Ronit Yerushalmi

Fertility status among women treated for aggressive non-Hodgkin's lymphoma

In young women treated for intermediate-high-grade non-Hodgkins lymphoma with CHOP (cyclophosphamide, adriamycin, oncovine and prednisone), there is insufficient data concerning gonadotoxicity or the need for fertility-preserving measures. The aim of the present study was to evaluate the fertility status in the first complete remission of women who were treated for aggressive non-Hodgkins lymphoma. A cohort of 36 women with aggressive non-Hodgkins lymphoma in first remission, who were treated in five university-affiliated hospitals in Israel, was evaluated. All women were aged younger than 40 years at diagnosis and received frontline protocols, including cyclophosphamide and adriamycin, mostly CHOP. Menstrual cycle characteristics, as well as pregnancies before the diagnosis, during treatment and in first complete remission, were evaluated. The patients mean age at the diagnosis was 28 ± 7 years (range 17 – 40 years). All patients were treated with chemotherapy, although 10 patients received additional radiotherapy. Follow-up time at first complete remission was 84 ± 48 months. Before diagnosis, all patients had menstrual cycles, which were regular in 31 (86%). Three patients received gonadtropin-releasing homone analogs, whereas nine received contraceptive pills together with cytotoxic treatment. During treatment, 18 patients (50%) had amenorrhea, six (17%) had irregular menstrual cycles, and 12 (33%) continued their regular cycles. All but two women resumed menses in the first complete remission, and these were regular in 22 (61%) patients. In 63% of patients, the menstrual cycle recovered within 3 months of the discontinuation of chemotherapy. Eighteen patients (50%) became pregnant during the first complete remission. There was no significant difference between those patients who received fertility-preserving measures versus the remainder concerning regular menstrual cycles recovery or pregnancies. The two patients who developed amenorrhea were 40 years old at the time of diagnosis. In conclusion, the rate of gonadal dysfunction is very low among young, CHOP treated, non-Hodgkins lymphoma female patients. Fertility-preserving techniques are not needed for women aged younger than 40 years and should probably be reserved for those who are at high risk for gonadal toxicity.

Beta-thalassemia minor during pregnancy

OBJECTIVE: To investigate pregnancy outcome of patients with β-thalassemia minor. METHODS: A population-based study comparing all pregnancies of women with and without β-thalassemia minor was conducted. Deliveries occurred during the years 1988–2002 at Soroka University Medical Center. A multivariate logistic regression model, with backward elimination, was constructed to find independent risk factors associated with maternal β-thalassemia minor. RESULTS: During the study period there were 159,195 deliveries, of which 261 (0.2%) occurred in patients with β-thalassemia minor. The following conditions were significantly associated with β-thalassemia minor: oligohydramnios (odds ratio [OR] 2.1; 95% confidence interval [CI] 1.2%, 3.7%), intrauterine growth restriction (IUGR; OR 2.4; 95% CI 1.4%, 4.2%), Jewish ethnicity (OR 1.5; 95% CI 1.2%, 1.9%), and previous cesarean delivery (OR 1.4; 95% CI 1.1%, 2.0%). No significant differences were noted between the groups regarding perinatal outcomes such as birth weight, low Apgar scores, congenital malformations, or perinatal mortality. Patients with β-thalassemia minor were more likely to have cesarean deliveries than were the nonthalassemic parturients (16.9% and 12.2%, respectively; P = .021). However, while controlling for possible confounders such as IUGR, oligohydramnios, and previous cesarean delivery, with another multivariate analysis with cesarean delivery as the outcome variable, β-thalassemia minor was not found as an independent risk factor for cesarean delivery (OR 1.3; 95% CI 0.9%, 1.9%). CONCLUSION: The course of pregnancy of patients with thalassemia minor, including perinatal outcomes, is favorable. Because higher rates of IUGR were found, we recommend ultrasound surveillance of fetal weight for early detection of IUGR. LEVEL OF EVIDENCE: II-2

Rituximab in a Patient with Acute Renal Failure due to B-cell Lymphomatous Infiltration of the Kidneys

Renal failure is known to occur in lymphoproliferative disorders because of ureteral obstruction or parenchymal infiltration by disease. Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B-lymphocytes. The pharmacokinetics and metabolism of rituximab is not well established. The extent of renal clearance is not fully known, with little experience reported on the use of rituximab in patients with renal failure. We present a case where rituximab was administered to a patient with acute renal failure due to bilateral kidney infiltration by non-Hodgkins lymphoma (NHL). The patients renal function improved on therapy, with no need for hemodialysis and there were no significant toxicities. Rituximab may be used as a treatment option for NHL patients with impaired renal function.

Pregnancy complications in women with inherited thrombophilia

Objective: The purpose of this study was to examine whether women with inherited thrombophilia have an increased risk of developing pregnancy complications. Methods: All singleton pregnancies with known inherited thrombophilia were compared to those without inherited thrombophilia for deliveries during the years 2000–2002 in a tertiary medical center. Data regarding inherited thrombophilia (International Classification of Disease 9th revision, Clinical Modification code 286.3) were available from the perinatal database in our center. Women lacking prenatal care were excluded from the analysis. Stratified analysis, using a multiple logistic regression model, was performed to control for confounders. Results: Out of 32,763 singleton deliveries that occurred during the study period, 0.2% (n=57) of the women were diagnosed with inherited thrombophilia. Using a multivariate analysis, with backward elimination, the following conditions were significantly associated with inherited thrombophilia: previous fetal losses [odds ratio (OR)=5.5; 95% confidence interval (CI) 2.9–10.3; P<0.001], recurrent abortions (OR=9.5; 95% CI 5.5–16.3; P<0.001), fertility treatments (OR=3.7; 95% CI 1.3–10.6; P=0.014), and intrauterine growth restriction (OR=7.2; 95% CI 3.4–15; P<0.001). Perinatal mortality was significantly higher in women with inherited thrombophilia than in those without known thrombophilia 5.3% (3/57) versus 0.6% (477/32,763) P=0.017. However, inherited thrombophilia was not found to be an independent risk factor for perinatal mortality (OR=3.05; 95% CI 0.90–10.3; P<0.073) in a multivariate analysis with perinatal mortality as the outcome variable, controlling for recurrent abortions, IUGR, and gestational age. Conclusion: Inherited thrombophilia, associated with previous fetal losses, recurrent abortions, fertility treatments, and intrauterine growth restriction, was not an independent risk factor for perinatal mortality.

Are platinum-based chemotherapeutic drugs safe for patients with Charcot-Marie-Tooth disease?

Dear Editor, Aggravation of neuropathic symptoms in CharcotMarie-Tooth (CMT) disease patients by vincristine treatment is well documented. Much less information exists on the effect of other antineoplastic drugs in these patients. We report a 53-year-old patient with CMT-1A whose sensory symptoms worsened abruptly and irreversibly after having received a low dose of a cisplatin-containing regimen for testicular carcinoma. This case suggests that CMT patients may be vulnerable to neurotoxic drugs and suggests the need for a systematic database on potentially hazardous drugs for patients with CMT. Subjects with preexisting polyneuropathies may be exceptionally vulnerable to the neurotoxic effects of various drugs (Chaudhry et al., 2003). Among the various combinations described to date, the abrupt worsening of CMT when exposed to vincristine is probably the most commonly reported (TrobaughLotrario et al., 2003), with at least 30 reported cases of vincristine-induced neuropathic syndromes in patients with CMT or hereditary neuropathy with liability to pressure palsies (Weimer and Podwall, 2006). In some cases, the preexisting hereditary neuropathy was only diagnosed in the wake of the neuropathic response to the administration of one or two doses of vincristine. As a result, additional considerations should be used when giving a vinca alkaloid to patients with CMT. Many physicians screen patients with hematological malignancies for signs of preexisting neuropathy prior to the initiation of chemotherapy. There is much less information regarding the effect of other drugs with known neurotoxic effects on subjects with CMT. The CMT Association has posted a list of all potentially neurotoxic drugs on its website, but the ‘‘safe’’ approach of avoiding all these drugs altogether, may deprive many CMT patients of clinically important treatments. A different approach was recently suggested by Weimer and Podwall (2006), who tried to stratify the risk of potentially neurotoxic drugs, according to published reports and data from the CMT North American database, which contains additional entries on drug exposure of CMT patients. We recently encountered a 40-year-old man who developed severe motor weakness resembling GuillainBarré syndrome after having received just two 2 mg doses of vincristine as part of a lymphoma regimen. Only after this event did he recall a family rumor regarding the presence of a hereditary neuropathy. He was switched to a non–vinca containing chemotherapeutic protocol and gradually improved to baseline. He and his family members were evaluated clinically and electrophysiologically and found to have an autosomaldominant demyelinating polyneuropathy. Genetic testing confirmed the diagnosis of CMT type 1A. The family history revealed the presence of an older brother who 2 years earlier had been exposed to cisplatin and experienced severe, irreversible deterioration of his neurological function. We report a 53-year-old man (patient YL) who developed cisplatin aggravation of CMT. As a young person, he was always last to arrive during long hikes, but this was attributed to orthopedic problems related to his pes cavus. In September 2000, right testicular painless swelling appeared. Orchiectomy confirmed embryonal carcinoma with a focus of mature cartilage tissue, invasion to the spermatic cord base, and staining for CD-30 but not for alfa fetoprotein and beta HCG. Serum alfa fetoprotein and beta human chorionic gonadotropin and systemic imaging were normal. With the diagnosis of high-risk (embryonal carcinoma predominant) stage I testicular nonseminomatous germ cell tumor, the patient was given two courses of adjuvant chemotherapy, consisting of cisplatin 20 mg/m2 days 1–5, etoposide 100 mg/m2 days 1–5, and bleomycin 30 mg days 2, 9, and 16. Treatment tolerance was poor, with severe general weakness and fatigue and an episode of neutropenic fever. Within days after the second course, he developed paresthesias in the feet and fingers, sensory ataxia requiring support Address correspondence to: Itzhak Wirguin, MD, Department of Neurology, Soroka Medical Center, Ben-Gurion University, P.O. Box 151, Beer-Sheva 84101, Israel. Tel: þ972 86400660; Fax: þ972 86403660; E-mail: wirguin@bgu.ac.il Journal of the Peripheral Nervous System 12:139–141 (2007)

A Patient with Werner's Syndrome and Erythroleukemia: Just Coincidence?

Werners syndrome is a rare clinical entity and approximately 150 cases have been reported in the medical literature. Werners syndrome, inherited by autosomal recessive transmission, is characterized primarily by a short stature, premature greying and balding, trophic ulceration of the legs, diabetes mellitus and hypogonadism. These features combine to present a picture of adult progeria. In this brief report we describe a 51-year-old Bedouin male with Werners syndrome, diagnosed as erythroleukemia (AML-6), and presenting as acute pancytopenia. The patient died two months after diagnosis. This is a rare case of erythroleukemia in a patient with Werners syndrome. We survey current knowledge of the cytogenetic pathogenesis of Werners syndrome and erythroleukemia, and attempt to explain the possible link between these two rare syndromes.

Risk Factors Affect Long-Term Compliance to Coumadin Treatment (Self-Reporting)

Abstract Low compliance to a prescribed Coumadin treatment can result in negative health outcomes. In this study we aimed to evaluate risk factors affecting patient compliance to Coumadin. For this purpose, two study phases were performed: Phase 1: a retrospective eight-year follow-up of databases from health care services; and Phase 2: a cross-sectional study with telephone interviews. A Total Compliance Index was constructed using the number of Coumadin purchases (40%), international standardised ratio (INR) tests (40%), and average INR values (20%). Multiple models for the Total Compliance Index were constructed using socio-demographic, treatment-related, and health care utilisation variables, use of drugs, patient-physician relationships and patient’s quality of life. 78.5 ± 3.4% of patients in the total population were non-compliant in the retrospective phase of the study, and 53.2% in the second, cross-sectional phase. Total Compliance Index was significantly associated with older age, number of doctor visits, and drugs from group C. We suggest that the Total Compliance Index for other drugs can be utilised as well.

Debulking Surgery for Patients with Diffuse Large B-cell Non-Hodgkin's Lymphoma

Chemotherapy and radiotherapy have been the principal modalities of treatment for diffuse large B-cell non-Hodgkins lymphoma (B-NHL) for over 30 years. Various treatment regimens have been designed over the years to try to increase response and cure rates. The role of surgery has been generally restricted to defined and limited situations including diagnostic tissue biopsies and treating abdominal emergencies such as organ rupture or perforation. We present two cases of refractory B-NHL, where surgery was used as a part of stepwise and multi-modal treatment with curative intent. In both cases, the treatment approach included standard dose chemotherapy, eradication of residual mass by surgery, high dose chemotherapy (HDC) with stem cell support and posttransplantant immunotherapy. Currently, 2 years after completing the therapy, both patients are well with no evidence of active disease. Based on our experience with 2 patients we believe that in specific cases of residual chemo-resistant lymphomatous mass, surgery should be considered as a part of a multimodal approach.