Dorit Blickstein

Serum CA 125 as a Prognostic factor in non-Hodgkin's lymphoma

Cancer antigen 125 (CA 125) is a glycoprotein expressed in normal tissues originally derived from coelomic epithelia such as peritoneum, pleura, pericardium, fallopian tubes and endometrium. Serum CA 125 levels are elevated in various benign and malignant conditions that involve stimulation of these tissues. Although elevated levels have been reported in patients with non-Hodgkins lymphoma (NHL), its role as a prognostic factor remained uncertain. In this study, serum CA 125 levels were measured prospectively in 108 consecutive patients with NHL: at diagnosis in 106, in remission in 39 and at relapse in 7. Levels were elevated in 43% at diagnosis. This finding was associated with advanced disease stage, bulky tumors, bone marrow involvement, extranodal disease (in stages III and IV), occurrence of B symptoms, pleural or peritoneal effusions, high serum LDH levels, high serum β2 microglobulin (β2-M) levels, elevated International Prognostic Score, poor performance status and partial or no response to treatment. No difference in CA 125 level was found between the indolent and aggressive lymphomas. Serum CA 125 levels at diagnosis had strong association with event-free and overall survival (<formula><italic>p</italic>=0.01</formula> and 0.003, respectively), with the patients with increased levels having worse survival. Patients with high CA 125 levels at diagnosis who achieved remission showed a significant decrease in CA 125 levels in remission. In conclusion, CA 125 is not only a reliable marker for staging and assessing tumor activity in NHL, elevated levels are also predictive of decreased survival.

Primary lymphoma of the breast: unusual presentation of breast cancer

OBJECTIVE To investigate 4 cases of primary lymphoma of the breast and review previous studies in a search for any preoperative characteristics that could assist the diagnosis of lymphoma of the breast. DESIGN Retrospective study. SETTING University hospital, Israel. SUBJECTS 4 women. MAIN OUTCOME MEASURES Accurate diagnosis before operation. RESULTS No special characteristics for early diagnosis of primary malignant lymphoma of the breast were found. The predominant involvement of right breast in primary lymphoma of the breast should be noted. CONCLUSIONS Even though primary lymphoma of the breast is rare, there are no laboratory or imaging signs of early diagnosis. Excisional biopsy or Tru-cut biopsy are the only correct methods of diagnosis.

Significance of BCR-ABL Transcripts in Bone Marrow Aspirates of Philadelphia-Negative Essential Thrombocythemia Patients

Philadelphia-negative (Ph-neg) essential thrombocythemia (ET), polycythemia vera (PV) and idiopathic myelofibrosis (IMF) form a syndrome of related chronic myeloproliferative disorders (MPD) characterized by expansion of one or more of the hematopoietic progenitors. Based on our previous finding of BCR-ABL transcripts in bone marrow aspirates of 12/25 Ph-neg ET patients, we have expanded our study up to 40 patients. Here we describe the rational for performing this study and report 19 of 40 patients who have BCR-ABL transcripts in their BM, 11 of them carry b3a2 and 8 carry b2a2. The two groups, BCR-ABL positive and negative, were completely identical with regard to clinical characteristics and laboratory data. We also report preliminary results of our attempt to examine concordance or discordance of BCR-ABL expression in the peripheral blood and bone marrow of Ph-neg ET patients.

Association between alopecia and response to chemotherapy in patients with hodgkin lymphoma

Alopecia and bone marrow suppression are prominent effects of doxorubicin-containing chemotherapy. The aim of the study was to validate our preliminary clinical observation that the lack of alopecia in Hodgkin lymphoma patients may predict poor response to chemotherapy and low rate of bone marrow suppression. Sixty-six patients with Hodgkin lymphoma were reviewed. They were treated between 1991 and 2001 with at least 4 courses of doxorubicin-containing chemotherapy (MOPP/ABV or ABVD) in 2 university-affiliated hematology departments. Thirty-four patients exhibited complete or near complete alopecia, and 32 retained their hair or had only minimal hair loss. The 2 groups were compared by response to treatment and episodes of bone marrow suppression. Alopecia was associated with a high rate of remission (OR 8.48, 95% CI 2.77-25.95), episodes of neutropenia (OR 3.55, 95% CI 1.28-9.84), leukopenia (OR 1.83, 95% CI 0.68-4.92), delays in scheduled treatments (OR 1.61, 95% CI 0.607-4.30), or number of courses with dose reduction (OR 1.63, 95% CI 0.56-4.74). Significantly more patients with alopecia had at least 1 of these parameters (88% versus 62%, P = 0.015; OR 4.50, 95% CI 1.27-15.94). In conclusion, in patients with Hodgkin lymphoma treated with doxorubicin-containing chemotherapy, the absence of alopecia may predict poor response to treatment along with fewer episodes of bone marrow suppression. The absence of alopecia in such patients should alert clinicians to the possibility of treatment failure.

Detection of methylated ABL1 promoter in philadelphia-negative myeloproliferative disorders

Aberrant methylation of tumor-suppressor gene promoter regions may play a causal role in the pre-neoplastic stage of cancer progression. In chronic myeloid leukemia, changes in the methylation status of the CpG-rich islands at several sites in the proximal ABL1 promoter (Pa) on the Philadelphia (Ph)-chromosome have been observed. It remains unclear if the Pa methylation precedes the translocation event (t9;22) that generates the Ph-chromosome or if Pa methylation is a stochastic event in a progenitor cell which will later acquire other mutations, namely t9;22. The present study was conducted to answer two questions: What is the methylation status of Pa in patients with Ph-negative myeloproliferative disorders (MPD)? Can the study of methylation in patients with Ph-negative MPD shed light on the initial events associated with the translocation? To probe CpG methylation, we used two methodologies; site-methylation-sensitive restriction enzyme assay and methylation-specific PCR analysis following modification of genomic DNA by bisulfite. Results showed that 22 of the 97 patients with Ph-negative MPD expressed BCR-ABL transcripts. Seven of the 97 patients possessed methylated Pa, but only 2 of them expressed BCR-ABL transcripts. In some of the patients, Pa methylation was a dynamic event. In conclusion, aberrant methylation in Ph-negative MPD could be an initial event triggering the occurrence of the t9;22 translocation and its clinical expression. These findings may shed light on the pathogenesis and progression of MPD.

Levels of proteins C and S do not decline subsequent to first line chemotherapy in lymphoma patients

Thromboembolic complications and decrease in protein C and S have been observed in patients while receiving combination chemotherapy for breast cancer. We investigated whether initial cytotoxic treatment of non‐Hodgkins lymphoma (NHL) and Hodgkins disease (HD) is also associated with changes in these anticoagulant parameters. For this purpose 25 patients with intermediate to high grade NHL and seven with HD, undergoing primary treatment with cytotoxic drugs were evaluated at three time‐points: pre‐therapy, mid‐therapy and post‐therapy. In contrast to the breast cancer patients, no significant changes in protein C, protein S and antithrombin III levels were observed in the NHL patients during the various stages of therapy. However in HD patients, the mean protein C values had a tendency to be higher at mid‐therapy compared to pre‐therapy and protein S levels had a tendency to be higher at mid‐therapy compared to post‐therapy. In lymphoma patients receiving primary cytotoxic treatment we did not find changes in anticoagulant parameters that can explain a chemotherapy‐induced hypercoagulable state, as has been reported in breast cancer patients.

Thrombocytosis Associated with Enzyme Replacement Therapy in Gaucher Disease

We describe a patient with an intact spleen and moderately severe symptoms of Gaucher disease in whom, after initiation of (low-dose) enzyme replacement therapy (ERT), thrombocytosis (720 × 109/l) was documented. Checking the International Gaucher Registry database revealed that this patient is the only nonsplenectomized patient of more than 1,000 treated patients to experience ERT-induced thrombocytosis. Platelet counts dropped immediately after the discontinuation of ERT.

Attempted suicide with rivaroxaban.

Dear Editor, A 47-year-old womanwas admitted to the emergency room 1.5 h after attempting suicide with 400 mg (20 tablets) rivaroxaban, prescribed for left leg deep vein thrombosis and a background of combined thrombophilia (heterozygote for factor V Leiden and low protein S level). The patient suffered from chronic severe iron deficiency anemia but refused any treatment. The patient was fully conscious, blood pressure 128/73 mmHg, heart rate 73 bpm, temperature 36.7 °C. Physical examination revealed no evidence of bleeding or wet purpura. Admission laboratory analyses included international normalized ratio (INR) 2.5, partial thromboplastin time (PTT) 54.8 s (normal up to 40 s), creatinine 0.65 mg/dl, normal liver enzymes, hemoglobin 6.3 g/dl, MCV 56 fl, and platelets 259 K/μl. She was treated with nasogastric lavage followed by 50 g of activated charcoal to reduce continuing drug absorption. Admission chromogenic anti-Xa assay using rivaroxaban calibrator and expressed as rivaroxaban plasma concentration was 691.9 ng/ml (mean therapeutic level expected 2 h after ingestion of 20mg is 270 ng/ml, and upper limit is 419 ng/ml). A day later, the plasma level of rivaroxaban decreased to 59.1 ng/ml, the INR normalized (1.07) as well as the PTT (25.6 s). At 36 h after ingestion, the plasma level of rivaroxaban was 0.0 ng/ml. Because of severe symptomatic anemia without bleeding, the patient received one unit of packed red blood cells with resultant hemoglobin increase to 8.3 g/dl. The patient was discharged in general good health and psychiatric condition after 3 days, with resumption of rivaroxaban 20 mg/day, iron therapy, and repeated psychiatric consultation. Rivaroxaban is an oral direct factor Xa inhibitor, which is rapidly absorbed and reaching maximal plasma level within 2–4 h. At present, there is no available specific antidote for an overdose, and prothrombin complex concentrate (PCC, activated PCC) or rFVIIa is recommended in case of overt bleeding [1]. A new but not yet approved antidote, andexanet alfa, shows effectiveness in reversing factor Xa inhibitors and should be considered in a life-threatening bleeding event [2–4]. Of note, all potential treatments are costly and may cause complications. Although an overdose was expected to cause overt bleeding, three other previous reports [5–7], as well as our case, did not describe any overdose complications. However, in one case [5], PCC was given due to concern of bleeding. In contrast to our case, others [7] measured plasma rivaroxaban concentration only 3 days after admission. More recently, Spiller et al. [8] described 223 cases reported to eight poison centers. They concluded that bleeding after Xa inhibitor ingestion is uncommon, and routine coagulation tests (INR, PT, PTT) are not reliable as predictors of bleeding risk. However, cases of larger acute ingestions in suicide attempt may result in significant anticoagulation. Our case shows that with adequate renal and liver function, available laboratory methods, and proper treatment with activated charcoal, fast clearance of rivaroxaban can be expected without bleeding complications. * Dorit Blickstein doritblickstein@gmail.com