Primary thrombocythemia and pregnancy: Treatment and outcome in fifteen cases

Pregnancy in patients with primary thrombocythemia (PT) is reported to be often complicated by recurrent abortion and fetal growth retardation. Fifteen pregnancies in nine patients with PT are reported. Nine pregnancies had a good outcome, with the birth of a healthy infant. There were two spontaneous abortions and three intrauterine deaths. One pregnancy was electively terminated after extensive thrombosis in the splanchnic district requiring surgical entero-resection. In five pregnancies the mother received no treatment; in ten pregnancies acetylsalicylic acid (ASA) was prescribed to the mother as soon as she was found pregnant, subcutaneous heparin was added from the middle trimester in seven cases. In patients treated with ASA and subcutaneous heparin pregnancies had a good outcome. Administration of ASA and heparin during pregnancy appears to improve the outcome in patients with PT and can prevent severe maternal complications, but requires close monitoring. © 1996 Wiley-Liss, Inc.     

Dose-dense adjuvant chemotherapy in HER2-positive early breast cancer patients before and after the introduction of trastuzumab: Exploratory analysis of the GIM2 trial

Dose-dense adjuvant chemotherapy is standard of care in high-risk early breast cancer patients. However, its role in HER2-positive patients is still uncertain. In this exploratory analysis of the GIM2 trial, we investigated the efficacy of dose-dense chemotherapy in HER2-positive breast cancer patients with or without exposure to trastuzumab. In the GIM2 trial, node-positive early breast cancer patients were randomized to receive four cycles of (fluorouracil)epirubicin/cyclophosphamide followed by four cycles of paclitaxel administered every 2 (dose-dense) or 3 (standard-interval) weeks. After approval of adjuvant trastuzumab, protocol was amended in April 2006 to allow use of trastuzumab for 1 year after chemotherapy completion in HER2-positive patients. The efficacy of dose-dense chemotherapy in terms of disease-free survival (DFS) and overall survival (OS) was assessed according to HER2 status and trastuzumab use. Out of 2,003 breast cancer patients, HER2 status was negative/unknown in 1,551 patients; among the 452 patients with HER2-positive breast cancer, chemotherapy alone or followed by trastuzumab was given to 320 and 132 patients, respectively. Median follow-up was 8.1 years. No significant interaction between HER2 status, trastuzumab use and chemotherapy treatment was observed for both DFS (p = 0.698) and OS (p = 0.708). Nevertheless, there was no apparent benefit in the HER2-positive group treated with trastuzumab (DFS: HR, 0.99; 95% CI 0.52–1.89; OS: HR, 0.95; 95% CI 0.37–2.41). Although dose-dense chemotherapy was associated with a significant survival improvement in high-risk breast cancer patients, its benefit appeared to be smaller (if any) in patients with HER2-positive disease who received adjuvant trastuzumab.     

Prevalence of Ischemia on Myocardial Perfusion Scintigraphy of Pre- and Postmenopausal Women

Background

In postmenopausal women, the presence of risk factors for coronary artery disease (CAD) increases. However, the difference in prevalence of ischemia between pre- and postmenopausal women with multiple risk factors for CAD has not been well established.

Objectives

To compare the prevalence of ischemia on Tc^99m-sestamibi myocardial perfusion scintigraphy (MPS) in pre-and postmenopausal women, and to evaluate whether menopause can be considered an independent risk predictor of ischemia in women with multiple risk factors for CAD.

Methods

This study retrospectively assessed 500 MPS of pre- and postmenopausal women with multiple risk factors for CAD. Statistical analysis was performed by using Fisher exact test and univariate and multivariate analysis, a p value ≤ 0.05 being considered significant.

Results

Postmenopausal women represented 55.9% of the sample; 83.3% were hypertensive; 28.9%, diabetic; 32.1%, smokers; 25%, obese; 61.2% had high cholesterol levels; and 34.3% had known CAD. Postmenopausal women were more often hypertensive, diabetic and dyslipidemic, and had lower functional capacity on exercise testing (p = < 0.005). The presence of ischemia on MPS did not significantly differ between the pre- and postmenopausal groups (p = 0.395). The only variable associated with ischemia on MPS was known CAD (p = 0.004).

Conclusion

The results suggest that, in women with multiple risk factors for CAD, menopause was not an independent predictor of ischemia on MPS. Those data support the idea that the investigation of ischemia via MPS in women with multiple risk factors for CAD should begin prior to menopause.     

Epstein-Barr virus lymphoproliferation after bone marrow transplantation

We review 15 cases of secondary B-cell lymphoproliferative disorders that occurred among 2,475 patients who received allogeneic bone marrow transplants (BMTs) at the Fred Hutchinson Cancer Research Center (Seattle) between 1969 and 1987. The histopathologic findings in 14 of the 15 patients spanned a wide spectrum of lymphoproliferative lesions. One patient had features characteristic of angioimmunoblastic lymphadenopathy. Epstein-Barr virus (EBV) genomic sequences were identified by Southern blot analysis in each of the 13 patients evaluated. Ten of the 12 lesions evaluated originated in donor cells. In two patients, who had mixed chimerism after transplantation, the lesions originated in host cells. The combined evidence from immunoglobulin light chain staining and the analysis of immunoglobulin heavy chain gene rearrangement indicated that the lesions in most patients represented polyclonal proliferations that gave rise to clonal subpopulations. The results indicate an overall actuarial incidence of 0.6% for this complication in BMT recipients. Anti-CD3 monoclonal antibody (MoAb) treatment of acute graft-v-host disease (GVHD) and T cell depletion of the donor marrow were statistically significant risk factors, and GVHD appeared to play a contributing role, particularly in the setting of human leukocyte antigen (HLA) disparity. Two patients had no identifiable risk factors. Prophylaxis or treatment with acyclovir had no detectable effect in the patients; all but two died with uncontrolled lymphoproliferation.     

Hepatitis C virus genotypes in a non-cirrhotic Italian population with chronic hepatitis C: correlation with clinical, virological and histological parameters. Results of a prospective multicentre study

To identify correlations between the distribution of hepatitis C virus (HCV) genotypes and demographic, pathological and virological parameters of HCV-infected patients, we prospectively recruited 650 patients with biopsy-proven chronic hepatitis C without histological aspects of cirrhosis; none had been treated with antiviral therapy. Data regarding gender, age, mode of HCV transmission, alanine aminotransferase (ALT) and HCV RNA levels, immunoglobulin M (IgM) anticore values, liver histology and histological activity were obtained from each patient and correlated on multivariate analysis with infecting HCV genotype. Fifty-five per cent of the patients were infected with HCV genotype 1, 20% with HCV genotype 2, 18% with HCV genotype 3 and 7% with HCV genotype 4. Non-transfusional HCV transmission, low ALT levels, IgM anticore reactivity and a low histological grading score were independent variables associated with HCV genotype 1. Older age, female gender, post-transfusional transmission and a high histological grading score were related to HCV genotype 2, whilst younger age, history of current/previous drug abuse, high ALT values, low IgM anticore reactivity and high viraemic levels were associated with HCV genotype 3. History of illicit use of intravenous drugs and low HCV RNA levels were the only independent variables correlated with HCV genotype 4. Genotype 1 remains predominant in Italy but the prevalence of HCV genotypes is changing in relation to age and mode of transmission: Italian patients with HCV genotype 3 are younger and exhibit higher levels of ALT and HCV RNA than patients with other genotypes.     

Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression

Fifty-two of 175 (30%) survivors of allogeneic marrow transplantation developed chronic graft-versus-hose diseases (GVHD). Five with limited chronic GVHD had an indolent clinical course with involvement of only the skin and liver. Forty-seven with extensive chronic GVHD had an unfavorable multiorgan disorder that resembled several autoimmune diseases. Thirteen patients with extensive disease (group I) were not treated and only 2 survive with Karnofsky scores >- 70%. Mortality resulted from infections and morbidity from sica syndrome, pulmonary and hepatic insufficiency, scleroderma-like skin disease, and contractures. Another 13 (group II) received a median of 8 mo prednisone and/or a brief course of antithymocyte globulin, and 3 survive without disability. The other 21 (group III) were treated with a combination of prednisone (1.0 mg/kg/q.o.d.) and either cyclophosphamide, procarbazine, or azathioprine (all 1.5 mg/kg/day) for a median of 13 mo. Combination therapy was well tolerated with only modest myelotoxicity. Fifteen in group III had a good and 4 a fair response to treatment while 2 with no response died. Azathioprine and prednisone was the most effective regimen. All therapy has been discontinued in 12 group III patients: GVHD returned in 5 (including 2 who died in spite of retreatment) while 7 remain free of GVHD for a median of 11 (range 6-30) mo observation. Only I group III survivor is disabled and 16 of the original 21 are alive 2-4 yr after transplant with Karnofsky scores of 70%-100%. Thus, combination immmunosuppression appears to favorably affect and, in some cases, premanently arrest the adverse natural course of extensive chronic GVHD.     

Marrow transplantation with or without donor buffy coat cells for 65 transfused aplastic anemia patients

Sixty-five multiply transfused patients with severe aplastic anemia were given cyclophosphamide followed by grafts anemia were given cyclophosphamide followed by grafts from HLA-identical siblings. The effect of the administration of viable donor buffy coat cells following the marrow inoculum was evaluated with regard to graft rejection and survival. Results in 43 patients so treated are presented along with those in 22 concurrent patients given marrow alone. Most patients given buffy coat had positive in vitro tests of sensitization indicating a high risk for graft rejection, while all but one of the patients given marrow alone had negative tests. Thirty of the 43 (70%) patients given marrow and buffy coat are alive between 10 and 61 mo (median 36) after grafting; 4 died after graft rejection and 6 with acute or chronic graft-versus-host disease (GVHD). Eleven of the 22 (50%) patients given marrow alone are alive between 29 and 65 mo (median 52); 7 died after graft rejection and 3 with GVHD. The addition of buffy coat cell infusions to the marrow inoculum reduced the risk of rejection and increased survival in the currently reported transfused patients when compared to patients grafted before 1976. However, there was an increased risk of chronic GVHD. Recipients of marrow from female donors survived slightly better (73%) than recipients of male marrow (58%).     

The effects of recombinant-DNA-derived interferons on the growth of myeloid progenitor cells

Interferons (IFNs) have been shown to have significant effects on hematopoietic cell growth. Previous studies defining these effects have utilized mouse and human alpha-, beta-, and gamma-IFN isolated from supernatants of stimulated cells. Despite purification, the possible presence of other lymphokines and soluble factors remains a concern. In this study, the effects of gene-cloned alpha- and gamma-IFN on colony- forming units of granulocyte/macrophage (CFU-GM) progenitors cultured from the peripheral blood of normal volunteers were examined. In addition, blast cell colonies from one patient with acute myelogenous leukemia (AML) were studied. The growth of normal CFU-GM and AML blast cell colonies was inhibited in a dose-dependent manner by gamma- and alpha-IFN. gamma-IFN was ten to 100 times more potent than alpha-IFN in that this species of IFN reduced colony formation by greater than 50% at concentrations of less than 15 antiviral U/mL. The effects of gamma- IFN were neutralized by a monoclonal antibody specific for gamma-IFN. These in vitro studies indicate that human gamma-IFN may be an important modulator of myelopoiesis. Although these data indicate a possible efficacy of gamma-IFN in the treatment of AML, the in vitro results should be considered for their in vivo significance.     

Specific lymphokine responses in cervical nodes of patients with laryngeal cancer

The role of lymphokines in modulating the immune response in patients suffering from neoplastic disease is still controversial. Recent studies indicate that in patients with head and neck cancer, a decrease in LIF (leukocyte migration inhibiting factor) production is usually present in advanced disease. In this study, the authors investigate:

• 1 the LIF production in lymphocytes derived from the peripheral blood and cervical nodes of patients with laryngeal carcinoma by using an autologous pattern (i.e., for each patient, the specific LIF production was challenged by means of an autologous cell extract derived from his own tumor);
• 2 the influence of histologically confirmed cervical node metastases on LIF production.

Our results indicate that:

• 1 There is a significant decrease in LIF production in patients with histologically proven cervical node metastases as compared to patients with no metastatic foci.
• 2 The decrease of LIF production is related to the presence of mononuclear adherent cells. When the latter are removed, there is a significant reversal of specific LIF suppression.

The possible meaning of the data is discussed.     

Evaluation of blocking mechanisms against immunological responses in patients with laryngeal carcinoma

The specific tumor-induced leukocyte inhibition factor (LIF) production in laryngeal cancer patients has been investigated before and after the removal of adherent cells in order to evaluate the existence of a suppressor activity; 20 patients served as subject. The LIF production, after challenging the lymphocytes with 3MKC1 autologous tumor extracts, was significant in 12 patients and showed a further significant increase after the removal of adherent cells. In 3 patients with no previous significant LIF production, there was a conversion to significance when the adherent cells were removed. The other patients did not show any significant variation. These data seem to suggest the existence of a suppressor activity exerted by adherent cells in laryngeal cancer patients on LIF production.