locally advanced (stage III) and metastatic disease (stage IV and recurrent) were 12 months and 7 months, respectively. 2 patients are alive and free of disease more than 6 years after diagnosis.

Our results are consistent with other published studies of EP in NSCLC. EP provides modest benefit in locally advanced NSCLC, with minimal toxicity.

Jules E. Harris Chair in Oncology.

Autologous Chondrocyte Transplantation - from Science Fiction to Routine Clinical Practice

Dror Robinson, Hana Ash, David Aviezer, Gabriel Agar, Nahum Halperin, Zvi Nevo

Dept. of Clinical Biochemistry, Sackler Medical School, Tel Aviv University, Ramat Aviv; Dept. of Orthopedic Surgery, Assaf Harofeh Medical Center, Zerifin; and CTI Ltd., Science Park, Kiriat Weizmann, Nes Ziona

Adult articular cartilage lacks the capacity for self-repair. The limiting factor appears to be the inability of chondrocytes to proliferate while embedded in the extracellular matrix typical of hyaline cartilage. Cartilage defects larger than 1 cm² change articular biomechanics and lead to eventual osteoarth-ritis and joint destruction.

During the past decade, several competing techniques have evolved to stimulate articular cartilage repair. Small lesions can be successfully treated by either micro-fracture or osteochondral cylinder grafting. The latter technique allows immediate weight bearing but leads to damage of previously uninvolved areas of articular cartilage, which limits its application to lesions of less than 2 cm².

When the damaged area is more extensive, grafting of autologous chondrocytes should be considered. First a diagnostic arthroscopy is performed to assess the damaged area and a small cartilage biopsy is taken. 6 weeks later, arthrotomy and chondrocyte transplantation are performed. In the interval, the antologous chondrocytes have expanded by 2 to 3 orders of magnitude. Our experience to date includes 10 cases with follow-up of 6 months to 5 years. Preoperative complaints of crepitation and locking disappear. There is functional improvement and pain reduction of approximately 50%. This procedure, currently limited to patients under 55 years of age with limited damage to an articular surface, for the first time allows reconstruction of damaged articular areas without resorting to allografts.

Smoking by an Israeli Hospital Staff, its Attitude to Smoking in Hospitals and to “Smoke-Free” Hospitals

Shabtai Varsano, Giora Hevion, Mila Garenkin

Depts. of Pulmonary Medicine, Asthma Care-Education Unit, Hospital Management Office, and Epidemiology and Medical Data Unit; Meir General Hospital, Sapir Medical Center, Kfar Saba and Sackler Faculty of Medicine, Tel Aviv University

Smoking within hospitals is common in general hospitals in Israel. It has a strong negative educational impact, has a negative image and curing its ill effects help keep our hospitals busy. An anonymous questionnaire was answered by 128 members of our hospital staff (28%). Their distribution, according to occupation and sex was representative of the rest of our hospital staff.

19% of our workers are smokers, a much lower proportion than in our general adult population. The proportion was highest among maintenance (40%) and sanitary-help staff (36%). 23% of nurses and 15% of physicians were smokers. This situation is better than that among Italian or Japanese medical staff, but much worse than among North American medical staff.

75% of our workers who smoke declared that they smoke outside the room in which they work. 66% and 72% of the staff believe that hospital workers and visitors, respectively, should smoke outside hospital buildings. Only 19% of all workers do not believe that a "smoke-free hospital" is attainable. 34% believe that a "smoke-free hospital" is achievable, and 47% said that it is perhaps achievable. 86% of all the workers, and 41% of the smokers, expect the hospital director to implement an effective policy of enforcing the law limiting smoking within hospitals (and other public buildings) in Israel. 60% are willing to contribute actively to this effort.

We believe these results strongly suggest that the time is ripe for implementation of the "smoke-free hospital" in Israel. This requires a strong and effective central policy, like that in the USA. We suggest measures that the Israel Ministry of Health take measures to successfully implement this policy.

Severe Hypercalcemia Due to Renal Transitional Cell Carcinoma

D. Zamir, J. Weizman, N. Erlich, M. Amar, P. Weiner

Depts. of Medicine A, Urology and Pathology, Hillel Yaffe Medical Center, Hadera

Hypercalcemia is a common metabolic disorder, especially in the elderly. The most common etioloare hyperparathy-roidism or malignancy, most often of the lung, breast, kidney or hematological system. Because hypercalcemia is an uncommon manifestation in urinary tract epithelial tumors, especially those of the renal pelvis, we present a man aged 62 years with hypercalcemia due to renal transitional cell carcinoma.

Preliminary Report of Experience with Laparoscopic Splenectomy

Joseph Kuriansky, Ron Bilik, Moshe Shabtai, Itamar Avigad, Amram Ayalon

Depts. of General Surgery and Transplantation and Pediatric Surgery, Sheba Medical Center, Tel Hashomer; and Sackler School of Medicine, Tel Aviv University

Laparoscopic splenectomy is effective and technically feasible for treating various hematological diseases such as idiopathic thrombocytopenic purpura (ITP), congenital sphero„cytosis, hemolytic anemia, and Hodgkin's lymphoma. An anterior approach to the vascular pedicle is usually described. However, in this approach to the splenic hilum, the dissection of the splenic artery is frequently difficult. The laparoscopic posterolateral approach involves dissection of the posterolateral attachments to the diaphragm, followed by the disection and ligation of all splenic branches near the splenic parenchyma. We used it in 9 adults and 4 children: 11 patients had ITP, 1 spherocytosis and 1 Hodgkin's lymphoma.

This procedure was completed in 13 patients, but in 2 it had to be converted to open surgery. Mean operating time was 3 hours and mean postoperative stay 3 days. Blood transfusion was not required and there were no postoperative complications.

Laparoscopic splenectomy is safe in both adults and children, and the posterolateral approach provides excellent visualization and allows control of the branches of the splenic vein and artery in the splenic hilum.

Brucellosis Presenting as Acute Abdomen

Nathan Kaufman, Noga Reichman, Edith Flatau

Dept. of Medicine B, HaEmek Medical Center, Afula

Usually symptoms of brucellosis are nonspecific and characterized by a wide range of complaints. Although the disease in Israel is almost exclusively food borne (caused by Brucella melitensis in unpasteurized goat milk products) so the main route of infection is the gastrointestinal tract, but gastrointestinal complications are rare, and only sporadic cases of ileitis or colitis have been described.

We present a 43-year-old woman with an acute abdomen, probably due to diverticulitis. It was diagnosed only after blood cultures were positive for Brucella melitensis. We believe that its protean manifestations should be consin addition to the other bizarre presentations of this disease, important in our region.

Proper use of Pressurized Hand-Held Inhalers in Patients with Chronic Airway Obstruction 

Shabtai Varsano, Ilana Jacoby, Mila Garenkin

Asthma Care and Education Unit, Dept. of Pulmonary Medicine, and Epidemiology Unit, Meir General Hospital, Sapir Medical Center, Kfar Saba; and Sackler School of Medicine, Tel Aviv University

Inhaling drugs via hand-held inhalers in recommended for those with chronic obstructive airway disease (COPD). Approximately 8%-9% of Israel's population use hand-held inhalers, many of them pressurized. Skill in using them and ability of chronic users to learn their proper use have not been assessed.

During 1993 and 1994 we studied 200 patients with bronchial asthma or COPD who regularly used a pressurized hand-held inhaler (PI), but were not trained to use it in our out-patient pulmonary clinic. Only a third were found to be skilled in its use. About half were completely unable to use it properly, and 17% used it in a suboptimal way. Remarkably, only 40% had been taught anything with regard to its use. About 75% of the suboptimal users significantly improved their skill in its use immediately after receiving a single individual teaching and corrective demonstration session. While 15% failed to learn the proper use of the PI, many of those who improved immediately after a single teaching session retained the learned skills for months.

We conclude that the physician who recommends the use of a PI is responsible for the patient's being taught its proper use in a demonstration session. Skill in its use should be reassessed periodically during the entire treatment period.

Diarrheal Disease among Care-Givers at Children's Day- Care Centers 

S. Koton, D. Cohen, M.S. Green

Israel Center for Disease Control, Ministry of Health and Gertner Institute, Chaim Sheba Medical Center, Tel Hashomer; Medical Corps, Israel Defense Forces; Dept. of Epidemiology and Preventive Medicine; Sakler Faculty of Medicine, Tel Aviv University

Diarrheal disease tends to spread from infected children to their families. Due to the increased risk of exposure, children's caregivers in day-care centers may have a higher incidence of diarrhea, particularly when caring for very young children. We therefore examined the incidence of diarrhea and antibodies to Shigella among caregivers in day-care centers, according to age groups of children in their care (<18, 18-34, and >35 months) and in comparison with the general population. 2 studies with a retrospective cohort and seroepidemiological cross-sectional design were carried out. Questionnaires were completed by 401 caregivers in 36% of all WIZO day-care centers. As a measure of past exposure to Shigella, levels of S. sonnei and S. flexneri antibodies were examined in the blood of 110 caregivers (ELISA method).

There was a higher incidence of diarrhea among young children, increasing the potential exposure to diarrheal agents among their caregivers. Nevertheless, no statistically significant differences in diarrhea incidence were found among caregivers of the various age groups during the previous year (p=0.768) and during the previous month (p=0.319), nor in absenteeism due to diarrhea during the last month (p=0.761). Levels of Shigella antibodies were similar among caregivers in all 3 groups. Diarrheal incidence was higher among women in the population control group than among caregivers during the previous year (p=0.005) and month (p=0.067). No statistically significant differences in levels of S. sonnei and S. flexneri antibodies were found between caregivers and women in the control group.

There was no evidence that diarrhea is an occupational hazard for caregivers of young children. An explanation may be the development of protective immunity against common diarrheal agents due to recurrent exposure.
 

Islet Autoantibody Assays in Type I Diabetes can Replace ICA Test

Daniel Lazar, Naomi Weintrob, Natalia Abramov, Sara Assa, Konstantin Bloch, Regina Ofan, Hadassa Ben-Zaken, Pnina Vardi

Institute for Pediatric Endocrinology and Diabetes, Schneider Children's Medical Center, Petah Tikva and Felsenstein Medical Research Center, Tel Aviv University

Islet cell antibodies (ICA) continue to serve as the basis of the principal serological test for definition of active autoimmunity of beta-cells. Its disadvantages are the need for human pancreatic tissue and difficulty in obtaining quantitative results. In the past decade biochemically-defined beta-cell antigens were described, leading to the development of sensitive and specific autoantibody assays, to predict insulin-dependent diabetes mellitus (IDDM). We examined the value of combined biochemically-based serological assays, such as autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and ICA512 (ICA512A) to replace the traditional ICA assay.

Blood samples of 114 newly diagnosed IDDM patients, aged 12‏5 yrs (range 2 months - 29 years) were tested for ICA (indirect immunofluorescence), IAA, GADA and ICA512A (radiobinding assay). The latter 2 assays were performed using recombinant human [35S]-labeled antigen produced by in vitro transcription/translation. We found that fewer sera scored positive for ICA and/or IAA (80.7%, 92/114) than for 1 or more of IAA, GAD, or ICA512 (88.6%, 101/114). We conclude that combined testing for IAA, GAD and ICA512 can replace the traditional ICA/IAA test to predict IDDM and is helpful in the differential diagnosis of insulin-dependent and noninsulin-dependent diabetes.

Laparoscopic Approach to Perforated Duodenal Ulcer

D. Rosin, Y. Kurianski, M. Shabtai, A. Ayalon

Dept. of General Surgery and Transplantation, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University

As laparoscopy becomes more prevalent, it is being used for a growing variety of abdominal operations, both electively and as emergency treatment. We describe our preliminary experience in laparoscopic repair of perforated duodenal ulcer. 2 women and 2 men, aged 40-78 were operated over a period of 4 months and in all laparoscopic suture and omentopexy were performed with meticulous abdominal lavage. Despite somewhat longer operative time but a similar period of hospitalization, the easier post-operative course and fewer wound complications justify this technique. The effectiveness of medical treatment of peptic disease, and especially the anti-Helicobacter pylori regimen, supports the view that closure of the perforation is usually enough, and vagotomy is not needed.

Topical Photodynamic Therapy in Basal and Squamous Cell Carcinoma and Penile Bowen's Disease

Yoram Harth, Bernard Hirshovitz

Photodynamic Therapy Unit, Elisha Medical Center, Haifa

Photodynamic therapy (PDT) is a noninvasive selective therapy for a specific group of skin tumors. 5-aminolevulinic acid 20% in a water-in-oil cream base was applied to the tumors as a photosensitizer and was followed after 12 hours by exposure to a high output light source emitting red (585-720 nm; 150 mW/cm²) and near infrared irradiation (1.25-1.6 mm; 50 mW/cm²) for 10-15 minutes (VersaLight, incoherent filtered light source). Complete responses were achieved after 1-3 treatments in 26/31 lesions of superficial or small nodular basal cell carcinoma (BCC) and 4/5 in superficial, squamous cell carcinoma (SCC) lesions. There was a patient with Bowen's disease of the penis. Follow-up was for 12-24 months. This noninvasive, nearly painless treatment gives excellent therapeutic and cosmetic results. Our data show its efficacy for certain subtypes of BCC, SCC and Bowen's disease. Further studies will determine the exact cure and recurrence rates with this modality and compare it to other modes of skin cancer therapy.

Aseptic Loosening of Joint Implants

Dror Fuchs, Chaim Zinman, Dina Lewinson

Orthopedic and Traumatology Dept. B, Rambam Medical Center; and Div. of Morphology Sciences, Bruce Rappaport Faculty of Medicine, The Technion, Haifa

The purpose of orthopedic joint implants is to improve joint movement. Within the past 30 years, biomechanical improvements affecting the life-span of the implants has brought a new type of problem: the biological response to debris from the implant material contributes greatly to aseptic loosening of the prosthesis. The process is mediated by osteotropic factors, cytokines released from mononuclear cells, and osteoblasts and osteoclasts in the bone-cement interface or bone-implant interface.

Paroxysmal Nocturnal Hemoglobinuria

Haim Ben-Ami, Yehuda Edoute

Medical Dept. C, Rambam Medical Center and Bruce Rappaport Faculty of Medicine, The Technion, Haifa

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disorder of blood cells which originate from an abnormal hematopoietic stem cell. The condition is characterized by nocturnal hemoglobinuria, chronic hemolytic anemia, and thrombosis. We describe a 60-year-old woman with PNH admitted with abdominal pain and jaundice, who had dark urine on arising after a night's sleep. The diagnosis was established by the typical clinical story and a positive Ham test. She was successfully treated with Halotestin and folic acid. Although PNH is rare, it should be considered in the differential diagnosis of hemolytic anemia. Early diagnosis and treatment are important.