End-of-life issues: Anencephalic infants as organ donors.
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Anencephaly↗
Biomedical subjects
R Lafreniere
Publications and source records attributed to R Lafreniere.
Air ambulance trauma transport: a quality review.
OBJECTIVE: Provincial air ambulance transports of injured patients were quality reviewed prospectively to determine utilization and appropriateness of care. METHODS: All trauma air ambulance transports over a 2-month span were reviewed prospectively. Revised Trauma Score, Injury Severity Score, probability of survival, prehospital time, distance of transport, procedures performed, and outcome were determined. Quality control questions were asked of the sending and receiving physicians. RESULTS: The majority of air ambulance transports reviewed (N = 97) were indicated for mechanism and severity of injury. Economics and requirement for advanced medical care were indications in only 15%. Physicians tended to perform more advanced procedures, likely related to higher patient Injury Severity Score (23 vs. 15, p = NS). Four problems with air ambulance access were identified. The overtriage rate was 5%. Inappropriate patient care was documented in six (6%) cases; a physician was present for only one of these. CONCLUSIONS: A low overtriage rate was documented, raising concerns that the undertriage rate may be too high. Injured patients air transported without physician accompaniment more often received inappropriate care, suggesting that physician accompaniment is beneficial.
Adult↗
Enhancement of true-positive rates for nonpalpable carcinoma of the breast through mammographic selection.
A retrospective review of 332 needle localization biopsies for nonpalpable mammographic abnormalities was performed. Twenty-one invasive and 12 noninvasive carcinomas were identified in this population, for a true positive biopsy rate of 10 percent. A review of all needle localization mammograms performed on these patients by a radiologist specializing in mammography identified 225 mammograms with a low probability of malignancy. In this group, there were four in situ and six invasive carcinomas (true positive biopsy rate of 4 percent). In the remaining 107 mammograms with a high probability of malignancy, there were eight in situ and 15 invasive carcinomas (true positive biopsy rate of 21.4 percent). In the low probability group, fine needle aspiration or excisional biopsy were recommended for six of the ten neoplasms and follow-up mammograms at three to six months for the remaining four (two in situ and two invasive carcinomas). Using selectivity, 225 biopsies could have been avoided at a savings of $97,368 (Canadian dollars) in fees for physicians alone while still identifying 29 of 33 neoplasms (87 percent of all neoplasms) and possibly delaying diagnosis for three to six months or longer in four of 33 neoplasms (13 percent, two in situ and two invasive) for which follow-up mammograms were recommended.
Adult↗
Granular cell neoplasm of the extrahepatic biliary tree: morphological, ultrastructural, and immunohistochemical study and review of the literature.
A recent case of a biliary granular cell tumor of the cystic duct prompted a literature review and an extensive pathological examination of the tumor in question. A total of 44 cases have been described mostly in black females. Most cases present with biliary symptoms, and simple surgical resection allows complete control of this benign condition. Granular cell tumors are most likely derived from neural crest cells.
Adult↗
Indwelling subclavian catheters and a visit with the "pinched-off sign".
Percutaneously inserted indwelling subclavian vein silastic catheters have revolutionized the administration of chemotherapeutic agents. Complications associated with insertion of such lines have always included bleeding, pneumothorax, haemothorax, arterial cannulation, and catheter displacement. Recently a patient receiving 5-fluorouracil and folinic acid for 11 months for small bowel carcinoma experienced a catheter fracture with distal segment embolization in the right atrium. A literature survey revealed 13 cases where mechanical shearing forces on the catheter caused by compression of the catheter between the clavicle and first rib were thought to be the cause for this complication. Interestingly all cases involved patients receiving chemotherapy. Radiologically, potential candidates for catheter fracture can be identified by the pinched-off sign with bending and pinching of the catheter at the thoracic inlet. Recommendations are for more lateral insertions of such percutaneously placed catheters and if the pinched-off sign is seen, then said catheters should be followed radiologically and probably should not remain in situ for longer than 6 months.
Adult↗
Production and characterization of tumor infiltrating lymphocyte clones derived from B16-F10 murine melanoma.
The adoptive transfer of tumor infiltrating lymphocytes (TIL) in conjunction with recombinant interleukin-2 (rIL-2) for the treatment of advanced cancer has recently been under intense investigation. Despite extensive research, the precise surface phenotype of TIL remains to be fully defined. To elucidate this unsolved problem, we established 11 TIL clones derived from rIL-2 expanded TIL obtained from B16-F10 murine melanoma tumors. These clones could be divided phenotypically into four groups: CD8 (+) T-cell clones, natural killer (NK)-cell clones, NK-like CD8 (+) T-cell clones, and double negative T-cell clones. Functionally, CD8 (+) T-cell clones demonstrated specific cytotoxic activity against B16-F10 melanoma cells, whereas NK-cell clones and double negative T-cell clones demonstrated only non-specific cytotoxic activity against NK-sensitive YAC-1 cells. NK-like CD8 (+) T-cell clones showed dual cytotoxic activity. Clones T1 [a CD8 (+) T-cell clone] and T2 [an NK-like CD8 (+) T-cell clone] which had cytotoxic activity against B16-F10 melanoma cells, demonstrated a proliferative response against immunoblotted B16-F10 melanoma antigens, whereas clones T7 (an NK-cell clone) and T10 (a double negative T-cell clone), which had no cytotoxic activity against B16-F10 cells, demonstrated no proliferative response against them. Winn assays revealed that only the CD8 (+) T-cell clone (T1) had an antitumor effect in vivo, whereas the double negative T-cell clone (T10) and NK-like CD8 (+) T-cell clone (T2) stimulated tumor growth in vivo. Adoptive immunotherapy using tumor-specific, highly cytotoxic TIL clones may represent a useful future immunotherapeutic option for the treatment of human tumors.
Adenocarcinoma↗
Generation of MC-38 adenocarcinoma tumor-specific tumor infiltrating lymphocytes by murine anti-CD3 antibody and recombinant interleukin-2.
The growth, in vitro cytolytic activity and phenotype of murine MC-38 adenocarcinoma tumor infiltrating lymphocytes (TILs) stimulated with anti-CD3 monoclonal antibody (mAb) and recombinant interleukin-2 (RIL-2) as compared to RIL-2 alone was investigated. When assayed for growth, anti-CD3 mAb + RIL-2 MC-38 TILs demonstrated an enhanced proliferative activity compared to RIL-2 alone (fold expansion, 16,228 and 365,713 compared to 112 and 5594, culture times: 55 and 118 days, experiments 1 and 2, respectively). TILs cultured with anti-CD3 mAb alone demonstrated little expansion (fold expansion 6 and 3, experiments 1 and 2, respectively). Early during culture, the anti-CD3 mAb + RIL-2 MC-38 expanded TILs demonstrated broad cytolytic activity (LU: day 17, against MCA-102: greater than 125, YAC-1: greater than 125, MC-38, greater than 125). This lytic picture reversed with time with increasing specificity demonstrated against MC-38 (LU: day 53, MCA-102: less than 1, YAC-1: less than 1, MC-38: 8). TILs expanded with RIL-2 alone demonstrated more lysis of the YAC-1 target and little lysis of the other targets.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenocarcinoma↗
Morphologic, phenotypic, and cytotoxic analyses of C57BL/6 murine non-parenchymal liver cells: new evidence associating murine liver large granular lymphocytes with monocyte precursors and implications for tumor immunotherapy.
Non-parenchymal liver cells (NPCs) have been implicated in murine host resistance to hepatic metastases. We have examined the relative cell number, morphology, phenotype, and cytotoxic potential of Percoll fractionated C57BL/6 murine liver NPCs. Low density (Percoll fractions 2 and 3) cells showed a large granular lymphocyte morphology and made up 76% of all NPCs recoverable, while high density (fractions 5 and 6) showed a small lymphocyte morphology and made up 10% of all NPCs. Low density cells demonstrated the following phenotype: 14% of the cells demonstrated the Thy 1.2 marker; 12%, the Lyt-2 marker; 67%, the L3T4 marker; 74%, the asialo GM1 marker; 30%, the 49H.8 marker; and 65%, the F4/80 marker. The high density cells expressed the same markers on 71%, 21%, 33%, 68%, 37%, and 19% of their cell surface, respectively. There were no differences phenotypically between high density NPCs and splenocytes except for the F4/80 expression (fractions 5 and 6 NPCs, F4/80 expression 19%, fresh splenocytes 60%). Dual color analysis of L3T4+ NPCs documented that fractions 2 and 3 cells also expressed the F4/80 marker on 85% of their cell surface and the Thy 1.2 marker on 11% of their cell surface. The high density fractions 5 and 6 L3T4+ cells expressed the F4/80 marker on 16% of their cell surface, and the Thy 1.2 marker on 89% of their cell surface. Cytotoxicity against YAC-1 [a natural killer (NK) sensitive target], MCA-102 (a NK resistant target), and WEHI-164 (a natural cytotoxicity target) were similar for fractions 2 and 3, and 5 and 6 cells. Based upon the expression of the F4/80 marker on L3T4+ cells that are Thy 1.2 negative and appear to be similar to LGLs morphologically (fractions 2 and 3 NPCs), we propose that these cells are monocyte precursors while fractions 5 and 6 cells are small lymphocytes. These findings with liver LGLs support the need for the evaluation of monocyte directed biological response modifiers in therapeutic models of murine hepatic metastases.
Animals↗
Generation of human autologous melanoma-specific cytotoxic T cells from tumor-involved lymph nodes.
Cytotoxic T lymphocytes (CTL) specific for autologous human melanoma have been successfully generated in vitro from tumor bearing lymph nodes without any stimulation by the autologous tumor. Tumor-involved lymph node cells (LNC) were cultured in serum free medium (AIM-V) containing 1,000 U/ml of recombinant interleukin-2. The best expansion and specific cytotoxicity of CTL were achieved in 4 to 6 weeks of culture. The predominant populations in cultured LNC-derived CTL were CD2+, CD3+, CD4-, CD8+, CD56-, and HLA-DR+ T cells. These data suggested that tumor-involved LNC may provide an alternative source for the generation of tumor-specific CTL in adoptive immunotherapy.
Antigens, CD↗
A new skin hook retainer as an aid to skin flap retraction.
A skin hook flange was created to ease and distribute the forces involved in skin hook retraction, shifting these forces from the fingertips to the shaft of the fingers of the person performing the retraction. It will allow for easier retraction and can be used on most standard skin hooks.
Dermatologic Surgical Procedures↗
Analysis of liver lymphoid cell subsets pre- and post-in vivo administration of human recombinant interleukin 2 in a C57BL/6 murine system.
The systemic administration of high dose recombinant interleukin 2 (RIL-2) can mediate significant reductions in the number of hepatic metastases in a murine system. This effect is sensitive to host irradiation. Both large granular (LGLs) and small (SLs) lymphocytes have been implicated as the cells mediating the antitumor effect. Utilizing selective Percoll fractionation of liver nonparenchymal lymphoid cells, we have attempted to determine the cell types involved in tumor immunotherapy of murine liver metastases during RIL-2 administration. At a RIL-2 dose of 25,000 units given i.p. three times a day, the total number of lymphoid cells seen in murine livers reached a peak on day 6 after the onset of RIL-2 therapy, lasting until day 10 and ranging from 25 to 29 times baseline values. Both LGLs and SLs were identified and SLs made up over one-half the cells present in murine livers. Phenotypic analysis of LGLs and SLs revealed that during exposure to RIL-2, bands 5 + 6 SLs expressed the Thy-1.2, Lyt-2, and Lyt-1 antigens to a greater degree than LGLs. LGLs exposed to RIL-2 demonstrated a decrease in the expression of the asialo GM1 antigen during exposure to RIL-2; however, the 49H.8 antigen normally expressed on natural killer cells and not on circulating T-cells was found only on LGLs. The role of murine liver LGLs and SLs needs to be further characterized.
Animals↗
MC-38 adenocarcinoma tumor infiltrating lymphocytes: correlation of cytotoxicity with time of tumor harvest after tumor inoculation.
Tumor infiltrating lymphocytes (TILs) are capable of mediating significant tumor regressions in vitro and in vivo in animal systems. In humans, however, many TIL cell lines are not cytotoxic in vitro, and clinical trials thus far have been less than encouraging. We attempted to correlate TIL cytotoxicity with time of tumor harvest and TIL cell surface antigenic expression. TILs harvested from early MC-38 adenocarcinoma tumors (days 9 and 20 post-tumor implantation), demonstrated significantly higher cytotoxicity against a variety of tumor targets compared to older TILs (days 31 and 37). The younger TILs had a higher expression of the Lyt-1 (Helper T cells), asialo GM1 (NK and T cells), and 49H.8 (NK cells) antigens. Comparison with the MCA-102 sarcoma, a tumor that does not lead to cytotoxic TILs, revealed a low expression of the Lyt-1 antigen on their cell surface. We conclude that TILs cytotoxicity is time-dependent and may be dependent on the presence of Lyt-1+ cells in the overall TIL population of cells.
Adenocarcinoma↗
In vivo administration of picibanil (OK-432) prior to tumor harvest leads to an enhancement of tumor-infiltrating lymphocyte (TIL) cytotoxicity.
TILs can be isolated and expanded in vitro in the presence of RIL-2. The resulting cells are highly cytotoxic in vitro and in vivo against a variety of tumor targets. Although most of the TILs bear T cell antigens on their cell surface, recent evidence suggests that natural killer (NK) cells may be part of the overall population of infiltrating cells. Based upon this evidence, we have evaluated the effects of Picibanil (OK-432), a well-known inducer of NK cell and T cell cytotoxicity, on TILs. OK-432 was administered intravenously at a dose of 100 micrograms, previously determined to be optimal for NK stimulation, to tumor-bearing animals. Two days later, control and experimental animals had their tumors harvested and processed in order to grow their TILs in vitro in complete medium containing RIL-2 at a final concentration of 1,000 U/ml. The following observations were made: 1) a greater than 300% increase in overall TIL number compared to controls on day 10 of culture returning to normal by day 30; 2) a marked increase in the percent of cells expressing cytotoxic and differentiation antigens in the experimental group compared to controls, such increase seen mostly from day 7 to day 10; 3) a marked increase in the cytotoxic activity of the experimental TILs against an NK-sensitive tumor target, the YAC-1 lymphoma, throughout the period of growth of the TILs (3-4 times controls) and to a lesser extent against an NK-resistant tumor target. These findings may have potential application, in immunotherapeutic trials against human tumors and may help to understand the reasons for the effectiveness of OK-432 in vivo against selected murine tumors.
Adenocarcinoma↗
Bloody nipple discharge during pregnancy: a rationale for conservative treatment.
Five cases of bloody nipple discharge during pregnancy without associated breast masses were seen over the past 3 years by the author. Because of the reported association of breast cancer with bloody nipple discharge, close follow-up of these women at monthly intervals during pregnancy and trimonthly during the postpartum period was carried out. In all instances, the discharge appeared late during the second trimester or during the third trimester of pregnancy. It was unilateral and spontaneous and arose from multiple ducts, and it was associated with an increase in breast size and always with the larger breast of the two. The discharge cytologic study done on all cases was negative for neoplastic cells and the discharges resolved spontaneously within 2 months of onset. Postpartum follow-up ranging from 6 months to 3 years has revealed no evidence of neoplastic changes thus far. Mammograms ordered before these patients were referred were not helpful due to the increase in density of the breast tissue secondary to the pregnancy. Because a few cases of breast cancer during pregnancy have presented solely with a bloody nipple discharge, I recommend extremely close follow-up of these women and no surgical intervention unless a mass is discovered or the nipple discharge cytology is either suspicious or positive at the initial visit or during follow-up.
Adult↗
Effects of cyclosporin on C57BL/6 splenocytes before and after culture with high-dose recombinant interleukin-2: implications for immunosuppression with cyclosporin.
Lymphokine-activated killer cells appear to arise from precursor cells bearing natural killer (NK) cell antigens. Cyclosporin (CsA) is a well-known immunosuppressive agent that can down-regulate NK cell cytotoxicity. Studies were initiated to evaluate the effects of CsA on splenocytes before and after exposure to recombinant interleukin-2 (rIL-2). Normal C57BL/6 mice receiving CsA at a dose of 100 mg/kg demonstrated a decrease in NK cell lysis against the YAC-1 lymphoma target in a 4-h chromium-release assay. When splenocytes obtained from CsA-treated mice were cultured for 3 days in complete medium containing 1000 U rIL-2/ml, they demonstrated a return of NK cell lysis to normal (mean cytotoxicity = 65 LU versus 60 LU for control and CsA-exposed splenocytes respectively; P, NS, five consecutive experiments) but revealed a decrease in the lysis of a NK-resistant target: the MCA-102 sarcoma (mean cytotoxicity = 20 LU vs 12 LU for control and CsA-exposed splenocytes respectively; P less than 0.02, five consecutive experiments). Fresh splenocytes cultured in media containing rIL-2 and CsA demonstrated a decrease in proliferation, cell-cycle S-phase fraction and cell yields compared to splenocytes cultured in media containing rIL-2 alone. In addition, a decrease in tumor cell lysis for NK-cell sensitive (mean percentage lysis = 98% vs 60%, rIL-2 vs rIL-2 + CsA; effector-to-target ratio 100: 1) and resistant targets (mean percentage lysis = 68% vs 28%, rIL-2 vs rIL-2 + CsA; effector-to-target ratio 100: 1) was also seen. CsA had no effects on the phenotypic antigenic expression of splenocytes cultured with high-dose rIL-2 although activated T cell antigens were down-regulated when fresh splenocytes were evaluated after in vivo exposure to CsA. These studies support the down-regulating effects of CsA on NK cell lysis and suggest that the rIL-2-activated cell population is heterogeneous as demonstrated by the differential down-regulation and recovery of NK-resistant cell lysis versus NK-sensitive cell lysis.
Animals↗
Synergistic actions of picibanil (OK-432) on recombinant interleukin-2 induction of tumor-infiltrating lymphocyte expansion, cytotoxicity, and phenotypic differentiation.
Tumor-infiltrating lymphocytes (TILs) comprise a subpopulation of lymphoid cells that infiltrate into growing tumors. These cells can be activated in vitro with recombinant interleukin-2 (rIL-2) to become highly cytotoxic against fresh tumor targets in vitro and against a variety of systemic metastases in vivo. OK-432 is a well-known inducer of NK cells and immune effector T cells. This study was designed to evaluate the effects of OK-432 on (a) the generation and (b) the cytotoxic potential of rIL-2-induced TILs. When TILs obtained from a murine colon adenocarcinoma (the MC-38 tumor) were cultured in complete media supplemented with 100 U of rIL-2/ml and 1.0 microgram of OK-432/ml, the number of TILs generated was greater than that seen with rIL-2 or OK-432 alone (number of TILs on day 15 of culture: 100 U of rIL-2/ml: 268 x 10(5) TILs; 1.0 microgram of OK-432/ml: 30 x 10(5) TILs; 100 U of rIL-2/ml + 1.0 microgram of OK-432/ml: 528 x 10(5) TILs). Higher concentrations of OK-432 had deleterious effects on TIL growth characteristics. TILs generated in 100 U of rIL-2 and 1.0 microgram of OK-432/ml of complete media demonstrated greater tumor lysis compared to rIL-2 alone (% lysis against MCA-102 target; 100 U of rIL-2/ml: 12%; 100 U of rIL-2/ml and 1.0 microgram of OK-432/ml: 50%; effector target ratio 20:1; p less than 0.001). Similar results were seen against the NK-sensitive YAC-1 lymphoma target.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
In vivo administration of recombinant interleukin-2 induces granulocyte-macrophage colony formation in a murine system.
The in vivo administration of recombinant interleukin-2 (rIL-2) in humans has led to anemia, thrombocytopenia, and eosinophilia. In an attempt to evaluate the effects of the in vivo administration of rIL-2 on murine bone marrow, we administered rIL-2 to C57BL/6 female mice i.p. three times a day at doses ranging from 10,000 to 100,000 U for 10 days; we then harvested blood and bone marrow from these animals every other day and performed the following analyses: White blood cell count, red blood cell count, hemoglobin concentration, histogram analysis of nucleated cell volume, manual differential counts, and in vitro colony-forming assays for granulocytes and monocytes (CFU-GM). The administration of rIL-2 induced an overall increase in the total white blood cell count that was dose-dependent for its appearance and overall number. This increase was secondary to an increase in monocytes and granulocytes but not to a change in lymphocyte number. Myeloid proliferative activity measured by CFU-GM revealed a biphasic pattern of activity. An early proliferation at 2 days was not followed by lymphocytosis. However, a second peak of proliferation at 6 days was associated with peripheral blood granulocytosis and monocytosis. After rIL-2 was discontinued on day 10, the CFU-GM activity returned to normal by days 16-18. These results suggest that the in vivo administration of rIL-2 may play an important role in the regulation of hematopoiesis.
Animals↗
Immunotherapy of murine hepatic metastases with lymphokine-activated killer cells expanded in serum-free media and recombinant interleukin 2.
It has been shown that the systemic administration of lymphokine-activated killer (LAK) cells with recombinant interleukin 2 (RIL-2) is effective in reducing the number of established pulmonary and hepatic metastases in murine models. Similarly, this modality of therapy has been proven effective against certain selected human tumors as well. In view of the rising concern with transmission of virally related communicable diseases such as hepatitis and AIDS, we have undertaken the evaluation of a serum-free medium (AIM V) for the generation and expansion of murine LAK cells for use in in vivo tumor immunotherapy against murine hepatic metastases. Day 3 LAK cells generated in AIM V medium demonstrated a greater percentage of viable cells than cells generated in serum containing complete medium (CM) (mean percentage of yield, 59 versus 25%, AIM V medium versus CM, respectively, P less than 0.001, N = 6 consecutive experiments). When day 3 LAK cells were transferred to new medium (CM to CM and AIM V to AIM V), a highly reproducible expansion of these cells was demonstrated which was significantly better for cells expanded in AIM V medium versus cells expanded in CM (mean fold expansion on day 21 of culture; 201 versus 54, AIM V medium versus CM, respectively, P less than 0.005, N = 4 consecutive experiments). When day 3 LAK cells, day 5 expanded LAK cells, and day 13 expanded LAK cells grown in CM or in AIM V medium were given in vivo with RIL-2 to mice harboring hepatic metastases, cells grown in AIM V medium demonstrated an increased antitumor activity compared to cells grown in CM. As an example in experiment 1, the mean number of metastases with day 5 expanded LAK cells grown in CM and given with RIL-2 was 47 while the mean number of metastases with day 5 expanded LAK cells grown in AIM V medium and given with RIL-2 was 5 (P less than 0.002). These experiments demonstrate that AIM V medium can be utilized to generate greater numbers of murine LAK cells with enhanced in vivo antitumor activity compared to cells generated in CM. These findings could be applied to the expansion of cytotoxic cells for human antitumor therapy.
Animals↗