[Network of care for breast cancers: a prospective survey among general practitioners]. / Réseau du soins en cancérologie mammaire: enquête d'opinion prospective auprès des médecins généralistes.

OBJECTIVE: To clarify the general practitioner (GP)'s current perception on a network dedicated to mammary cancers in a rural department. METHODS: A survey by questionnaire was carried out from March to September 1999. This questionnaire made of 3 different sheets and 4 parts entitled "your practice in oncology", the "partnership", "GPs and network", "expectations" respectively, was mailed to 233 GPs board certified by the Conseil Départemental de l'Ordre des Médecins. Questionnaire included space for free comments and a specification sheet. There was no letter of reminder following the first mail. RESULTS: The rate of spontaneous answers was 48% (112/233). Representativeness of the sample was considered coherent with age, sex-ratio, mean duration of setting up, practice modalities in the department of Aube. GPs took care, on annual average, over 6 patients with breast cancer. They generally referred their patients to the oncologist team at the Centre hospitalier général. Such a choice was mainly sustained by the quality of patient reception, the psychological support and the fraternal relationship. GPs were mostly concerned (76%) by the management of both chemotherapy side effects and psychological problems occurring in their patients. By popular request, they wished the setting up of a hot line and a systematic historical reminder of the adverse effects joined to the mail. As far as the network was concerned, 83% of the GPs thought it could be helpful, but only 60% would actively participate. Reasons for such a discrepancy are discussed taking free comments into account. CONCLUSIONS: GPs in the Aube department seem eager to practice in a more collective way, which places the patient in the heart of the medical approach. However they demand to play a key role according both to their knowledge of the whole file and to the trust the patients are putting on them.

Distribution of cycling T lymphocytes in blood and lymphoid organs during immune responses.

Proliferation of murine T lymphocytes in blood, lymph nodes, and spleen was studied in four in vivo stimulation systems, using BrdU pulse-labeling of DNA-synthesizing cells. The T cell response to the superantigen Staphylococcus enterotoxin B (SEB) was studied in detail. Vbeta8+ T cells showed a peak of DNA synthesis 16-24 h after SEB injection, and the percentage of BrdU+ CD4 and CD8 T cells was higher in blood than in lymph nodes and spleen. DNA synthesis was preceded by massive migration of Vbeta8+ cells from blood to lymphoid organs, in which the early activation marker CD69 was first up-regulated. SEB-nonspecific Vbeta6+ cells showed minimal stimulation but, when cycling, also expressed a high level of CD69. The other systems studied were injection of the IFN-gamma inducer polyinosinic:polycytidylic acid, infection by the BM5 variants of murine leukemia virus (the causative agent of murine AIDS), and T cell expansion after transfer of normal bone marrow and lymph node cells into recombinase-activating gene-2-deficient mice. In each case, a peak of T cell proliferation was observed in blood. These data demonstrate the extensive redistribution of cycling T cells in the first few hours after activation. Kinetic studies of blood lymphocyte status appear crucial for understanding primary immune responses because cycling and redistributing T lymphocytes are enriched in the circulating compartment.

Outpatient treatment with subcutaneous interleukin-2 and interferon alfa administration in combination with fluorouracil in patients with metastatic renal cell carcinoma: results of a sequential nonrandomized phase II study. Subcutaneous Administration Propeukin Program Cooperative Group.

PURPOSE: We report the results of the Subcutaneous Administration Propeukin Program (SCAPP) II trial of an outpatient treatment in renal cell carcinoma using interleukin-2 (IL-2) and interferon alfa-2a (IFN-alpha) administered subcutaneously in combination with fluorouracil (5-FU). The objective of this multicenter trial was to confirm that the combination of IL-2, IFN-alpha, and 5-FU leads to a response rate greater than 20%. PATIENTS AND METHODS: Patients with metastatic renal cell carcinoma were included in this study. During the induction phase of the treatment, which lasted 10 weeks, IL-2 and IFN-alpha were administered subcutaneously three times a week for 8 weeks at doses of 18 MIU and 9 MIU, respectively. During these 8 weeks, every Monday, 5-FU was administered at a dose of 750 mg by intravenous infusion over 30 minutes. After evaluation, responding patients or patients with stable disease (SD) were given maintenance treatment, until disease progression (PD) or the appearance of unacceptable toxicity. Each maintenance cycle consisted of a 2-week treatment followed by a three-week rest period. During treatment, IL-2 and IFN-alpha were administered subcutaneously three times a week at doses of 18 MIU and 9 MIU, respectively. Every Monday, 5-FU was administered at a dose of 750 mg by intravenous infusion over 30 minutes. RESULTS: This trial was closed when the sixth sequential analysis showed the lack of benefit from this combination. At the end of the induction period, of 62 patients, 12 (19%; 95% confidence interval [CI], 10% to 31%) reached an objective response, including one complete response (CR), 16 presented with SD, and 27 showed PD. Twenty-seven patients (43%) developed severe toxicity that required reduction of the planned doses (13 patients), delayed treatment (eight patients), or treatment termination (six patients). Seventeen patients were given maintenance treatment. One- and 2-year survival rates were estimated at 55% and 33%, respectively. The 2-year survival rate was 15% in 11 patients who presented with three poor-prognosis factors and 41% in 51 patients who initially presented with no, one, or two poor-prognosis factors (P = .04). CONCLUSION: As in other recently published studies that used 5-FU, IL-2, and IFN-alpha, the multicenter SCAPP II trial in patients with metastatic renal cell carcinoma generated severe toxicity. This sequential trial failed to confirm the favorable results previously obtained by Atzpodien and Sella with this combination of three drugs. Its efficacy, assessed on the response and survival rates, is near to the results observed in programs that used IL-2 alone given subcutaneously.

Changes in 1,25-(OH)2D3 synthesis and its receptor expression in spleen cell subpopulations of mice infected with LPBM5 retrovirus.

This study examines the influence of chronic retroviral infection of mice with a LPBM5 virus mixture on the paracrine system involving immune cells and 1,25-(OH)2D3 in the spleen. Plasma ionized calcium, 25-(OH)D and 1,25-(OH)2D of infected mice were unchanged. In contrast, the specific binding of 1,25-(OH)2D3 to spleen cytosol and the number of monocyte/macrophages expressing 1,25-(OH)2D3 receptors (VDR) were markedly increased. The retroviral infection also influenced the local production of 1,25-(OH)2D3 in the spleen. It did not alter this production in monocyte/macrophages but increased that in isolated T cells. Isolated B cells in control mice did not produce 1,25-(OH)2D3, but they increased the ability of isolated T cells to produce this metabolite during coculture incubations. Infection altered this cell interaction as 1,25-(OH)2D3 production in infected T cells decreased when these cells were cocultured with infected B cells. Thus, chronic retroviral infection alters both the local vitamin D metabolism and VDR expression by immune cells in mice. These findings suggest close local interactions between 1,25-(OH)2D3 and immune system activation during retroviral infection.

[Subcutaneous administration of interleukin-2 in ambulatory treatment of patients with metastatic renal cancer. Three-year results of the SCAPP I program]. / Traitement ambulatoire par interleukine 2 administrée par voie sous-cutanée chez des patients porteurs d'un cancer du rein métastatique. Résultats à 3 ans du programme SCAPP i.

We report a french experience of subcutaneous administration of interleukin-2 in treatment of patients with metastatic renal cell carcinoma. Thirty-nine patients with metastatic renal cell carcinoma were included in the study. During the 10-week induction period, interleukin-2 was administrated subcutaneously 5 days a week for 8 weeks. The weekly dosage were 90 MIU during weeks 1 and 6; 63 MIU during weeks 2 to 4 and 7 to 9. After evaluation, responders and patients with stable disease received maintenance treatment which was discontinued upon the appearance of disease progression or unacceptable toxicity. During the maintenance period, interleukin-2 was administered 5 days a week for 4 weeks followed by a 2-week rest period. The weekly dosages were 90 MIU in week 1 and 63 MIU in weeks 2 to 4. After completion of induction treatment, 7 of 39 evaluable patients (18%) had objective responses with 1 complete response. A diminution of dose or interruption of treatment occurred with 7 patients because severe toxicity. Other systemic side effects in the remaining patients were acceptable. Seventeen patients received maintenance treatment. The median follow-up of all the patients included was 21 months. The 1, 2 and 3 years survivals were 64%, 33% and 22% respectively. This multicentric trial confirms the efficacity of subcutaneously-administered interleukin-2 in patients with metastatic renal cell carcinoma in terms of both response rate and survival. Unfortunately, increasing total doses of administrated interleukin-2 does not seem to increase efficacity according to response rate, but is more toxic.

In vivo effects of vitamin D on the proliferation and differentiation of rat keratinocytes.

The hormonal form of vitamin D appears to be a physiological regulator of the epidermogenesis. While its differentiation-promoting effect is well accepted, there are conflicting reports of its action on keratinocyte proliferation. This study evaluates the specific changes induced by vitamin D treatment in the epidermis of rats nutritionally deprived of vitamin D by cell size analysis, acridine orange flowcytometry, and the immunohistochemical detection of proteins related to the different stages of differentiation (epidermal calcium binding protein and suprabasal keratins recognized by KL1 antibody) The total keratinocyte and isolated keratinocyte subpopulations were studied. Vitamin D deficiency was associated in the total population with a lower percentage of actively proliferating cells and with a lack of differentiation markers. Study of the isolated cell populations demonstrated, however, that small cells were actively proliferating, whereas they were mainly in the resting stage in the normal epidermis. Treatment with vitamin D dramatically increased cell proliferation and stimulated the appearance of differentiation markers. Some of the observed effects, such as an increase in proliferation and the appearance of epidermal calcium binding protein, were due to the normalisation of the vitamin D deficiency-induced hypocalcemia, whereas the expression of suprabasal keratins was directly dependent on vitamin D. We conclude that the action of vitamin D on the epidermis is associated with increases in both proliferation and differentiation of keratinocytes. Vitamin D itself and its resulting action on calcium homeostasis appear to contribute to the observed effects.

Subcutaneous recombinant interleukin-2 (rIL-2) in out-patients with metastatic renal cell carcinoma. Results of a multicenter SCAPP1 trial.

BACKGROUND: This multicenter phase II trial was conducted in order to evaluate the efficacy and toxicity of the subcutaneous route of administration of rIL-2 in the treatment of patients with metastatic renal cell carcinoma and to check whether an increased cumulative dose of rIL-2 increases efficacy. PATIENTS AND METHODS: Thirty-nine patients with metastatic renal cell carcinoma were included in this study. During the induction period, rIL-2 was administered subcutaneously 5 days a week for 8 weeks. The weekly dosages were 90 MIU during weeks 1 and 6;63 MIU during weeks 2 to 4 and 7 to 9. After evaluation, responders and patients with stable disease received maintenance treatment which was discontinued upon the appearance of disease progression or unacceptable toxicity. During the maintenance period, rIL-2 was administered 5 days a week for 4 weeks followed by a 2-week rest period. The weekly dosages were 90 MIU in week 1 and 63 MIU in weeks 2 to 4. RESULTS: After completion of induction treatment, 7 of 39 evaluable patients (18%) had objective responses (95% CI: 9% to 37%) with one complete response. Treatment was interrupted or reduced due to toxicity for seven patients: Neuropsychiatric symptoms (3 patients), joint pain (1 patient), major asthenia and anorexia (1 patient), stroke (1 patient), and septicemia (1 patient). Other systemic side effects in the remaining patients were acceptable. Seventeen patients received maintenance treatment. In none of the patients did the response status improve during this maintenance period. The median follow-up of all of the patients included was 19 months. The one- and two-year survivals were 65% and 33%, respectively, ad the median duration of response was 11 months (5 to 16+). CONCLUSIONS: This multicentric study confirms the efficacy of subcutaneously-administered rIL-2 in patients with metastatic renal cell carcinoma in terms of both response rate and survival. The role of a maintenance therapy needs further evaluation.

Resistance to murine AIDS in offspring of mice infected with LP-BM5. Role of CD8 T cells.

The murine-acquired immunodeficiency syndrome (MAIDS) is caused by a mixture of murine leukemia viruses (LP-BM5 MuLV). The influence of perinatal contact with retroviruses or their Ags on the response to infection was tested by infecting with LP-BM5 (MuLV) the adult offspring of mice with MAIDS. These offspring were resistant to disease after virus challenge. Most of them were free of defective viral DNA, and even those with molecular evidence of infection had lymphoid cells with a lower infectious capacity to cause MAIDS in naive recipients. No ecotropic, xenotropic, or mink cell focus-forming (MCF) virus expression was found at the age of 5 wk, which is the time of LP-BM5 (MuLV) challenge. However, at 22 wk of age, one-half of the offspring from MAIDS mothers had ecotropic virus-expressing cells in their spleens. At the time of suckling, offspring from infected mothers had enhanced percentages of B cells and CD4 and CD8 T cells in the spleen, possibly followed by a slight persistent splenomegaly. These results suggest that immune reactivity, rather than tolerance to the virus, is responsible for resistance to disease after challenge. The offspring of MAIDS mice could clear the virus after challenge. This clearance was mediated by CD8 T cells, as continuous CD8 T cell depletion initiated at the time of viral challenge abrogated the resistance of these mice to MAIDS.

Murine AIDS protects mice against experimental cerebral malaria: down-regulation by interleukin 10 of a T-helper type 1 CD4+ cell-mediated pathology.

The retrovirus LP-BM5 murine leukemia virus induces murine AIDS in C57BL/6 mice that has many similarities with human AIDS; Plasmodium berghei ANKA causes experimental cerebral malaria in the same strain of mice. The outcome of malaria infection was studied in mice concurrently infected with the two pathogens. The retrovirus significantly reduced the gravity of the neurological manifestations associated with Plasmodium berghei ANKA infection. The protection against experimental cerebral malaria induced by murine AIDS increased with duration of viral infection and, hence, with the severity of the immunodeficiency. Interleukin 10, principally from splenic T cells, was shown to play a crucial role in this protection.

The significance of the pre-challenge immune status of mice for development of retrovirus-induced immunodeficiency syndrome (MAIDS).

The effects of vaccination with RNA-free viral pseudoparticles, preinfection with non-pathogenic ecotropic virus, and induction of tolerance to viral proteins in newborns on the outcome of murine immunodeficiency syndrome (MAIDS) were studied. The parameters used to follow disease progression were: lymphopenia, circulating B and T8 cells, serum IgG and IgM levels, lymphoproliferation and skin graft rejection. Immunization with RNA-free viral pseudoparticles had no effect on any of these parameters. Preinfection of adults with ecotropic virus and the induction of tolerance in newborns to virus antigens both attenuated the early symptoms of viral infection and delayed the onset of immunodeficiency and lymphoproliferation in some mice, but did not significantly alter the number of deaths due to MAIDS. Failure of immune-based therapy to produce successful protection against MAIDS suggests that immune destruction caused by the persistent virus rather than hyperimmune activity is the main pathogenic factor in this disease.

Epidermal calcium-binding protein: a marker of early differentiation of basal layer keratinocytes of rats.

Epidermal calcium-binding protein (ECaBP) is present in the cells of the basal layer of the epidermis and other stratified epithelia. Since the basal layer compartment contains at least two types of cells: slow-cycling, poorly-differentiated, and actively proliferating, more differentiated cells, it was of interest to determine whether they both contained ECaBP. Basal and nearly suprabasal layer keratinocytes from newborn rat epidermis were fractionated into three fractions on the basis of cell size, using low-gravity sedimentation. The cell differentiation in each subgroup was estimated by cell size, morphology, cell cycle stage, RNA/DNA content, and the presence of specific keratins. The presence of ECaBP in these fractions was detected by immunocytochemistry and immunoblotting. Double staining with ECaBP antibodies and propidium iodide followed by flow cytometry was used to correlate ECaBP production and the stage of cell cycle. The relative cell size, measured by the light scattering was used to study the relationship between cell size and ECaBP production. The results show that small keratinocytes with low DNA and RNA content (G0 cells) do not express ECaBP. ECaBP was found only in intermediate size basal keratinocytes with higher DNA and RNA contents, corresponding to actively proliferating S phase cells. Large keratinocytes, which express suprabasal keratin and have low DNA and high RNA content, cease to express ECaBP. ECaBP may, therefore, be a useful marker for assessing the movement of cells from poorly differentiated reserve compartment towards proliferation and further differentiation in both physiological and pathological situations.

Multiple vertebral hemangiomas with neurological signs. Case report.

A case of multiple vertebral hemangiomas with progressive neurological deficit is presented. Successful treatment was accomplished using preoperative embolization, palliative surgical decompression, and postoperative radiation therapy. The patient has remained asymptomatic for 6 years. The authors review the role of current imaging modalities and options for therapeutic intervention. Preoperative embolization, palliative surgical decompression, and postoperative radiotherapy appear to provide a satisfactory outcome in patients with multiple hemangiomas and may represent an effective alternative to more aggressive surgical intervention.

Characteristics of homogeneously small keratinocytes from newborn rat skin: possible epidermal stem cells.

The aims of the present study were to characterize the phenotype, growth kinetics, and proliferative activation in culture of a population of poorly differentiated homogeneously small (HS) keratinocytes. These slow-cycling cells were separated by unit gravity sedimentation from a population of actively proliferating basal keratinocytes in newborn rat skin. This population (approximately 1% of the total basal keratinocytes) consisted of extremely small cells with little cytoplasm or RNA. Their positive KL4 staining demonstrates that they were keratinocytes. HS keratinocytes did not, however, contain epidermal calcium binding protein. Acridine orange, bivariate Hoechst, and ethidium bromide flow cytometry of in vitro bromodeoxyuridine-labeled cells as well as Ki67 staining showed that HS keratinocytes were in the G0 stage of the cell cycle and did not actively proliferate in vivo. [3H]thymidine label-retaining cells were found only in the HS cell population, showing that HS cells may originate from a central position in the epidermal proliferative unit. Growth of HS cells in vitro was characterized by a delayed but progressive increase in RNA before entry into the cell cycle. The clonogenic efficiency of HS cells in primary culture was much less than that of larger cells. Subclones of HS cell colonies exceeded primary colonies in their cloning efficiency and proliferative potential, suggesting that HS cells, although normally prevented from dividing, retain a high self-renewal capacity. They also maintain the ability to differentiate. The results are consistent with the concept that HS cell population may represent the epidermal-specific progenitor cells which act as stem cells in this tissue.

Radiotherapy in the management of cutaneous epidemic Kaposi's sarcoma.

Between June 1986 and December 1988, we treated 149 patients who had AIDS-related epidemic Kaposi's sarcoma with cutaneous irradiation. According to Mitsayasu's staging, 34 patients (23%) had Stage I disease, 82 (55%) Stage II, 0 Stage III, and 33 (22%) Stage IV. Fifty-eight patients (39%) had previously presented with one or more opportunistic infections. Ninety-four patients (63%) had received previous treatment of their Kaposi's sarcoma: 85 (57%) with interferon and 43 (29%) with vinblastine. Among the 149 patients, we treated 88 (59%) with extended cutaneous irradiation using 4- and/or 8-MeV electron beam energy and 61 patients (41%) with localized irradiation using 45-kVp x-ray energy. The total prescribed dose was 30 Gy: 20 Gy in 2 weeks (2.5 Gy/fraction, 4 times/week), followed by 2 weeks of no irradiation, and then 10 Gy in one week by the same dose schedule. Twenty patients (13%) with edema of the lower limbs were treated using 4-Mv photon therapy with bolus. Of the 131 evaluable patients, 63% achieved a complete remission (CR) and 30% a partial remission (PR) after a mean period of 1.5 months (range: 0.5-3 months). The clinical disease stage, anatomic site, and irradiation technique did not significantly influence the remission rates, although we noticed a higher CR rate when localized irradiation was used (71% vs 55.5% for localized and extended irradiation, respectively; p = 0.08). The overall tolerance was acceptable. Complications were severe epidermitis with skin ulcerations (8% of patients), exudative epidermitis (26%), dry epidermitis (60%), and varying degrees of erythema (6%). Of the 87 patients whose AIDS remained relatively clinically stable during the observation period, recurrences occurred in 56 (64%) after an average of 5.5 months (range: 1.5-12 months). We conclude that radiotherapy is useful and can be recommended as a palliative treatment to relieve pain and physical discomfort or to achieve cosmetic improvements for patients with epidemic Kaposi's sarcoma. We also conclude that radiotherapy is most beneficial in the early stages of disease, when localized treatment is practical.

External irradiation prior to conservative surgery for breast cancer treatment.

From 1981 to 1987, 138 patients with breast cancer unsuitable for primary tumorectomy received initial external radiotherapy (45 Gy/25f/35d) in order to reduce the tumor volume so that secondary limited surgery could be performed. There were 81 T2 and 57 T3. Fifty-seven percent of the patients had a tumor larger than 4.5 cm. After completion of the radiotherapy, 22 patients (16%) showed no more evidence of a tumor either clinically or radiologically and received a boost of 25 Gy. In 52 cases (38%) the tumor regression allowed for secondary tumorectomy followed by a boost of 20 Gy. Sixty-four patients (46%) showed either little or no tumor regression: radical surgery was performed in 14 cases (10%) and high dose boost curietherapy (37 Gy) in the 50 (36%) remaining patients who refused mastectomy. Breast conservation in good condition was thus obtained in 74 patients (54%). Sufficient tumor regression to allow secondary tumorectomy was more often observed in T2 than in T3, in poorly differentiated tumors or mucinous type, and in tumor with well defined mammographic aspects. Actuarial 5-year local control and disease-free survival rates after limited surgery were, respectively, 90% and 73%. No particular complications were observed after secondary tumorectomy. This therapeutic approach is encouraging in patients with large T2 and T3 breast tumors, but a longer follow-up is required to assess definitive conclusions.

Stage I-II squamous cell carcinoma of the oral cavity treated by iridium-192: is elective neck dissection indicated?

This is a retrospective analysis of 233 evaluable patients with stage I-II squamous cell carcinoma of the oral cavity treated by definitive branchytherapy. Minimum follow-up is 3 years. Treatment of neck was chosen by a multidisciplinary team, according to age, medical status and availability for regular follow-up. One hundred and ten patients (47%) underwent elective neck dissection (END); 28 (25%) had positive nodes and received neck irradiation post-operatively. One hundred and twenty three patients (53%) were regularly followed up only, with therapeutic neck dissection (TND) reserved for cases of node relapses. In the END group, there were 19 neck relapses (17%): 12/60 (20%) in patients with mobile tongue carcinoma and 7/50 (14%) in patients with floor of the mouth carcinoma. Salvage treatment was successful in 9/19 (47%) cases. In the TND group, there were 21 neck relapses (17%): 16/82 (20%) in patients with mobile tongue carcinoma and 5/41 (10%) in patients with floor of the mouth carcinoma. Salvage treatment was successful in 13/21 (62%) cases. Ten-year survival is 37% for the END group and 31% for the TND group. Tumour stage and infiltration into underlying tissues increased the probability of neck relapse and death. Furthermore, a multivariate analysis showed that patients treated in the TND group had a higher probability of death than patients treated in the END group (p less than 0.04).

Cell size and RNA content correlate with cell differentiation and proliferative capacity of rat keratinocytes.

Keratinocytes from rat skin were separated according to their size in a specially designed unit-gravity sedimentation chamber. The fractions obtained with this technique showed clear morphological differences, and analysis of size distribution confirmed that size was the criterion for separation. Simultaneous DNA and RNA staining of the fractions with acridine orange and subsequent flow cytometric analysis enabled one to classify cells into resting, proliferating, and differentiating stages. Cell size was not directly correlated with proliferation in situ as determined with acridine orange flow cytometry, nor with proliferative capacity in culture as assayed by BrdU/Hoechst flow cytometry. The smallest cells, exhibiting low DNA and RNA content, which do not proliferate in vivo, required a prolonged period of serum stimulation in vitro to initiate RNA and DNA synthesis. Cells of intermediate size exhibited early RNA synthesis and maximal proliferative capacity, whereas the largest cell population displayed no RNA synthesis in culture and the least proliferative capacity. In conclusion, these results suggest that RNA synthesis early after serum stimulation, in addition to a specific, optimal cell size, correlates with the proliferative capacity of keratinocytes in cell culture.