[Evaluation of the effect of pathology slide review on clinical practice in an oncology center]. / Evaluation de l'influence de la relecture histologique sur la prise en charge médicale des patients traités dans un centre d'oncologie.

Our aim was to evaluate the clinical impact of pathology review in an oncology center, in which review is not performed for every patient. This retrospective study involved 100 consecutive patients, whose slides were reviewed in our center. A standardized data sheet was filled out by oncologists for each patient. Pathology review was considered as responsible for a major (35%), moderate (40%), or mild or no (25%) modification of clinical practice. Modification concerned either initial investigations, treatment or medical follow up, and was independent of the reason for which review was performed. Eleven patients underwent a second biopsy. Whatever the possible discrepancies between initial and review diagnosis, our results show that pathological review has a major influence on clinical practice in patients with cancer.

Glycosylated nuclear lectin CBP70 also associated with endoplasmic reticulum and the Golgi apparatus: does the "classic pathway" of glycosylation also apply to nuclear glycoproteins?

The subcellular plurilocalization of some lectins (galectin-1, galectin-3, galectin-10, calreticulin, etc.) is an intriguing problem, implying different partners according to their localization, and involvement in a variety of cellular activities. For example, the well-known lectin, galectin-3, a lactose-binding protein, can act inside the nucleus in splicing events, and at the plasma membrane in adhesion, and it was demonstrated that galectin-3 interacts in the cytoplasm with Bcl-2, an antiapoptotic protein. Some years ago, our group isolated a nuclear lectin CBP70, capable of recognizing N-acetylglucosamine residues. This lectin, first isolated from the nucleus of HL60 cells, was also localized in the cytoplasm. It has been demonstrated that CBP70 is a glycosylated lectin, with different types of glycosylation, comparing cytoplasmic and nuclear forms. In this article, we have studied the localization of CBP70 in undifferentiated HL60 cells by electron microscopy, immunofluorescence analysis, and subcellular fractionation. The results obtained clearly demonstrated that CBP70 is a plurilocalized lectin that is found in the nucleus, at the endoplasmic reticulum, the Golgi apparatus, and mitochondria, but not at the plasma membrane. Because CBP70, a nuclear glycoprotein, was found to be associated also with the endoplasmic reticulum and the Golgi apparatus where the glycosylation take place, it raised the question: where does the glycosylation of nuclear proteins occur?

Preliminary results on the activity of oxaliplatin (L-OHP) in refractory/recurrent non-Hodgkin's lymphoma patients.

BACKGROUND: Many patients with advanced NHL ultimately relapse and require salvage treatment. Oxaliplatin, a diaminocyclohexane (DACH) platinum, has shown a differential spectrum of cytotoxicity with cisplatin, with activity in primary or secondary cisplatin-resistant solid tumors (colon and ovarian cancer). We report the tolerance/activity of this platinum derivate in previously-treated NHL patients. PATIENTS AND METHODS: From July 1988 to February 1994, 22 patients (11 men, 11 women) with recurrent NHL received single-agent oxaliplatin (100-130 mg/m2 i.v. over two hours with antiemetic premedication, q three weeks). All had been previously treated (median number of prior chemotherapy regimens 2, range 1-7) > or = 1 alkylating agent: 22 patients, anthracyclines: 18 patients, cisplatin: four patients, and radiation: 11 patients. Fourteen patients (63%) had progressive disease as best response to their last chemotherapy, and were considered treatment-refractory. All histologies were centrally reviewed in accord with the R.E.A.L. Classification; they were: eight follicular, five MCL, three diffuse large cell, two MALT, one lymphoplasmocytoid, and three other. RESULTS: A total of 144 cycles were administered for a median number of 6 (range 1-30) per patient. The objective response rate was 40% (95%, CI: 21-64), including one CR (MCL) and eight PRs (four follicular, two MCL, two MALT). The median response duration was 27 months (range 5-44). Treatment-related toxicity was limited to grade 1-2 nausea/vomiting and reversible grade 1-2 peripheral neuropathy in most of the patients. CONCLUSION: Oxaliplatin is an active agent in relapsed/refractory NHL, including the MCL type. Its safety profile makes this agent a good candidate for the development of combined salvage regimens. Further phase II studies are needed to confirm these preliminary results.

Oxaliplatin/cisplatin (L-OHP/CDDP) combination in heavily pretreated ovarian cancer.

The aim of this study was to evaluate the toxicity and the activity of two non-cross-resistant platinum compounds: oxaliplatin (L-OHP) and cisplatin (CDDP) in platinum pretreated ovarian cancer patients. Chemotherapy consisted of L-OHP and CDDP given sequentially as 2 h infusions on day 1 at their standard recommended dose (130 mg/m2 for oxaliplatin, 100 mg/m2 for cisplatin) every 3 weeks. Dose reductions (20-35%) were planned according to baseline haematological and renal status, but the dose ratio between L-OHP and CDDP was always maintained at 1.3. Cycles were repeated until progression or treatment limiting toxicities. From September 1992 to November 1994, 25 patients with pretreated ovarian cancer entered this salvage programme. They had received a median number of three previous chemotherapy lines (1-7), one at least platinum based. Previously cisplatin had been given to 22 patients at a median total dose of 600 mg/m2 (170-1175), while 18 had received carboplatin to a median total dose of 1135 mg/m2 (200-2450). 9 patients had also received and were resistant to taxanes (paclitaxel, 6 patients, docetaxel, 3 patients), while the rest were considered ineligible for simultaneously ongoing single-agent taxane phase II trials. 13 and 12 patients, respectively, were considered to have platinum refractory and potentially sensitive disease, according to Markman's criteria. 77 cycles of L-OHP/CDDP were given, with a median of three cycles/patient (range 1-6) and were evaluable for toxicity. The limiting toxicity of the L-OHP/CDDP combination was a cumulative, sensory peripheral neuropathy, severe (> or = grade 3 CTC) after more than three cycles, but reversible within a few months of its discontinuation. Grade 3-4 (WHO scale) neutropenia and thrombopenia were seen in 35-40% of cycles, with one neutropenic treatment-related death (septic shock). 22 patients with measurable/evaluable disease were assessable for antitumoral activity. Two complete responses (CR) (8%) (one proven histologically at laparotomy (pCR)) and 8 partial responses (PR) (32%) for an overall objective response rate (ORR) of 40% (95% CI, 21-61%) (intent to treat). The median duration of response was 4 months. Seven responses were seen among 12 potentially platinum-sensitive tumours (58%, CI 95% 28-85%), while 3/13 platinum refractory patients (23%, CI 95% 5-54%) had an objective response. These encouraging results are the basis for new first- and second-line combination treatment programmes in ovarian carcinoma.

Long-term prognostic and predictive factors in 107 stage II/III breast cancer patients treated with anthracycline-based neoadjuvant chemotherapy.

The heterogeneity of therapeutic modalities and eligibility criteria and the lack of long-term follow-up in most reports of neoadjuvant chemotherapy for breast cancer preclude us from drawing conclusions about its value in clinically relevant patient subgroups. The present study aims to identify predictive and prognostic factors in 107 non-inflammatory stage II/III breast cancer patients treated between November 1980 and October 1991 with an anthracycline-based induction regimen before locoregional surgery. Preoperative chemotherapy comprised 3-6 cycles of doxorubicin (pirarubicin after 1986), vindesine, cyclophosphamide and 5-fluorouracil. Type of subsequent surgery and adjuvant treatment were decided individually. In analysis of outcome, univariate comparisons of end points were made using the log-rank test, and significant (P < or = 0.05) pre- and post-therapeutic factors were incorporated in a Cox multivariate analysis. With a median follow-up of 81 months (range 32-164+ months), the median disease-free survival (DFS) is 90.5 months while median overall survival has not yet been reached. Cytoprognostic grade and histopathological response in both the primary and lymph nodes were independent covariates associated with locoregional relapse with or without DFS and overall survival. Eleven patients with pathological complete response remain free of disease with a 68-month median follow-up, while the 18 with residual microscopic disease on the specimen showed a 60% cumulative incidence of locoregional recurrence. Despite encouraging response rates based on clinical or radiological evaluation (87% or 70%), neither method showed any significant correlation with pathological response and failed to contribute prognostic information on patients' outcome. Pathological evaluation of antitumoral activity of primary chemotherapy remains a major source of prognostic information and might be used to select patients in need of additional adjuvant treatment.

Human T-cell lymphotropic virus-1-positive T-cell leukemia/lymphoma in a child. Report of a case and review of the literature.

Adult T-cell leukemia/lymphoma is a monoclonal T-cell neoplasm associated with human T-cell lymphotropic virus-1 (HTLV-1) that occurs almost exclusively in adults. This report concerns a Romanian girl who had recurrent skin eruptions since infancy, subcutaneous tumors in childhood, and peripheral blood lymphocytosis, which initially developed at the age of 12 years. The circulating lymphocytes were of helper T-cell immunophenotype. Serologic studies demonstrated a number of HTLV-1 antigens in the child and her mother, and molecular analyses revealed monoclonal T-cell-receptor gamma gene rearrangement and detectable HTLV-1 proviral DNA. Conventional cytogenetic studies revealed a t(3;6)(q23;q27) chromosome translocation in most of the neoplastic cells. The patient initially responded well to interferon alfa therapy and showed regression of skin lesions and diminished lymphocytosis, but 4 years later, she developed massive lymphadenopathy and leukemic infiltration of the breast. At last clinical follow-up, at the age of 17 years, the patient had stable low-level peripheral lymphocytosis and subcutaneous tumors while being continuously treated with interferon alfa. Our review of the literature revealed six additional children with HTLV-1-associated T-cell leukemia/lymphoma, including one case with a similar clinical presentation and ethnic background. To our knowledge, the t(3;6)(q23;q27) translocation identified in this patient's neoplasm has not been previously reported in adult T-cell leukemia/lymphoma cases and may explain the early onset of disease. Although adult T-cell leukemia/lymphoma is rare in Romania, the identification of healthy carriers and vertical transmission raise the possibility that Romania might be an endemic region for HTLV-1 infection.

Iodixanol in leg phlebography: a randomized, double-blind parallel group phase III trial comparing iodixanol to ioxaglate.

PURPOSE: To evaluate the safety and efficacy of iodixanol (Visipaque) in phlebography in order to obtain experience from the use of this contrast medium in this i.v. indication. PATIENTS AND METHODS: Phlebography was performed in 150 patients, as a comparative prospective, double-blind, randomized parallel group study comparing iodixanol 270 mgI/ml with ioxaglate 320 mgI/ml. The tolerability was assessed from occurrence of discomfort, adverse events up to 30 min following injection and late adverse events. Efficacy was assessed by recording the diagnostic information on each venous segment. Statistical analysis was performed using the Cochran-Mantel-Haenszel test in order to correct for a possible centre effect. RESULTS: Frequency of patients reporting discomfort (P=0.002) or adverse events (P<0.001) was statistically significantly lower after the injection of iodixanol than after ioxaglate. There was no statistical difference regarding late adverse events and diagnostic information. CONCLUSION: Iodixanol 270 mgI/ml yielded the same diagnostic information as ioxaglate 320 mgI/ml and was associated with fewer patients reporting adverse events and discomfort.

Phase I trial of Perrimustine, a new cysteamine (2-chloroethyl) nitrosourea: an intrapatient escalation scheme.

The recently synthesized nitrosourea, N-[N'-chloro-2-ethyl-N'-nitrosocarbamoyl]-S-methyl cysteamine sulfoxide (Perrimustine), is water soluble and has a high alkylating activity, similar to that of the widely used nitrsoureas BCNU and CCNU, and a low carbamoylating activity. Preclinical studies with a broad spectrum of murine tumors indicate that this new compound may be clinically useful. The maximally efficient dose range (MEDR) in L1210 bearing mice was 45 mg/m2 (subcurative dose) to 67 mg/m2 (subtoxic dose). The present phase I trial used an intrapatient escalation schedule, so that each patient entering the study received a potentially active dose. The first dose injected was 1:100 of the MEDR suboptimal dose to check for anaphylactic sensitivity. Patients were then given increasing doses at increasing time intervals until toxicity was observed. The highest dose was given on day 150-230. The main toxic effect was myelosuppression [five out of the 24 patients evaluated: one grade 4 thrombocytopenia, two grade 3 thrombocytopenia; anemia and leucopenia were milder (grade 1 to 2 on OMS scale)]. Of the 19 patients evaluated for clinical response, one showed response after the 45 mg/m2 dose (disappearance of the cerebral metastasis with persistence of hepatic localizations in a patient with melanoma) and the disease was stabilized in two cases (a pleural mesothelioma and a renal carcinoma with lung metastases) after 26 and 37 weeks, with total cumulative doses per m2 of 232 and 196 mg, respectively.

Combined differentiation therapy in myelodysplastic syndrome with retinoid acid, 1 alpha,25 dihydroxyvitamin D3, and prednisone.

The myelodysplastic syndrome (MDPS) provides an opportunity for identifying host factors (genetic, endocrine, immune) involved in initiation and progression of preleukemia into frank acute myeloid leukemia. The aim of this study was to identify bone marrow (BM) cellular and humoral dysfunctions central to the development of MDPS and useful in therapeutic follow-up studies. Our preclinical studies have shown that (1) the characteristic stromal cell composition of the normal BM microenvironment was impaired in MDPS and in AML in 67 and 86% of the cases, respectively; (2) the 1 alpha,25(OH)2D3 concentration in BM plasma was abnormal in 50% of MDPS and 30% of AML; and (3) an inverse correlation existed in MDPS between the 1 alpha,25(OH)2D3 concentration and the frequency of F-CFU, (r = 0.41, p < 0.02), suggestive of a regulatory interaction between this secosteroid hormone and BM stromal cells. The analysis of clonal extinction of BM blast cells in response to all trans retinoic acid (RA), 1 alpha,25(OH)2D3, and colony stimulating factors (PHA-LCM), either alone or in various combinations, revealed individual patterns of responses in the cases of MDPS or AML. The results indicate the necessity for preclinical studies to select patients for combined differentiation therapy. Our ongoing clinical trials suggest that RA (Roaccutan, 20 mg/day continuously) as induction therapy, followed at weeks 6 to 8 by prednisone (40 mg/day for 15 days) and 1 alpha,25(OH)2D3 (Rocaltrol, 3 x 0.25 micrograms/day for 3 months) may induce a long-lasting hematological remission in MDPS.

Retinoic acid in mono- or combined differentiation therapy of myelodysplasia and acute promyelocytic leukemia.

Myelodysplastic preleukemic syndromes (MDPS) and acute promyelocytic leukemia (APL) share a surprising in vivo sensitivity to the hormonally acting 13 cis or all trans retinoic acids (transRA). Here we show that transRA as a monotherapeutic agent induced a stable remission in APL at the third relapse. In MDPS, treatment with prednisone and 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25D3) 13 cis RA induced a long-lasting hematological remission. Initially both patients had an impaired BM microenvironment which regenerated on retinoid therapy as judged by reappearance of the Hematon fraction in the BM aspirates. Our preclinical experiments using long-term liquid BM cultures (LTBMC) indicated that several individual patterns of growth and differentiation responses can be induced by combinations of transRA, 1 alpha,25D3 and hemopoietic growth factors (HGFs). The biological responses may vary from complete clonal extinction to a significant growth stimulation of the leukemic blast cell populations. These results further support the importance of preclinical studies in selecting "good" responders for, and excluding "poor" responders from protocols using differentiation therapy.

Identification of mammary metastatic cells in the bone marrow as a marker of a minimal residual disease and of their proliferative index as a factor of prognosis--an immunocytologic study with monoclonal antibodies.

A study of 200 patients with breast cancer at different stages was carried out. Proliferating mammary cells in bone marrow were detected using a double-staining method with monoclonal antibodies. Mammary cells were visualized with antibodies raised against human breast tissue or carcinoma. DNA-synthetising cells (S-phase) were detected on the same slide, using the monoclonal antibody antibromodeoxyuridine (BrdU), after cell incubation with BrdU. Mammary cells could be detected in the bone marrow of 60% of the studied cases. In 50% of the samples with such 'micrometastasis', a high labelling index of the carcinoma cells was found. The correlation between the presence of micrometastasis and the general prognosis at the stage of residual disease is discussed.

Serum lipid-bound sialic acid as a tumoral marker in minimal residual tumors.

The lipid-associated sialic acid (LASA) level in serum was increased in 663 out of 794 patients (83.5%) of which 55.1% were CEA negative. There were 16.5% LASA (possibly false) negative, CEA positive patients. There were 24.1% false positives in 116 patients without malignant tumors. In manifest prostatic carcinoma 94.2% of the LASA values but only 36.5% of the prostatic acid phosphatase values were increased. Similarly, in breast and pulmonary carcinoma, LASA was more sensitive than CEA. In 499 patients with minimal residual disease, 203 (41.5%) were LASA-negative, of which 180 were CEA-negative. Out of 180 LASA positive patients, 70 have relapsed, as have 70 out of 219 patients with increases in both LASA and CEA. The sensitivity of LASA (87%) in lymphoma was higher than that of the erythrocyte sedimentation rate (53.3%), of C-reactive protein (51.2%), serum copper (64.7%) and of six other markers.

Pulmonary sarcoidosis associated with Leydig cell testicular neoplasm.

The first case of association between Leydig cell testicular tumor and sarcoidosis is reported. From a review of the literature, this is the ninth case of association between a testicular tumor and Besnier's disease. Lung biopsy should always be performed in patients with testicular cancer when retroperitoneal lymph node involvement cannot be demonstrated in order to avoid unnecessary antineoplastic chemotherapy.

Influenza vaccination in the elderly: improved antibody response with Imuthiol (Na diethyldithiocarbamate) adjuvant therapy.

To improve influenza vaccine efficacy in hospitalized elderly, we compared the evolution of antibody level after vaccination in three patient groups. A sample of apparently primo vaccinated elderly were randomized to receive either Imuthiol (Na diethyldithiocarbamate: group 1) or a placebo (group P). They were compared to patients who had been vaccinated annually for several years (group C). All patients were immunized in the same week. Antibody responses increase within 15 days to reach a plateau in group P and C, while they continue to increase in the Imuthiol treated group, reaching higher antibody levels 30 days after vaccination. This higher antibody rise in group I is essentially due to higher antibody responses in patients with initially low antibody levels and who exhibited at least a four-fold antibody rise. This effect of Imuthiol on influenza antibody responses was observed in spite of a lower nutritional status in this group, a condition that induces lower antibody responses. The higher antibody responses observed in the Imuthiol treated group allow longer protection against influenza.

Clinical characterization of imuthiol.

Imuthiol is a nontoxic agent recruting and regulating T cells. Phase III studies in chronic bronchitis and bronchiectasis showed that immune functions were restored to normal, or near normal values. Cure was obtained in rheumatoid arthritis, tuberculosis and chronic infections in the elderly. Imuthiol is an effective agent for the treatment of syndromes and disease states where the underlying defect is a T-cell deficiency or dysfunction.

A phase I trial of trans-1-diaminocyclohexane oxalato-platinum (l-OHP).

Oxalato-platinum in a new platinum derivative which was found to be active in experimental tumors and devoid of nephrotoxicity. A phase I study was conducted in cancer patients according to a new design following the recommendations of our Institution's ethical committee to avoid the major drawback of classical phase I studies in which many patients receive the experimental drug at doses far under the potentially active dose extrapolated from experimental studies. The potentially active dose of l-OHP was determined from the Maximally Efficient Dose Range (MEDR) to be between 45 mg/m2 (subcurative dose) and 67 mg/m2 (subtoxic dose). The patients in this study received with increasing intervals 1/100, 1/10, 1/5, 1/3, 1/2, 2/3, 3/4, 1, of the low dose of the MEDR, this dose being reached after 90 to 120 days on study. 23 evaluable patients have entered the trial of which 19 reached the low dose of MEDR (45 mg/m2). Gastro-intestinal toxicity, nausea and vomiting, similar to those with CDDP occurred in all patients at or above the dose of 30 mg/m2. Renal toxicity was monitored with creatinine level and did not occur in any patient at any dose nor did significant hematologic toxicity occur. Thus nausea and vomiting appear to be the limiting toxicity of the drug. Responses were observed in this phase I study in lung cancer (1), breast cancer (1), melanoma (1) and perhaps hepatoma (major decrease in alpha FP levels) (1). The proposed starting dose for phase II studies is 45 mg/m2 but we plan to continue dose escalation during the phase II according to the design of Jones and Holland. This new study design allows each patient entering a phase I study to be treated with a potentially active dose of the drug studied.

An oriented phase II trial of THP-adriamycin in breast carcinoma.

THP-ADM is a new anthracycline with broad antitumor activity without cardiac toxicity or alopecia in experimental models. Phase I studies had established a proposed dose for phase II trials of 50 mg/m2 every three weeks. This modality gave an insignificant result in breast carcinoma. Cellular pharmacokinetics suggested that a longer time of administration could be more efficient. In this phase II trial oriented to advanced breast cancer, we have used 3 consecutive daily doses of 20 mg/m2/day in monthly cycles with dose escalation in each patient. We have observed 28% partial remissions (PR). Two patients previously treated with adriamycin had PR. Significantly less alopecia and no cardiac toxicity were observed.

An original method for submacroscopic metastases visualization in cases of cancer minimal residual disease.

Scintigraphic imaging due to its sensitivity is in many cases one of the most powerful techniques for demonstrating metastases. Severe limitations still exist in cancer when it is necessary to detect the presence of a few tumour cells in the residual minimal disease. In preliminary experiments it had been observed that an immunomodulator isolated from Nocardia bacteria (Nocardia Soluble Peptidoglycan Derivative: NSPD) electively bound to a model of activated macrophages. An hypothesis has been put forward that the enhanced detection of macrophages that are usually present in the vicinity or inside tumours should represent a polyspecific test for scintigraphy of a variety of metastases. NSPD radiolabelled with 99mTechnetium is not usable when injected intravenously due to its physiochemical properties. It has therefore been encapsulated into liposomes then administered via the respiratory tract as an aerosol. Amphiphilic properties, as well as its low molecular weight allow a rapid diffusion of NSPD in blood. Scintigraphy of metastases was possible from 1.5 to 6 hours after inhalation. The first stage of the study was carried out on 5 patients bearing known metastases (skin, lymph nodes, bone) from malignant melanoma that all were imaged with 99mTc-NSPD. The test was then applied to patients with a high risk of recurrent cancers (melanoma: 6, breast tumour: 7) based on the detection in their plasmas of high Lipid Associated Sialic Acid (LASA) concentrations. The association of these two sensitive techniques has resulted in the detection of very small metastases that were not seen using conventional scintigraphy; they were then confirmed histologically.