Biomedical subjects
Publications and source records attributed to N Haim.
A 39-year-old male developed primary brain lymphoma 33 years after receiving scalp irradiation for tinea capitis. This is the first reported association between cranial irradiation during childhood and subsequent development of primary brain lymphoma.
A total of 30 consecutive patients with refractory or relapsing non-Hodgkin's lymphoma (NHL) were treated with a combination of dexamethasone, etoposide (VP-16), ifosfamide, and cisplatin (DVIP). In all, 9 subjects (30%) showed a partial response and 10 (33%) achieved a complete response (CR) lasting from 2.5 to 24+ months. Aggressive histology, no prior therapy with VP-16, a CR to previous chemotherapy, and a treatment-free interval of greater than 6 months prior to the present study were associated with the high CR rate. DVIP caused pronounced myelosuppression (median granulocyte nadir and median platelet nadir, 380/mm3 and 73.000/mm3, respectively), but no drug-related death occurred. We conclude that DVIP is an effective salvage combination, especially in aggressive NHL, that produces acceptable toxicity.
The negative predictive value (PV-) and positive predictive value (PV+) of gallium-67 scintigraphy and computed tomography (CT) were compared after treatment in 43 patients with Hodgkin disease and in 56 patients with non-Hodgkin lymphoma. The usefulness of these studies in predicting survival was also evaluated. In patients with Hodgkin disease, the PV- of Ga-67 scintigraphy was 0.84 and of CT was 0.88. The PV+ was 0.80 for Ga-67 studies and only 0.29 for CT. In patients with non-Hodgkin lymphoma, the PV- of Ga-67 scintigraphy was 0.84 and of CT was 0.80. The PV+ was 0.73 and 0.35, respectively. For both groups, the differences in disease-free survival between patients with negative and positive Ga-67 studies were significant (P less than .05 in Hodgkin disease and P less than .001 in non-Hodgkin lymphoma), but the differences were not significant for CT. These data show that, after treatment of patients with lymphoma, Ga-67 scintigraphy is a good predictor of clinical outcome and can be used beneficially in patient treatment.
48 patients with stage I-II low-grade non-Hodgkin's lymphoma were treated by radiation and/or chemotherapy between 1970 and 1986. The histologic types were diffuse lymphocytic well differentiated, eleven patients; nodular lymphocytic poorly differentiated, 28 patients; nodular mixed, nine patients. Complete remission was obtained in 45 patients (94%). Overall survival was 83% and 68% at five and ten years, respectively. Five and ten-year relapse-free survival of complete responders was 71% and 57%, respectively. Univariate analysis of potential prognosticators showed the following to significantly increase the survival rate: one or two sites of disease (p less than 0.01), stage I (p less than 0.02), age less than 65 years (p less than 0.02), complete excision of tumor mass (p less than 0.03), and the use of radiotherapy (p less than 0.02). The extent of radiotherapy field did not affect survival. Multivariate analysis by the stepwise proportional hazards model of Cox showed that the use of radiotherapy was the factor which significantly produced better survival figures (p less than 0.03). It is concluded that two thirds of stage I-II low-grade lymphoma patients are potentially curable; radiotherapy plays a major role in the management.
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Among 715 patients with non-Hodgkin's lymphoma referred to this oncology center between 1973-1989, there were 7 (0.9%) with primary lymphoma of the testis. The mean age was 55 (range 23-78). The presenting symptom in all the 7 was testicular mass or swelling. 6 of them underwent inguinal orchiectomy and 1 had a testicular biopsy. The pathological subtype of the lymphoma in all 7 was the diffuse large cell type. The disease stage was IE in 3, IIE in 3 and IVE in 1. Only 1 had bilateral testicular involvement. 6 were treated primarily with various combinations of chemotherapy and 1 by radiotherapy. 3 developed recurrent disease (2 treated primarily with chemotherapy and 1 by radiotherapy) and died 14, 19 and 27 months, respectively, after diagnosis. 3 are alive with no evidence of recurrent lymphoma. Follow-up in an additional patient has been too short for evaluation. Primary testicular lymphoma is a relatively rare form of extranodal lymphoma. It has a tendency to early systemic progression and is potentially curable by aggressive combination chemotherapy.
The course of vincristine-induced neuropathy was evaluated in 14 patients who developed muscle cramps during chemotherapy. Cramps were noticed between 3 days and 4 months after the initiation of vincristine and following a cumulative dose of 1-9.4 mg/m2 (median 3.1 mg/m2). All patients reported daytime cramps and only 4 experienced nocturnal cramps. The lower extremities were involved in 11/14 and the upper extremities in 10/14 patients. Duration of cramps ranged from 1 to greater than 9 months. Physical examination revealed signs of peripheral neuropathy in all patients. Cramps were the first symptom of neurotoxicity in 4 patients. Other symptoms were noted in all patients, but only 3 had motor manifestations other than muscle cramps. Although symptoms of neuropathy tended to persist for several months, a rapid symptomatic improvement was noticed after withdrawal of vincristine. We conclude that vincristine-induced muscle cramps are not necessarily associated with severe neurotoxicity and should not automatically indicate interruption of therapy.
Between 1973 and 1989, 739 patients with non-Hodgkin's lymphoma were referred here for treatment, of whom 10 (1.4%) had primary brain lymphoma (PBL) and 1 had acquired immunodeficiency syndrome (AIDS). There were 7 females and 3 males (mean age 58 years, range 35-77). Duration of symptoms ranged from several days to 3 weeks. The presenting symptoms were secondary to increased intracranial pressure. Computerized tomography (CT) performed in 8 revealed a solitary lesion in 7. Other CT scan features were various degrees of contrast enhancement, edema and midline shift. The most common site was the frontal lobe; infratentorially, the cerebellum was the most frequent site. The diagnosis was established in 8 patients by surgery and in 2 at autopsy. The most common subtype was the diffuse, large cell, immunoblastic lymphoma. 5 patients were irradiated following subtotal excision and 2 had combined radiation therapy and high-dose methotrexate-based chemotherapy; only 1 had no postoperative treatment. All patients treated by radiotherapy alone died within 3-5 months after diagnosis. The 2 who received combined therapy are alive, 15 and 48 months after diagnosis, respectively.
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Forty-five patients with cisplatin-induced peripheral neuropathy (PN) were evaluated retrospectively after treatment with cumulative doses of cisplatin ranging from 201 to 1952 mg/m2. The patients were followed for up to 23 months (median, 4.5 months), and 32 of them were evaluated more than once. Severity of symptoms was related to higher cumulative doses of cisplatin but with marked individual variability. Off-therapy deterioration of the PN continued in 14 patients (31%) for 2.5 to 5.5 months after withdrawal of cisplatin, and only four patients showed some improvement during the follow-up period. Symptomatic deterioration often was heralded by new onset of muscle cramps (with normal Ca2+/Mg2+ levels) and/or by manifestations of probable spinal dorsal column and/or nerve root demyelinating syndromes presenting as either Lhermitte's sign and/or as an electric-shock sensation along the upper extremities when outstretched in 90 degrees shoulder abduction. Cramps and demyelinating syndromes were each noted in 31% of the patients. Muscle cramps tended to resolve several months after withdrawal of therapy, and demyelinating syndromes were always transient (1.5 to 6.0 months) and did not progress despite ongoing therapy in five patients. Our study indicates that, after withdrawal of therapy, patients with cisplatin-induced PN may continue to deteriorate for several months. Manifestations of muscle cramps and demyelinating syndromes signify a worsening course of the PN but should not automatically indicate interruption of therapy.
Ninety-five newly diagnosed patients with diffuse large cell lymphoma (DLCL) treated by cyclophosphamide (CTX), doxorubicin (ADM), vincristine (VCR), and prednisone (CHOP regimen) chemotherapy were evaluated for survival factors including dose intensity (DI). DI calculations were done for the initial cycles needed to achieve maximal response. The medians of the relative DI for CTX, ADM, and VCR were 0.9, 0.86, and 0.79, respectively. The median of the average relative DI (ARDI) was 0.83 (range, 0.28 to 1.14). The univariate analysis of potential prognostic variables showed that the following significantly decreased the survival rate: age older than 60 years (P = 0.0005), Stage III to IV (P = 0.02), male sex (P = 0.03), and all four DI variables (CTX, ADM, VCR, and ARDI) less than the median (P = 0.01 to 0.0001). A multivariate analysis by the stepwise proportional hazards model of Cox indicated that the factors predicting a poor prognosis were ARDI less than the median (P = 0.0003) and age older than 60 years (P = 0.02). A multivariate survival analysis of those who achieved complete remission showed ARDI less than the median (P = 0.0003), CTX less than the median (P = 0.02), and Stage III to IV (P = 0.02) to be the most negative factors regarding survival. In conclusion, a high DI in the initial cycles of CHOP chemotherapy for DLCL has a significant positive impact on survival.
One hundred sixty-four sera samples of patients with malignant diseases were analyzed for the presence of autoantibodies to ssDNA, dsDNA, poly(I), Poly(G), cardiolipin, histones, RNP, Sm, Ro(SSA), and La (SSB). No distinction could be made between these patients and a comparative group composed of age-adjusted healthy subjects when measuring antibody levels to these autoantigens by the ELISA technique. This finding remained valid after further subgrouping of the patients according to age, sex, and histologic origin of the tumor. The authors conclude that in contrast to the known clinical coexistence of neoplasia in autoimmune states, there is no increased incidence of antinuclear autoantibodies in malignant conditions.
During 1977-1985, 50 patients with Stages III and IV large cell lymphoma (diffuse histiocytic [DH] and diffuse mixed [DM] types, Rappaport classification) were treated with the CHOP regimen (cyclophosphamide, adriamycin, Oncovin and prednisone). The male:female ratio was 1:1, the mean age at treatment 57 years, and mean follow-up 37 months. 80% had the DH type and 20% the DM type. 46% were in Stage III and 54% in Stage IV. The average relative dose intensity of CHOP was 0.68, which was well tolerated. In 68% a complete response was achieved after a mean of 4 treatment cycles. The average number of cycles for all patients was 7.2. The 5-year survival for those in Stage III was 50% and in Stage IV, 34%. Females survived better than males (60% vs 23%, respectively; p less than 0.02). The 5-year survival of the complete responders was 60% and their relapse-free survival 44%. In our experience, CHOP is a useful combination in the treatment of DH and DM lymphoma; it has yet to be proved in a randomized fashion that the current third generation of combinations is superior to it.
During the period between 1970-1984, 481 patients with previously untreated non-Hodgkin's lymphoma were referred to the Northern Israel Oncology Center, Haifa. There were 264 (54.9%) Ashkenazi Jews, 123 (25.6%) non-Ashkenazi Jews, and 86 (17.9%) Arabs. The mean age at diagnosis was 60 +/- 15 years for Ashkenazi Jews, 45 +/- 22 years for non-Ashkenazi Jews, and 36 +/- 22 years for Arabs. Ashkenazi Jews had a higher rate of nodular lymphoma compared to non-Ashkenazi Jews and Arabs. Extranodal lymphoma occurred more frequently in non-Ashkenazi Jews and Arabs. Lymphoma of the small intestine was more common in Arabs than in Ashkenazi and non-Ashkenazi Jews. Despite these differences in the pattern of disease, 5 year actuarial survival figures for the various ethnic groups were similar.
The clinicopathologic findings in a patient who developed dysphagia and obstruction of the middle third of the esophagus 12 years after mastectomy for breast carcinoma are presented. Endoscopic biopsy revealed metastatic breast carcinoma with pseudoepitheliomatous hyperplasia of the overlying esophageal mucosa. To the best of our knowledge, the case represents the first reported association between esophageal metastasis and pseudoepitheliomatous hyperplasia of the esophageal squamous epithelium.
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29 patients with previously untreated clinical stage I and II extranodal non-Hodgkin's lymphoma of the head and neck received involved or extended field radiotherapy at the Northern Israel Oncology Center during the years 1968 to 1979. Complete initial locoregional control was achieved in all patients; however, 18 patients (62%) relapsed. Two of the relapsing patients (11%) had "in field" failure, and one (6%) had "marginal" failure, with no evidence of disease elsewhere. 13 of the relapsing patients (72%) failed at distant sites, and two of these (11%) both locally and systemically. 13 of 15 patients (87%) with lymphoma of Waldeyer's ring relapsed, most commonly in the abdominal cavity. Only one of seven patients (14%) with lymphoma of the paranasal sinuses recurred. The five- and ten-year actuarial survival of all patients was 50% and 46%, respectively. While patients with lymphoma of the paranasal sinuses had a survival probability of 86% at ten years, patients with disease originating in Waldeyer's ring had an actuarial ten-year survival of 18% only. The prognosis of younger patients was better than the prognosis of patients older than 65. Although this series is too small and heterogeneous to derive definite treatment recommendations, it is suggested that radiotherapy to doses of 4000 to 6000 cGy can control most local disease. The overall results of radiation therapy alone have been unsatisfactory in our patients with lymphoma of Waldeyer's ring and the parotid gland due to failure outside the locally treated area, frequently in the abdominal cavity. Precise staging procedures are needed to detect sites of occult disease which require the use of systemic chemotherapy. It is felt that adequately staged, localized, small size non-Hodgkin's lymphoma of the paranasal sinuses can be treated by radiotherapy alone without loss of curability.
Pleotropic resistant human breast cancer cells (MCF-7), selected for resistance to Adriamycin, were used to study the production of DNA strand breaks by etoposide (VP-16) and its relationship to drug cytotoxicity. It was shown that the resistant MCF-7 cell line was cross-resistant to VP-16, and the degree of resistance was found to be 125-200-fold. Alkaline elution studies indicated that the parental cell line was very sensitive to VP-16 which caused extensive DNA strand breakage. In contrast, little DNA strand breakage was detected in the resistant MCF-7 cells, even at very high drug concentrations, indicating a good agreement between strand breaks and cytotoxicity. Further studies indicated that the nuclei isolated from the parental cell line were more resistant to VP-16-induced DNA strand breaks than the intact cells, while the opposite was found in the resistant cell line. In addition, the alkaline elution studies in isolated nuclei showed only a 2-fold reduction of VP-16-induced DNA breaks in nuclei from the resistant cells. In agreement with this result, it was found that nuclear extract from the resistant cells produced 2-3-fold less VP-16-induced DNA breaks than that from the sensitive cells in 32P-end-labeled SV40 DNA. VP-16 uptake and efflux studies indicated that there was a 2-3-fold decrease in net cellular accumulation of VP-16 in the resistant cells. Although the reduced uptake of VP-16 and decreased drug sensitivity of topoisomerase II appear to contribute to the mechanism of action and the development of resistance to VP-16, they do not completely explain the degree of resistance to VP-16 in this multidrug-resistant MCF-7 cell line indicating that other biochemical factors, such as activation of VP-16, are also involved in drug resistance and suggesting that the resistance is multifactorial.