Do oxidized zirconium heads decrease tribocorrosion in total hip arthroplasty? A study of retrieved components.

AIMS: The aim of this study was to evaluate fretting and corrosion in retrieved oxidized zirconium (OxZr; OXINIUM, Smith & Nephew, Memphis, Tennessee) femoral heads and compare the results with those from a matched cohort of cobalt-chromium (CoCr) femoral heads. PATIENTS AND METHODS: A total of 28 OxZr femoral heads were retrieved during revision total hip arthroplasty (THA) and matched to 28 retrieved CoCr heads according to patient demographics. The mean age at index was 56 years (46 to 83) in the OxZr group and 70 years (46 to 92) in the CoCr group. Fretting and corrosion scores of the female taper of the heads were measured according to the modified Goldberg scoring method. RESULTS: The OxZr-retrieved femoral heads showed significantly lower mean corrosion scores than the CoCr heads (1.3 (1 to 2.75) vs 2.1 (1 to 4); p < 0.01). Mean fretting scores were also significantly lower in the OxZr cohort when compared with the CoCr cohort (1.3 (1 to 2) vs 1.5 (1 to 2.25); p = 0.02). OxZr heads had more damage in the proximal region compared with the distal region of the head. Location had no impact on damage of CoCr heads. A trend towards increased corrosion in large heads was seen only in the CoCr heads, although this was not statistically significant. CONCLUSION: Retrieval analysis of OxZr femoral heads showed a decreased amount of fretting and corrosion compared with CoCr femoral heads. OxZr seems to be effective at reducing taper damage. Cite this article: Bone Joint J 2019;101-B:386-389.

In vitro effect of doxorubicin on non-proliferating and proliferating epithelial cells.

In vitro cultured mouse kidney epithelial cells were exposed for 2 hr to 0.5 microgram/ml of Doxorubicin. The proliferative activity of the cells was determined by combined DNA and total nuclear protein measurements. The sensitivity of the cells to the drug was higher in proliferating cells as compared to non-proliferating ones, that is, those exhibiting low amounts of total nuclear protein per unit DNA.

Long term effects on the immune system following local radiation therapy for breast cancer. I. Cellular composition of the peripheral blood lymphocyte population.

Local radiation therapy for breast cancer depletes the blood of various subsets of lymphocytes. Previous studies showed that the recovery is still incomplete at 30 months. To further elucidate the recovery we examined blood lymphocyte counts of 138 disease-free women and various lymphocyte subsets in 102 of these patients. These patients, 5-6 and 10-11 years earlier, had entered a clinical trial in which preoperative irradiation (45 Gy) was evaluated against postoperative irradiation (45 Gy) or surgery only. Patients who had undergone surgery only served as controls. Total lymphocyte counts of the irradiated patients were still significantly reduced 10-11 years after treatment. This reduction was mainly attributable to a subnormal level of T-cells as determined by the monoclonal antibody Leu-1 and the ability to form rosettes with sheep erythrocytes, whereas the number of non-T cells, expressing C'3 receptors, did not differ significantly from the controls. Within the T-cell population a subset with helper/inducer phenotypes, detected by Leu-3a antibodies, was significantly reduced even 10-11 years after irradiation. T-cells with suppressor/cytotoxic phenotypes, stainable with Leu-2a antibodies, however, had already recovered 5-6 years after irradiation. The duration of the radiation induced reductions of different lymphocyte subsets may be related to the physiological turn-over of the cells or a changed distribution of cells in the body.

Long-term outcome of radical radiation therapy for prostatic carcinoma: 1967-1987.

PURPOSE: This study was done to review long-term results of radical radiotherapy for prostate cancer. METHODS AND MATERIALS: The records of 674 patients with Stage T1a, T1b, T2a, T2b, T3, and any T,N1,M0 disease, treated with external beam radiotherapy between January 1, 1967 and December 1987, were reviewed. These patients were treated to an average total dose of 66 Gy, with an average fractional dose of 2.05 Gy, using megavoltage. The duration of follow-up for surviving patients ranged from a minimum of 7 years to more than 20 years. RESULTS: The survival for 151 Stage T1a,T1b patients was 98.5% at 5 years, 93.6% at 10 years, and 75.2% at 15 years. Survival for 346 Stage T2a,b patients was 94.4% at 5 years, 67.9% at 10 years, and 41.5% at 15 years. Survival for 92 Stage T3 patients was 87.3% at 5 years, 54% at 10 years, and 26.6% at 15 years. The survival for 85 any T,N1,M0 patients was 73.9% at 5 years, 34.4% at 10 years, and 8.5% at 15 years. At 15 years, 75.2% of Stage T1a,b patients, 41.5% of Stage T2a,b patients, 21.7% of Stage T3 patients, and 8.5% of Stage T,N1,M0 patients remained free of local recurrence and distant metastases. The elevation of prostatic acid phosphatase prior to radiotherapy was an unfavorable prognostic factor, with impact on both loco-regional recurrences and survival. CONCLUSIONS: The external beam radiotherapy for localized carcinoma of the prostate produced a good loco-regional control, NED, and overall survival. Patients with smaller tumors and low grade fared better than the ones with more aggressive and/or bulky tumors. The weakness of this study is the absence of serial prostate-specific measurements, which were not available during the period under study. The complication rate requiring surgical intervention was low, i.e. 0.4%.

Depressed responder and stimulator capacities of peripheral lymphocytes from patients with advanced breast cancer in the mixed lymphocyte culture.

Peripheral lymphoid cells of patients with carcinoma of the breast were examined for reactivity (responders) against allogeneic lymphoid cells in the one-way mixed lymphocyte culture. The latter cells were also tested for response against the patients' lymphocytes (stimulators). The responder and stimulator capacities of lymphoid cells of patients with advanced cancer were found to be significantly reduced compared to cells from healthy subjects. Such defects were not observed in disease-free women previously treated for primary carcinoma of the breast. The results support the view that there is an abnormality of the lymphocyte-monocyte pool of cells in patients with advanced cancer.

Possible role of prostaglandin producing monocytes in the depression of mitogenic responses of blood lymphocytes following radiation therapy.

Previous studies have shown that the depression of mitogenic responses of cultured blood lymphocytes following radiation therapy can largely be explained by immunosuppressive cells. In this investigation we have shown that the addition of silica, a monocyte toxic agent, to the cultures enhance the PHA- and PPD-responses of the cells at completion of irradiation. Such an effect, however, was not noted before radiation treatment was started. Similar results were obtained by adding indomethacin, an inhibitor of prostaglandin synthesis, to the cultures. The results thus indicate that immunosuppressive monocytes which mediate their activity by prostaglandins are involved in the reductions of mitogen responses of blood lymphocytes following irradiation.

Long-term effects on the immune system following local radiation therapy for breast cancer. 4. Proliferative responses and induction of suppressor activity of the blood lymphocyte population.

The long-term effect of local irradiation for breast cancer on the blood lymphocyte population was examined in 149 women who had been disease-free for 5-6 and 10-11 years. The patients were included in a clinical trial aiming at determining the value of pre- and post-operative irradiation (45 Gy) compared to surgery only. It was observed that the relative mitogen responses of lymphocytes to phytohaemagglutinin (PHA) and Concanavalin (Con A) and in a mixed lymphocyte culture (MLC) were significantly lower in irradiated compared to unirradiated patients at least a decade after treatment. The prolonged reductions of mitogen responses after irradiation could partly be due to an increased proportion of lymphocytes which may express suppressor function since the Con A-inducible suppressor activity of lymphocytes was significantly higher in irradiated compared to unirradiated patients.

Neuroimmunoregulation and cancer (review).

It is certain that neuroimmune mechanisms play a role in host defence against cancer. However, this interaction is highly complex and many variations are possible according to the nature of the neoplasms involved. There are indications that adaptive immunity is present in a significant proportion of tumor bearing hosts, and this defence may be boosted by specially designed vaccines and cytokines. Natural immune mediators are also implicated in resistance against tumor development. Here we review the evidence suggesting that hormonal manipulation of the host can result in the elevation of immune defences against cancer. Such manipulation strengthens both the adaptive and natural immune defences of the host, both of which play significant roles. Natural defence mechanisms are boosted by cytokines and hormones during febrile reactions which are now known as the acute phase response. It is suggested that hormonal stimulation of immune mechanisms coupled with the usual immunostimulants already in use may be employed to good advantage for the combination immunotherapy of cancer. Modern molecular biology approaches permit the development of laboratory monitoring procedures which may be used for the prediction and follow-up of therapeutic success.

Spindle cell carcinoma of the breast: four cases and review of the literature.

The clinical and morphologic features of four cases of spindle cell carcinoma of the breast are presented, and the comparable features of 35 previously reported cases are reviewed. All tumors contained histologically malignant squamous carcinoma that tended to blend with a spindle cell "pseudosarcomatous" stroma. Patients with this rare tumor tend to present at the same age as patients with other histologic types of breast carcinoma, but the spindle cell tumors are somewhat larger. Although the number of reported patients is too small to serve as a basis for firm conclusions, the prognosis appears similar to that for patients with conventional infiltrating duct carcinoma of the breast.

Long-term effects on the immune system following local irradiation for breast cancer. Pokeweed mitogen induced immunoglobulin secretion by blood lymphocytes and serum immunoglobulin levels.

Previous studies have shown that the PWM driven immunoglobulin (Ig) secretion by blood lymphocytes in vitro is reduced shortly after local radiation therapy for breast cancer. In this investigation we have examined the long-term effects of radiation therapy (45 Gy) on this lymphocyte function. A total of 111 disease-free patients treated for operable breast cancer 5-6 and 10-11 years earlier were examined. The Ig classes studied were IgM, IgA and IgG. All patients belonged to a clinical trial where the effect of pre- or post-operative local radiation therapy was evaluated against surgery only. Significant reductions of the amount of spontaneously released IgM in vitro were observed among irradiated patients as compared to the unirradiated 5-6 and 10-11 years after treatment. Such a difference was not observed for IgA and IgG. The PWM induced Ig secretions did not differ significantly between the three patient groups. The long standing reduction of the spontaneous release of IgM by blood lymphocytes in vitro probably lacks clinical significance since the serum levels of this Ig class, as well as IgA and IgG, were similar in irradiated and unirradiated patients.

Immunohistochemical analysis of estrogen receptors in cells obtained by fine needle aspiration from human mammary carcinomas.

An immunocytochemical assay for the estrogen receptor has been used to analyze the receptor content in tumor cells obtained by fine needle aspiration from human breast carcinomas. The results were compared with receptor determinations on cryostat sections of freshly frozen tumors and by biochemical technique based on radiolabelled ligand binding. The staining intensity and fraction of positive cells were comparable in cryostat sections and tumor cell specimens obtained by fine needle aspiration. Moreover, there was a good correlation between the semiquantitative receptor level estimated by the immunoperoxidase technique and the biochemical assay. These results show that tumor cell specimens obtained by fine needle aspirates can be used for estrogen receptor analysis by the immunocytochemical technique.

Combination therapy of the H2712 murine mammary carcinoma with cytotoxic T lymphocytes and anti-estrogens.

BACKGROUND: The triphenylethylene antiestrogenic agents, tamoxifen (TX) and toremifene (TO), are currently being used for the therapy of estrogen dependent breast carcinomas and for some other estrogen receptor positive tumors. Some observations indicate that these drugs may have a beneficial effect on estrogen receptor negative tumors as well. MATERIALS AND METHODS: The H2712 mammary carcinoma of C3H/HeJ mice was studied in combination immunotherapy experiments using cytotoxic T lymphocytes (CTL) and TX or TO. The effect of TX and TO on the in vitro lysis of H2712 cells by CTL was also investigated. Finally, the H2712 cells were examined for the presence of estrogen receptors. RESULTS: Both TX and TO potentiated the lysis of H2712 cells by CTL in vitro, and exerted a growth inhibitory and therapeutic effect on H2712 mammary carcinomas in vivo. The therapeutic effect of CTL isolated from tumor bearing mice was improved on H2712 carcinomas when the animals were also treated orally by TX or TO. Using the dextran-coated charcoal assay, H2712 cells were found to be negative for classical estrogen receptors. CONCLUSIONS: These results indicate that the anti-estrogens, TX and TO, have the ability to suppress the growth of the estrogen receptor negative mammary carcinoma and to amplify target cell lysis by tumor-reactive CTL. By this mechanism these drugs enhance host immunity to an estrogen receptor negative tumor.

Combination immunotherapy of the P815 murine mastocytoma with killer cells, IL-2 and anti-estrogens.

BACKGROUND: Lymphokine activated killer (LAK) cells, cytotoxic T lymphocytes (CTL) and interleukin-2 (IL-2) all are being tested in cancer immunotherapy with modest success. The anti-estrogenic drug, toremifene (T0), was found earlier to amplify cancer immunotherapy with killer cells in mice. Here T0 is examined in combination with CTL and IL-2 in immunotherapy experiments. MATERIALS AND METHODS: The P815 mastocytoma of DBA/2 mice was treated with combinations of CTL, LAK cells and T0 and combinations of CTL, IL-2 and T0 along with control groups. Tumor growth rate and mortality has been recorded. RESULTS: Combined treatment with CTL and LAK cells cured 25% of tumor bearing animals, as did treatment with tamoxifen (TX) or T0 alone. When killer cells were given in conjunction with anti-estrogens the cure rate was 75% with both TX and T0. Human recombinant IL-2 significantly inhibited tumor growth but no cures occurred. CTL alone cured 25% of the animals. When CTL and IL-2 treatment was given jointly with T0 75% of tumor bearing animals were cured. CONCLUSIONS: The results indicate that treatment with anti-estrogens increased the efficiency of immunotherapy by killer cells. This was true also when CTL therapy was supplemented with IL-2 treatment.

Immunotherapy of the SL2-5 murine lymphoma with natural killer cells and tamoxifen or toremifene.

It is well established that tamoxifen (TX) has a therapeutic effect on estrogen receptor positive tumors by inhibiting the binding of estradiol to its receptor. However, repeated clinical observations indicate that tamoxifen may also have beneficial effects on estrogen receptor negative tumors. In vitro cytotoxicity experiments were performed with the SL2-5 murine lymphoma using interleukin (IL)-2 activated syngeneic NK cells as effectors with or without TX or TO treatment. The effect of TX or TO (10 mg/kg/day/animal in feed) on the immunotherapy of SL2-5 lymphoma with syngeneic IL-2 activated NK cells was also investigated in syngeneic DBA/2 mice. Assays of SL2-5 cells for estrogen and progesterone receptors were also performed. Both TX and TO enhanced significantly the susceptibility of the SL2-5 lymphoma to lysis by IL-2 activated NK cells in vitro. When TX or TO treatment was combined with NK cell immunotherapy of this tumor, both drugs potentiated significantly tumor regression and cure rate when compared to groups receiving NK therapy alone. This tumor does not express classical receptors for estrogens or progesterone. These results indicate that combination treatment with the antiestrogens, TX and TO, acts synergistically with the immunotherapeutic effect of IL-2 activated NK cells in a syngeneic tumor host system.

Anti-estrogens potentiate the immunotherapy of the P815 murine mastocytoma by cytotoxic T lymphocytes.

Many animal and human tumors are infiltrated with killer cells. Recent studies have shown that the stimulation of such killer cells with interleukin-2 improves their tumor rejecting capacity. In this paper we demonstrate that the anti-estrogens, tamoxifen (TX) and toremifene (TO), enhance host resistance by sensitizing the tumor target to killer cell mediated lysis. The P815 mastocytoma syngeneic to DBA/21 mice was used. Cytotoxic T lymphocytes (CTL) were detected in the spleens of mice 12-14 days after tumor inoculation. In vitro target, effector, or both cell types were treated with either TX (1 microM) or TO (5 microM) for 4 hours prior to cytotoxicity testing by 51Cr release. Mice bearing P815 mastocytomas, 5 mm in diameter, were treated orally with TX or TO and were given CTL isolated from the spleens of tumor bearing donors i.p. Tumor growth, mortality, and immunological memory in cured animals were monitored. Both TX and TO treatment sensitized P815 target cells to lysis by CTL isolated from tumor bearing animals. The transfer of killer cells from the spleens of tumor bearing mice produced tumor suppression in the recipients, which could be enhanced by additional oral treatment by TX or TO. Complete cure was achieved in a significant number of animals, showing partial or complete resistance to a subsequent lethal dose of P815 cells. These experiments indicate that killer cells isolated from mice bearing progressive tumors can have an immunotherapeutic effect in syngeneic tumor bearing recipients and that the antiestrogens, TX and TO, may be used to potentiate the immunotherapy of this tumor.

Lymphocyte subpopulations and reactivity in breast cancer recurrence following adjuvant postoperative chemotherapy.

The size of various subset of blood lymphocytes and stimulations with PHA and allogeneic cells (MLC) were examined in 45 women with breast cancer receiving postoperative adjuvant cyclic chemotherapy with chlorambucil, methotrexate, and 5-fluorouracil (LMF). The patients who remained disease-free (n = 19) and those who relapsed (n = 26) during a 4.5 to 6-year follow-up period had similar initial values; and similar kinetics of the examined immunological parameters during and following completion of treatment.

Long-term effects on the immune system following local radiation therapy for breast cancer. III. Changes of spontaneous and lectin dependent cellular cytotoxicity.

Long-term effects of local radiotherapy (45 Gy) on the spontaneous and PHA-mediated cytotoxicity of the peripheral blood lymphocyte population was studied in disease-free breast cancer patients 5-6 and 10-11 years after treatment. The patients were all part of a randomized trial in which pre- or post-operative radiotherapy was evaluated against surgery only. PHA-mediated cytotoxicity for 51Cr-labelled chicken erythrocytes seemed to be somewhat increased in patients who were irradiated 5-6 years earlier (p less than 0.025). This increase was not detectable after a disease-free period of 10-11 years. No significant differences between the various treatment groups were observed for spontaneous cytotoxicity against Chang and K 562 cells. The proportion of Leu 7+ lymphocytes was significantly increased in patients who received radiation therapy 5-6 years earlier (p = 0.029) and there was a significant correlation between PHA-mediated cytotoxicity and proportion of Leu7+ cells.

Antiestrogens affect both pathways of killer cell-mediated oncolysis.

BACKGROUND: Our previous studies indicate that antiestrogenic drugs tamoxifen (TX) and toremifene (TO) augment immune oncolysis induced by various killer cells. The underlying mechanism(s), however, have not been fully elucidated. MATERIALS AND METHODS: Ovarian carcinoma cells freshly isolated from cancer patients and the human erythroleukemia cell line, K562 were used as targets for killer cells and/or the anti-Fas monoclonal antibody, CH-11 in 51Cr release assays. In a number of experiments, extracellular Ca++ was chelated by EGTA/MgCl2 to distinguish Ca(++)-dependent perforin/granzyme pathway from Fas/FasL pathway. Fas expression was studied by flow cytometry. RESULTS: Ovarian carcinoma cells were sensitized by antiestrogens towards enhanced cytolysis mediated by autologous cytotoxic lymphocytes. Antiestrogens also significantly augmented the killing of ovarian carcinoma cells triggered by anti-Fas monoclonal antibody. Flow cytometry analyses showed an upregulation of Fas (CD 95/Apo-1) upon TX or TO treatment in a number of cases. By contrast, antiestrogen treatment did not induce Fas expression in the Fas-negative K562 cells; yet, natural killer cell-mediated cytotoxicity against K562 was augmented by antiestrogens and maximal lysis was achieved when both target and effector cells were treated. The presence of Ca++ chelator (EGTA/MgCl2) in the assay abrogated killing of K562 and its antiestrogen--mediated augmentation. This indicates the involvement of the perforin/granzyme pathway. CONCLUSION: Antiestrogens can influence both Fas/FasL and perforin/granzyme pathways of killer cell--mediated oncolysis.

Antiestrogens sensitize human ovarian and lung carcinomas for lysis by autologous killer cells.

BACKGROUND: The antiestrogens tamoxifen (TX) and toremifene (TO) were shown previously to enhance the lysis of target cells by natural killer cells (NK), lymphokine activated killer (LAK) cells, and by cytotoxic T lymphocytes (CTL). MATERIALS AND METHODS: CTL were cultured from lung cancer tissue and from ascites fluid of ovarian carcinoma patients with the aid of human recombinant interleukin-2 (hrIL-2). The target, effector or both cell populations were pretreated by TX, TO and/or with human recombinant interferon-alpha (IFN-alpha). RESULTS: Significant enhancement of cytotoxicity occurred when the tumor targets or both the target and effector cells were treated with TX, TO or when these drugs were used in combination with IFN-alpha. The lytic activity of CTL cultured from draining lymph nodes of lung cancer patients, was also observed after similar treatment. The lytic effect of autologous LAK cells derived from peripheral blood was increased to a lesser extent, which could be amplified by additional treatment with IFN-alpha. CONCLUSIONS: The antiestrogens TX and TO and IFN-alpha enhance the lysis of autologous tumor cells by CTL and LAK effectors.

Effect of radiation therapy and in vitro x-ray exposure on lymphocyte subpopulations and their functions.

Radiation treatment of breast cancer patients (45.0 Gy) profoundly affected the peripheral blood lymphocytes. The number of these cells was markedly reduced with non-T-cells being more extensively depleted than T-cells immediately after radiation. The long-lasting lymphopenia, on the other hand, was mainly due to reduced number of T-cells. Antigen and mitogen stimulability, MLC reactivity, pokeweed (PWM)-induced immunoglobulin (Ig) production in vitro, and different cytotoxic functions decreased. Depletion of lymphocytes largely restored the radiation-depressed lymphocyte reactivity. The effects of in vitro exposure of blood lymphocytes to x-rays were similar to those seen after radiotherapy. Non-T-cells and T-cells with Fc-receptors for IgG were relatively radiosensitive. This latter observation agreed well with demonstrated increase of PWM-induced Ig synthesis after in vitro exposure to x-rays. T-suppressor cells defined by monoclonal antibodies were, however, radioresistant. The cytotoxic functions were reduced. No correlations were found between the pretreatment immunological status or the extent of radiation-induced immunological suppression, respectively, and prognosis.