Delayed pulmonary toxicity syndrome following high-dose chemotherapy and bone marrow transplantation for breast cancer

We have intensely followed 45 consecutive women who underwent high-dose chemotherapy (cyclophosphamide/cisplatin/BCNU) and autologous bone marrow transplant (HDC/ABMT) for primary breast cancer with pulmonary function testing and computed tomography at regular intervals up to 126 wk (median follow-up, 72 wk). Our results show a high incidence of interstitial pneumonitis requiring steroids (64%), but no deaths due to pulmonary toxicity. The DL(CO) reaches a nadir of 58.2 +/- SEM 3.4 (expressed as a percent of baseline value) 15-18 wk following HDC/ABMT, and marginally improves with time. To a much lesser extent, vital capacity is reduced with a parallel drop in FEV1, suggesting mild restrictive changes without significant obstruction. Patients who develop pulmonary symptoms of cough or dyspnea have a corresponding significantly greater and earlier decline in DL(CO). Chest computed tomography was neither sensitive nor specific for diagnosing pulmonary toxicity. For patients who received steroids for pulmonary toxicity, there was a subsequent improvement in DL(CO) of 17.1% (p = 0.0001). Because our patients do not fit with the recent definition of idiopathic pulmonary syndrome (IPS), we propose the term delayed pulmonary toxicity syndrome (DPTS) to better describe the milder form of lung toxicity seen in our patient population. We were unable to correlate the severity of DPTS with age, tobacco use, baseline pulmonary function, or systemic exposure to BCNU, cyclophosphamide, or cisplatin. These data suggest that factor(s) other than, or in addition to, chemotherapy systemic exposure can contribute to DPTS. Furthermore, early identification and institution of systemic corticosteroids may improve lung function.     

Effect of chemotherapy for acute myelogenous leukemia on hematopoietic and fibroblast marrow progenitors

AIMS: The generation and characterisation of a monoclonal antibody that specifically recognises the mdr-1 encoded protein, P-glycoprotein (P-170), on routinely processed formalin fixed, paraffin wax embedded tissue sections. METHODS: The monoclonal antibody, designated 6/1C, was produced following a combination of in vivo and in vitro immunisation regimens in Balb/c mice with a synthetic 12 amino acid peptide that corresponds to amino acids 21-32 (believed to be intracellularly located) of P-170 and has insignificant homology with the mdr-3 encoded P-170. Antibody 6/1C was characterised by western blotting and immunocytochemistry on cytospins of paired multidrug resistant or sensitive cell lines, including mdr-1 and mdr-3 transfected cells, and by immunohistochemistry on normal and malignant formalin fixed paraffin wax embedded tissue sections. RESULTS: Antibody 6/1C showed a single band at 170 kDa on western blots of multidrug resistant cell lysates and mdr-1 transfected cell lysates that was absent on similar preparations of drug sensitive cells and mdr-3 transfected cells. Immunocytochemical studies on cytospins of multidrug resistant cells and mdr-1 transfected cells revealed strong inner plasma membrane/cytoplasmic staining. Staining was negligible on drug sensitive cells and cells transfected with the mdr-3 gene. Immunohistochemical studies on formalin fixed, paraffin wax embedded normal adult kidney, liver, and breast tissue and a range of fetal tissues exhibited staining patterns of a variety of secretory surfaces consistent with documented mdr-1 specific staining. Specific staining of malignant cells in similarly treated sections of breast tumours was seen also with antibody 6/1C. Staining on paraffin wax embedded tissue with this antibody did not require any pretreatment of tissue sections. CONCLUSIONS: This new monoclonal antibody, chosen for its specificity with the mdr-1 encoded P-170 and its reactivity on routinely fixed paraffin wax embedded tissue samples without pretreatment, appears to be useful for the investigation of P-170 in archival material. It is especially useful for retrospective studies on pretreatment and post-treatment tissue sections, and could help establish when and how rapidly mdr-1 associated drug resistance develops during chemotherapeutic regimens. Immunohistochemical assessment of P-170 expression in many cancers has potential for diagnostic purposes and may influence the choice of chemotherapeutic drugs used in the treatment of refractory tumours.     

Effect of allowing for ethnic group in prenatal screening for Down's syndrome

We conducted a study to investigate ethnic group differences in levels of serum markers used in screening for Down's syndrome [serum alpha-fetoprotein (AFP), unconjugated oestriol (uE3), total human chorionic gonadotrophin (hCG), free alpha- and free beta-hCG, and dimeric inhibin-A], to estimate the extent to which maternal weight differences between ethnic groups explain these differences, and to estimate the effect of adjusting for ethnic group and maternal weight on screening performance. Serum measurements were taken from women who were screened prenatally for Down's syndrome. AFP, uE3, and hCG concentrations were available from 9462 white, 4215 black, and 4392 South Asian women with singleton pregnancies without Down's syndrome or neural tube defects between 15 and 22 weeks' gestational age. Frozen serum samples were available from a subset of 922 white, 449 black, and 135 South Asian women and were used for measurement of free alpha-hCG, free beta-hCG, and inhibin. Values were expressed as multiples of the median (MOM) for women of the same gestational age. There were statistically significant differences in the serum marker levels between ethnic groups that were not explained by differences in maternal weight. The main differences were found in black women compared with white women; black women had serum AFP levels 22 per cent higher (95 per cent confidence interval 20-24 per cent), total hCG levels 19 per cent higher (16-22 per cent), and free beta-hCG levels 12 per cent (3-21 per cent) higher. The other differences were less than 10 per cent. Adjusting for ethnic group only had a small estimated effect on screening performance: a maximum of about 0.5 per cent extra detection at a 5 per cent false-positive rate. At a fixed risk cut-off level, the false-positive rate will not be materially different between different ethnic groups. Adjusting serum markers for ethnic groups improves Down's syndrome screening performance to a very small extent. It is worthwhile because of its established value in AFP screening for open neural tube defects.     

Effect of routine screening for Down's syndrome on the significance of isolated fetal hydronephrosis

OBJECTIVE: To determine the risk of Down's syndrome in fetuses with isolated hydronephrosis at 18-23 weeks in an unselected general population after routine screening for Down's syndrome, using first trimester nuchal translucency measurement and second trimester maternal serum biochemistry. POPULATION: All pregnant women undergoing a routine 18-23 week ultrasound scan, from a population who had been offered screening for Down's syndrome. SETTING: A district general hospital serving a low risk obstetric population. METHODS: Prospective study of all routine 18-23 weeks ultrasound scans. The prevalence of isolated hydronephrosis and Down's syndrome was determined and the relative risk for Down's syndrome was calculated for different ultrasound findings. RESULTS: 10,971 women were scanned at 18-23 weeks during the study period. Down's syndrome was diagnosed in 14 of 20 cases before this stage using first trimester nuchal translucency measurement and second trimester maternal serum biochemistry. Isolated fetal hydronephrosis was diagnosed in 423 pregnancies (3.9%); none of these pregnancies were affected by Down's syndrome. The relative risk for Down's syndrome was 0.18 (95% CI 0.06-0.53) for women with a normal scan (n = 9983). When multiple ultrasound markers were found (n = 565), the relative risk for Down's syndrome was 2.00 (95% CI 0.18-22.10) and 9.00 (95% CI 1.14-71.30) for all other aneuploidies. CONCLUSION: The finding of isolated fetal hydronephrosis does not significantly increase the age-related risk for Down's syndrome. The presence of multiple ultrasound markers is associated with an increased risk of aneuploidies other than Down's syndiome. These findings are explained by the reduced prevalence of Down's syndrome as a result of prior screening and diagnosis of this condition.     

Effect of CDDP/5'-DFUR combination chemotherapy for advanced or recurrent gastric cancer

CDDP/5'-DFUR combination chemotherapy was performed on 17 patients with non-resected and recurrent gastric cancer (clinical stage were IVb in all patients). They were treated with 1,400 mg/m2 of 5'-DFUR on days 1-4 orally following by withdrawal 10 days, every 2 weeks repeatedly and 80 mg/m2 of CDDP (c. i. v., on day 5, every 4 weeks). This chemotherapy was performed for at least 2 courses on all patients. Eight of 17 patients achieved a partial response and the overall response rate was 47.1% (differentiated type 57.1%, undifferentiated type 45.5%). Response rates of each lesion were as follows: primary foci 42.9%, abdominal lymph nodes 57.1%, hepatic metastasis 60.0% and ascites 33.3%, respectively. Improvement of performance status was seen in 12 of 17 patients (70.6%). The overall median survival time was 227 days. The median outpatient period was 113 days. There was no high-grade toxicity over grade 2. Therapeutic toxicity of grade 2 was manifested as renal dysfunction (23.5%), nausea/vomiting (17.6%), leukopenia (5.9%) and anemia (5.9%). We evaluated the therapeutic effect by visual examination after completion of the second course. However, poor effect and high incidence of renal dysfunction were found in patients treated with this therapy over four times. Therefore, the maximum effect seemed to be revealed after completion of the fourth course. From the present study, CDDP/5'-DFUR combination chemotherapy seems to be effective for patients with high-grade advanced gastric cancer and improved their quality of life.     

Effect of preoperative chemotherapy on the outcome of women with operable breast cancer

PURPOSE: To determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies. PATIENTS AND METHODS: Women (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship between outcome and tumor response. RESULTS: There was no significant difference in DFS, DDFS, or survival (P = .99, .70, and .83, respectively) among patients in either group. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy (67.8% v 59.8%, respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P = .23). Outcome was better in women whose tumors showed a pCR than in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively; P < .0001), even when baseline prognostic variables were controlled. When prognostic models were compared for each treatment group, the preoperative model, which included breast tumor response as a variable, discriminated outcome among patients to about the same degree as the postoperative model. CONCLUSION: Preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology. Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases; however, knowledge of such a response provided little prognostic information beyond that which resulted from postoperative therapy.     

Effect of defibrination on tumor growth and response to chemotherapy

Other investigators have demonstrated fibrin deposition in tumors. Experiments were therefore designed to test whether systemic defibrination would alter tumor growth or tumor response to chemotherapy with cyclophosphamide. Defibrination with Ancrod, a venom extract of Agkistrodon rhodostoma, did not significantly affect tumor sensitivity to chemotherapy. Similarly, defibrination plus fibrinolytic therapy with streptokinase did not affect responsiveness to cyclophosphamide. Long-term defibrination did not affect tumor growth. These results suggest three possible interpretations: (a) the coagulation system may not be important in tumor growth and response to chemotherapy; (b) adequate clearing of fibrin from the tumor was not accomplished in our experiments; or (c) other factors such as platelet deposition may be involved and platelet function was not inhibited by the therapies used in our experiments.     

Nine-month chemotherapy for pulmonary tuberculosis

There is extensive favorable worldwide experience with short-course chemotherapy (SCC) for pulmonary tuberculosis. It has not yet been shown, however, that daily, unsupervised SCC would be efficacious in the United States, especially in large urban centers where compliance rates are poor and alcohol abuse is common. From January 1977 to February 1980, 75 patients began treatment using SCC combining isoniazid and rifampin for nine months, accompanied by ethambutol during the first 60 days. This report describes results achieved under "field conditions" with all medications self-administered except during the first few days of hospitalization. Forty-nine patients successfully completed this regimen. No patients failed chemotherapy during treatment and no relapses have occurred during follow-up through June 1981. There were no serious drug-related side effects. This study supports the results of similar studies conducted in other countries and provides further evidence that this regimen can be adopted more widely in this country.     

Initial chemotherapy for primary resectable large-cell lymphoma of the stomach

BACKGROUND: We aimed to evaluate the safety and effectiveness of a conservative approach with short-term chemotherapy with or without consolidation radiotherapy in primary resectable large-cell gastric lymphoma in patients not requiring emergency surgery at presentation. PATIENTS AND METHODS: Seventeen consecutive patients presenting with resectable primary large-cell lymphoma of the stomach not requiring immediate surgery were initially treated with chemotherapy with or without consolidation radiotherapy. Subtotal or total resection of the stomach was planned only as salvage treatment for those patients who failed locally, or as emergency surgery in instances of acute iatrogenic complications of treatment. Chemotherapy included four to six cycles of an anthracycline-containing regimen, and consolidation radiotherapy was planned on the entire stomach and surrounding lymph node areas for complete responders readily capable of compliance with a daily treatment schedule at our Institution. RESULTS: None of the patients in the present series experienced acute iatrogenic morbidity or mortality from local complications. After a median follow-up of almost six years, two patients failing first-line chemotherapy have died of progressive lymphoma, while 15 patients are well and currently disease-free. CONCLUSIONS: Up-front chemotherapy as initial treatment for primary gastric large-cell lymphoma appears to be a safe and effective treatment by which most patients can probably be spared surgical gastrectomy. Consolidation radiation therapy on the stomach can probably improve on the effectiveness of chemotherapy alone. More experience is needed to elucidate the prognostic factors, treatment-related long-term toxic effects and the feasibility of such a treatment administered outside of highly specialized institutions.     

Regional chemotherapy via the pulmonary artery for pulmonary metastases

Regional chemotherapy with Adriamycin via the pulmonary artery produces significantly higher tissue levels in the infused canine lobe than systemic administration. Seven patients with soft tissue sarcomas who had received the maximum dose of Adriamycin and had shown metastatic tumor recurrence to the lungs, received small doses of 10 to 20 mg of Adriamycin in the lobar arteries supplying areas with tumor via a Swan-Ganz catheter, temporarily occluding with its inflated balloon the infused artery. One partial objective regression was noted. A total of 56 injections of Adriamycin was given through individual lobar arteries in the seven patients. This preliminary experience indicates the feasibility and relative safety of the use of the pulmonary artery for regional chemotherapy of pulmonary malignant tumors and suggests further cautious exploration of this method.     

Myelodysplastic syndrome associated with immunoblastic lymphadenopathy-like T-cell lymphoma: simultaneous clinical improvement with chemotherapy

A 75-year-old woman presented with anemia, lymphadenopathy, hepatomegaly and lingual tumor, but no constitutional symptoms. The laboratory data showed pancytopenia and polyclonal hypergammaglobulinemia. A bone marrow aspirate represented an apparent myelodysplastic syndrome (MDS) feature, specifically, refractory anemia with excess of blasts. A lymph-node biopsy revealed the disappearance of normal architecture, small arborizing blood vessels, large lymphoid cells with prominent cytoplasm (so-called pale cells) and a clonal proliferation of T-lymphocytes. The patient was diagnosed as having MDS associated with immunoblastic lymphadenopathy (IBL)-like T-cell lymphoma. She was subsequently treated with cyclophosphamide, adriamycin, vincristine and prednisolone for lymphoma which successfully induced a remission of not only the T-cell lymphoma but also the MDS. The case suggested that MDS might be a paraneoplastic complication of IBL-like T-cell lymphoma.     

Primary chemotherapy for early breast cancer

The use of primary chemotherapy represents a novel approach being used with increasing frequency in the management of early breast cancer. Many studies now testify to the usefulness of this modality in increasing the frequency of breast conservation. The acceptance of high-risk breast cancer as a systemic, and therefore predominantly medical rather than a surgical, disease suggests, however, that its role is likely to be far more reaching. While some trials have so far suggested the possibility of a survival benefit for this approach, definitive conclusions are not yet possible and await the final mature results from several large randomized studies. Even if such studies do not show a large extra benefit for primary chemotherapy over existing adjuvant treatment, the use of the primary tumour as an in vivo model of individual chemosensitivity and the identification of molecular markers as early predictors of response, suggest that this approach will become an integral part of the modern multidisciplinary management of early breast cancer.     

Treatment of diencephalic syndrome with chemotherapy: growth, tumor response, and long term control

The c-Jun N terminal kinases (JNKs) are members of the mitogen activated protein kinases family, which have been shown to be preferentially activated either by cytokines or stress stimuli. In this study we identify a selective and potent antisense oligonucleotide to RhoA (ISIS 17131) and investigate its effect on JNK activation induced by IL-1beta and H2O2 in A549 cells. The RhoA antisense oligonucleotide was able to inhibit JNK activation when A549 cells were stimulated by H2O2, but did not have any effect on IL-1beta induced JNK activation. Consistent with the idea that the phosphatidylinositol 3-kinase (PI 3-kinase) activates the small G protein exchange factors, H2O2 activated the PI 3-kinase. Additionally, Wortmannin, a potent inhibitor of the PI 3-kinase and phospholipase A2 (PLA2), and AACOCF3, also a PLA2 inhibitor, were able to inhibit JNK activation induced by H2O2, but they had no effect on JNK activation when stimulated by IL-1beta. These results suggest that, in A549, IL-1beta and H2O2 induce JNK activation by two independent pathways.