Phase II study of edatrexate in chemotherapy-naive patients with metastatic breast cancer. A phase II trial of the new antifolate edatrexate (10-ethyl-10-deaza-aminopterin) was performed in thirty-eight patients with metastatic breast cancer who had never received chemotherapy. Edatrexate was administered as a weekly intravenous bolus injection at a dose of 80 mg/m2. Sites of metastases included visceral (31%), soft tissue/lymph node/bone (51%), and bone only (18%). Thirty-two patients were evaluable for response; there were 3 complete responses (CR) and 8 partial responses (PR), yielding a response rate (CR plus PR) of 34% (95% confidence limits, 17.9% to 50.9%). Responses were seen in soft tissue metastases, in visceral metastases (liver, lung) and in one patient with bone metastases. Median duration of response was 30 weeks (range 12-66 weeks). Substantial toxicity was observed. The dose-limiting toxicities were mucositis, myelo-suppression and skin toxicity. The general toxicity profile was similar to that usually reported for methotrexate, but mucositis and skin toxicity were more pronounced. Edatrexate appears to be an active drug in the treatment of chemotherapy-native patients with metastatic breast cancer.


Factors influencing complete response and survival in patients with head and neck cancer treated with platinum-based induction chemotherapy. A Hellenic Co-operative Oncology Group Study. One hundred fifteen consecutive patients with locally advanced carcinoma of the head and neck were treated between August 1984 and August 1989 with three cycles of either of two platinum-based induction chemotherapies, followed by local treatment. After the completion of chemotherapy 26 (23%) patients had complete responses (CR). Several pre-treatment characteristics were analyzed for a possible correlation to CR to induction chemotherapy and to survival. The following variables were closely interrelated: sex, history of smoking, alcohol abuse, histologic type, tumor site and grade. Tumor stage and negative history of smoking were correlated with CR. The variables which were individually correlated with survival were keratinization, CR to chemotherapy, alcohol abuse, histologic type, site and grade of the primary tumor, serum albumin level and tumor stage. A regression analysis after Cox's model to identify a limited set of predictors selected CR, serum albumin, tumor grade, performance status and nodal status as the most significant; when analyzing the data without the time-dependent variable CR, the factors selected by the model were serum albumin, tumor grade, performance status and tumor stage. In conclusion, serum albumin level, tumor grade, performance status and tumor stage prior to treatment can be used to define risk classes in our patient population.


An outpatient phase I study of a subcutaneous interleukin-2 and intramuscular alpha-2a-interferon combination in advanced malignancies. The aim of this phase I study was to exploit the potential efficacy of an alpha-2a-interferon (alpha-2a-IFN)-subcutaneous interleukin-2 (IL-2) combination, bypassing the toxicity usually associated with bolus or continuous infusion of IL-2. Therefore, nineteen patients with metastatic malignancies (7 melanomas, 6 renal cell carcinomas and 6 soft tissue sarcomas) were treated according to a dose escalating schedule of subcutaneous IL-2 combined with intramuscular alpha-2a-IFN for 5 days/week for 3 consecutive weeks. Cycles were repeated every 2-4 weeks unless disease progressed. Alpha-2a-IFN (3 MU/die) was given continuously, including during the rest weeks. IL-2 doses were started at 2 MIU/day/sqm and the MTD of 6 MIU/day/sqm was progressively reached. The dose of IL-2 was given twice daily every 12 hours. Both of the cytokines were administered in an outpatient setting. The main side effects were fever, chills, fatigue, hypotension, nausea and vomiting. Toxicity was correlated with IL-2 dose level. It was found to be mild at 2 and 4 MIU/day/sqm, while, in contrast, grade III toxicity was observed only at the highest dose of 6 MIU/day/sqm. However, this grade III toxicity was manageable and did not prevent continuation of the treatment as long as the dose was not increased above 6 MIU/day/sqm. Three patients, one with melanoma and two with renal cell carcinomas, obtained clinical partial responses. In eight patients, stable disease, and in the remaining eight, progression, were observed. The data suggest that the combined use of the two BRMs has manageable side effects and would seem to be efficacious. A phase II study at the recommended dose of 6 MIU/day is now necessary.


A therapy impact questionnaire for quality-of-life assessment in advanced cancer research. The first part of the validation procedure used for a Therapy Impact Questionnaire (TIQ) on quality-of-life assessment in advanced cancer patients is described. The TIQ is composed of 36 items which assess both disease and therapy impact according to four dimensions that operationally define quality of life: physical symptoms (24 items), functional status (3 items), concomitant emotional and cognitive factors (6 items) and social interaction (2 items). A global judgement expressed as "have you been feeling ill" further completes the TIQ. Patients answered each question using a 4-point verbal Likert scale: not at all, slight, a lot and very much. The TIQ was given to 1,000 consecutive patients who were no longer responsive to cancer treatment and presented symptoms due to disease progression. The compliance rate was quite high (87%). Results of confirmatory factor analysis were consistent with the operational dimensions identified during questionnaire construction. In particular, the dichotomized answers to 3 functional status items could be used as a Guttman scale. In a sub-sample of 50 patients, the reproducibility of functional status items was assessed using a 7-item parallel form. The intraclass correlation coefficient obtained indicated a reasonably high reproducibility. On the basis of the analyses conducted, the TIQ appears to be a reliable and concise instrument for studies aimed to assess the effectiveness of therapies in advanced cancer patients.


A pilot study of suramin in the treatment of progressive refractory follicular lymphomas. Ten patients with progressive follicular lymphomas (seven with follicular mixed lymphomas, three with follicular, small cleaved cell lymphomas) with clinical indications for systemic therapy received parenteral suramin. Each had failed from one to six prior chemotherapeutic regimens and three had in addition received prior radiation therapy. All had measurable disease and nine of the ten had documented bone marrow involvement at the start of therapy. Suramin was administered at an initial infusion rate of 350 mg/m2/day, which was then modified on the basis of subsequent weekly plasma suramin concentrations in order to reach a final plasma concentrations of 250-350 micrograms/ml. Treatment cycles were repeated at eight week intervals. Nine of ten patients are evaluable for response. Five of nine evaluable patients achieved a partial remission as defined by a greater than 50% decrease in the sum of the product of all measurable lesions. Sites of response include: Peripheral (five patients) and central (four patients) adenopathy, disappearance of biopsy-proven skin involvement (one patient), malignant pleural effusions (one patient) and shrinkage of an enlarged spleen (two patients). Disappearance of B symptoms occurred in the one responder with these symptoms. Response duration varied from 3 to 9 months (mean 5.6 months) with time to subsequent systemic therapy varying from 5 to 12 months (mean 8 months). Drug related toxicity included the development of polyradiculopathy (one case), liver function abnormalities (three cases), thrombocytopenia (five cases), vortex keratopathy (two cases) and bacterial infection (two cases). We conclude that suramin has significant activity against follicular lymphomas refractory to standard chemotherapy and that its precise role in the treatment of lymphoproliferative neoplasms in general warrants further investigation.


Hypersensitivity reactions to cisplatin and carboplatin--a report on six cases. Anaphylactic reactions to platinum compounds are well recognised, but uncommon. These vary from true type I reactions to direct histamine release due to nonimmunological mechanisms. We present 6 cases to illustrate this--5 due to cisplatin and a report of this occurring with carboplatin--with a near fatal outcome in 3 of the cases.


Specific inflammatory cell infiltration of hepatic schizonts in BALB/c mice immunized with attenuated Plasmodium yoelii sporozoites. We compared immunization of BALB/c mice with radiation-attenuated versus killed sporozoites of the rodent malaria parasite, Plasmodium yoelii. We employed a suboptimal schedule of only two immunizations, in expectation that some parasites might break through the resultant low level immunity and that it might thus be possible to study the response of the host against these 'breakthrough' schizonts. As a measure of protective immunity, we used histological means to determine the percentages of challenge sporozoites prevented from completing development into hepatic schizonts within the liver. Immunization with attenuated sporozoites led to almost complete protection, whereas immunization with similar dosages of killed sporozoites led to approximately a 75% protection. Fluorescent antibody titers against sporozoites were similar in both sets of immunized animals. However, serum from mice immunized with attenuated sporozoites had a protective effect upon passive transfer into immunologically naive mice subsequently challenged with normal sporozoites; serum from mice immunized with killed sporozoites had no such effect. When mice suboptimally immunized with attenuated sporozoites were challenged, we observed breakthrough schizonts being infiltrated with inflammatory cells, primarily mononuclear cells, and neutrophils; partial depletion of CD4+ or CD8+ cells within these mice prior to challenge prevented the infiltration of breakthrough schizonts. Thus, cellular infiltration of schizonts was apparently secondary to earlier action by lymphocytes. This infiltration was also not observed in mice immunized with killed sporozoites. The more effective protective immunity induced by attenuated sporozoites could be due to their ability to release antigen into the cytoplasm of hepatocytes that they invade or their ability to continue differentiating, thereby presenting new antigens that are not seen after immunization with killed sporozoites.


Adjuvant arthritis and immunity to the mycobacterial 65 kDa heat shock protein. The mycobacterial 65 kDa heat shock protein (HSP65) is of critical significance in the model of adjuvant arthritis (AA). Arthritogenic and protective T cell clones obtained from arthritic rats recognized the 180-188 sequence of HSP65. Previous reports have shown that administration of HSP65 prior to disease induction led to resistance to arthritis in the AA model and in several other models of experimental arthritis. Here, we report the development of immunity to HSP65 and the critical 180-188 epitope during the course of AA. Following Mycobacterium tuberculosis (MT) immunization both antibodies and T cell responses to HSP65 were detected. Proliferative responses to the 180-188 epitope were seen exclusively in the local draining lymph node cells at day 14 after immunization. The anatomical distribution and course of T cell responses to HSP65 and its 180-188 epitope are compatible with T cell regulated control of the disease. Although lower HSP65 antibody levels were observed in the animals with severe arthritis, in individual animals no evidence was obtained for a relationship between development of HSP65 humoral immunity and arthritis severity. Nevertheless, during disease exacerbation, elicited by HSP65 immunization during disease development, elevated T cell responses against HSP65 and its 180-188 epitope were found. In contrast, we obtained evidence that successful transfer of arthritis resistance to naive recipients depends on the transfer of HSP65 specific T cells. On the basis of these results, it seems that HSP65 plays a crucial role in the T cell regulatory events involved in both the induction of, and protection against, AA.(ABSTRACT TRUNCATED AT 250 WORDS)


Transcription factors in mouse fetal thymus development. T cell precursors from murine fetal liver enter the fetal thymus where they proliferate, differentiate, and mature. These processes are accompanied by changes in the pattern of transcription factors known to control the expression of specific genes. We have monitored the expression of five different transcription factors during mouse fetal thymus ontogeny: nuclear factor (NF)-kappa B, cAMP-response-element binding protein (CREB), NF-IL-2A, msNF-AT1, and hNF-AT1. NF-kappa B binding activity was not detected in extracts from fetal liver but was present in the thymus at day 14 of embryogenesis. Thereafter, NF-kappa B expression was biphasic, being maximal at 14-16 days gestation and in newborn mice, and decreased during the intermediate gestational stages and in the adult. An inverse correlation was observed between NF-kappa B binding activity in the nuclei and levels of its inactive precursor in the cytoplasm of all samples analyzed. In contrast, CREB activity was uniform throughout thymus development. Similarly, NF-IL-2A activity was detected in fetal liver and thymic extracts from different gestational stages, in approximately equivalent amounts. However, band shift experiments revealed three distinct NF-IL-2A-DNA complexes, whose relative abundance is altered during thymic ontogeny. Likewise, NF-AT1 transcription factor appears to be heterogeneous and includes representatives which are differentially (msNF-AT1) or stably (hNF-AT1) expressed during thymic development. These results are discussed in the context of present knowledge about T cell development within the thymus.


The effect of cytokines and mitogens on the induction of C epsilon germline transcripts in a human Burkitt lymphoma B cell line. IL-4 is known to induce a 1.8 kb constant epsilon (C) transcript in human peripheral blood mononuclear cells (PBMC). This is a C germline or 'sterile' transcript which is encoded by a germline exon (I) located 5' of the epsilon switch (S) region and the four C germline exon including 3' untranslated region. Among the human B cell lines examined, one Burkitt lymphoma B cell line, DND39 (Epstein-Barr virus negative, sIgM+, CD40+), was found to respond to IL-4 and express the C germline transcript. Induction of C germline transcript in DND39 cells was entirely dependent on the presence of IL-4. Phorbol myristate acetate enhanced its expression in DND39 cells as well as in the purified B cells in combination with IL-4. Pokeweed mitogen (PWM) enhanced the expression of C germline transcripts induced by IL-4 in PBMC but the enhancing activity was not observed when purified B cells or DND39 cells were used. Supernatants obtained from PWM-stimulated PBMC strongly enhanced the expression of C germline transcript in DND39 cells when co-stimulated with IL-4. None of the known cytokines tested mimicked this effect, suggesting that PWM may induce in T cells or monocytes a novel cytokine production that works synergistically with IL-4 and enhances the expression of IL-4-induced C germline transcripts. A similar enhancing effect was observed when anti-CD40 mAb was added to the IL-4-stimulated DND39 cells. Interestingly, transforming growth factor-beta strongly suppressed it. Taken together, DND39 cells resemble normal B cells in terms to responsiveness to IL-4 and should be a useful tool to study the molecular mechanisms of regulation of C germline transcription and class switching to IgE.


Inhibition of lipopolysaccharide-induced activation of immature B cells by anti-mu and anti-delta antibodies and its modulation by interleukin-4. Soluble anti-Ig or anti-mu antibodies completely abrogate the lipopolysaccharide (LPS)-stimulated proliferation of purified B cells obtained from spleens of 5-7 day old mice. This provides further evidence for the powerful nature of the negative signals transduced by sIgM receptors on immature B cells. In addition, ligation of sIgD receptors (expressed by approximately 30% of these cells) by two out of three monoclonal anti-delta antibodies inhibits the response to LPS by some 50%. Ligation of sIgD on purified sIgD+ B cells (greater than 98% sIgD+) completely inhibited the LPS response of these cells. The inclusion of IL-4 in these cultures partially (with anti-mu), or completely (with anti-delta), restored the proliferative response. Immobilized anti-mu or anti-delta caused comparable levels of inhibition as the soluble antibodies: IL-4 again rescued the inhibition caused by immobilized anti-delta, but not that induced by anti-mu. These results therefore indicate that engaging either sIgM or sIgD receptors on developing B cells delivers negative (tolerogenic) signals. They also implicate IL-4 as a major (although not the only) T cell-derived influence which can modulate these signals. Finally, the data suggest that extensive cross-linking of sIgM (by immobilized anti-mu) causes more profound unresponsiveness in immature B cells, which cannot be rescued by IL-4 alone.


Albumin binding proteins of endothelial cells identified by anti-idiotypic antibodies. Studies were conducted to identify and localize albumin binding proteins (ABPs) in endothelial cells using rabbits polyclonal anti-idiotypic antibodies (Ab2) raised against the affinity-purified anti-bovine serum albumin IgG. Ab2 were purified by fast performance liquid chromatography. The anti-idiotypic nature of the IgG was assessed by (i) the capacity to inhibit albumin binding to its specific antibody in a dose-dependent manner, (ii) the lack of interaction with albumin, and (iii) the interaction with anti-albumin antibodies of diverse origins. The latter characteristic indicates that although polyclonal, the purified anti-idiotypic antibodies contain some of the Ab2 beta type. The binding of Ab2 to cultured bovine aortic endothelial cell surfaces was saturable and specific as demonstrated by radioimmunoassay (RIA) and immunofluorescence studies respectively. A competitive RIA was used to test whether Ab2 competed for albumin binding to bovine aortic endothelial cells (BAECs) (presumably to ABPs). It was found that Ab2 inhibited binding of [125I]albumin to BAECs in a dose-dependent fashion. Immunoblot analysis of extracts of BAECs, microvascular endothelial cells, and lung showed that both Ab2 and albumin bind specifically to two polypeptides with an apparent molecular mass of 18 and 31 kDa. In addition, upon radioiodination of BAECs apical membrane proteins, Ab2 bound specifically and immunoprecipitated restrictively two radiolabeled cell surface proteins of 18 and 31 kDa. The results provide direct evidence for the presence of the 18 and 31 kDa peptides (ABPs) on the endothelial cell membrane and/or associated structures, i.e. open plasmalemmal vesicles and uncoated pits.


Tyrosine phosphorylation of IgM- and IgD-associated molecules of a human B lymphoma cell line B104. We investigated tyrosine phosphorylation and structural properties of the IgM-associated molecules in comparison with IgD-associated molecules in a recently established human surface IgM+, IgD+ B lymphoma cell line, B104, the growth of which was irreversibly inhibited by anti-IgM mAbs but not by anti-IgD mAbs. Tyrosine kinase activity and tyrosine phosphorylated proteins were detected in anti-IgM and anti-IgD immunoprecipitates from digitonin lysates of B104 cells with the use of an in vitro kinase assay followed by a re-immunoprecipitation experiment with anti-phosphotyrosine mAbs. Tyrosine phosphorylated proteins of 74, 58-44, 41, and 39 kDa were detected in anti-IgM immunoprecipitates, whereas tyrosine phosphorylated proteins of 74, 58-44, and 39 kDa, but not 41 kDa, were detected in anti-IgD immunoprecipitates. Crosslinking of surface IgM and surface IgD stimulated rapid tyrosine phosphorylation of different sets of proteins which included tyrosine-phosphorylated proteins of the same or similar molecular weights as those detected in the anti-IgM and anti-IgD immunoprecipitates respectively. After deglycosylation by N-glycosidase, both the IgM- and IgD-associated phosphoproteins (pp58-pp39) gave rise to the same three bands of 29, 27, and 26 kDa. Proteolytic peptide mapping of these three deglycosylated proteins showed that the primary structures of the IgM- and IgD-associated molecules are identical, suggesting that the IgM- and IgD-associated phosphoproteins (pp58-pp39) are the products of the same or closely related genes. One of the products, pp41, may be associated with IgM, but not with IgD, although the same gene product may be associated with IgD in a different glycosylation pattern.


Human thioredoxin/adult T cell leukemia-derived factor activates the enhancer binding protein of human immunodeficiency virus type 1 by thiol redox control mechanism. Transcription from the human immunodeficiency virus type 1 (HIV-1) provirus is activated by a cellular factor, NF kappa B, recognizing the tandemly repeated 10-base-pair sequences, termed the kappa B sequence, present in the enhancer region within the viral long terminal repeat (LTR). Using electrophoretic mobility shift assay (EMSA), which demonstrates specific DNA-protein interaction in vitro, we could demonstrate that reducto-oxidative modulation of NF kappa B dramatically changes its DNA binding activity and that a cellular physiological reducing catalyst, thioredoxin (TRX) also known as adult T cell leukemia derived factor (ADF), fully restored the DNA-binding activity of the oxidized NF kappa B. We also observed that purified TRX/ADF protein could augment gene expression from HIV LTR as demonstrated by transient chloramphenicol acetyltransferase (CAT) assay. These observations confirmed the previous notion that ADF might be an inducing factor of cellular interleukin-2 receptor alpha subunit (IL-2R alpha) through the kappa B sequence that is a common central cis-regulatory element in both IL-2R alpha and HIV gene expression. These observations indicate that reducto-oxidative regulation (or redox regulation) of a cysteine residue(s) on the NF kappa B molecule might play an important role in its specific DNA interaction and that it might provide a clue to the understanding of a pathway of cellular signal transduction to NF kappa B that is independent from the known pathways involving protein phosphorylation.


Bcl-2 prevents death of factor-deprived cells but fails to prevent apoptosis in targets of cell mediated killing. 'Programmed cell death' has been used to describe the death of cells killed by cytotoxic T cells or growth factor deprivation. Although bcl-2 can prevent death of cells deprived of growth factor, it failed to protect cells against T cell killing. In spite of bcl-2 expression, the DNA of targeted cells was degraded into nucleosome-sized fragments. Therefore the early steps in apoptosis induced by factor deprivation differ from those triggered by cytotoxic T cells, although they share a common final pathway featuring degradation of the DNA and loss of cytoplasmic membrane integrity.


Skin distribution and differential expression of transforming growth factor beta 1 and beta 2. Transforming growth factor beta (TGF-beta) 1 and 2 have both become increasingly important in cutaneous biology, but their expression and distribution in human skin are not entirely clear. In this report, normal forearm skin from four volunteers was investigated for TGF-beta 1 and beta 2 immunostaining with antibodies that detect preferentially either cell- or matrix-associated forms of these peptides. Marked cell-associated TGF-beta 1 was found in the dermis, particularly around blood vessels and ducts; cellular TGF-beta 2 immunostaining was less prominent, and was predominantly around blood vessels. Neither TGF-beta 1 nor -beta 2 could be detected in the epidermis or epithelial structures, and the dermal matrix contained minimally detectable amounts of the two isoforms. In all cases, dermal matrix and cells contained greater amounts of TGF-beta 1 than TGF-beta 2. Previous studies have shown that both TGF-beta 1 and -beta 2 can induce dramatic increases in extracellular matrix, and both peptides have been implicated in the pathogenesis of fibrosis. We therefore investigated TGF-beta 1 and -beta 2 immunostaining in involved forearm skin of four patients with systemic sclerosis. Compared to normal skin, fibrotic specimens showed increased amounts of matrix and epidermal TGF-beta 1, but not TGF-beta 2. We conclude that TGF-beta 1 and -beta 2 expression in human skin is differentially regulated, and that their distribution is varied and complex.


Effects of several growth factors on cultured neurofibroma cells. Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder characterized by abnormalities affecting multiple tissues derived from the neural crest. The peripheral neurofibromas are numerous and sometimes reach several hundred in number. In this study, the possible involvement of several growth factors in neurofibroma growth was investigated in vitro. When explants of neurofibroma tissue were cultured, macrophage-like cells with pseudopodia migrated out first, and later took on a slender fusiform shape. These cells contained S-100 protein and were identified as Schwann cells. They did not proliferate under standard culture conditions. Nerve growth factor (NGF) was helpful in maintaining the differentiated phenotype of Schwann cells, but did not stimulate their proliferation. Immunohistochemical staining for type IV collagen revealed that some large flattened polygonal cells had a mesh of type IV collagen on the surface. These cells were perineurial cells. The proliferation of cells derived from neurofibroma was stimulated by basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and transforming growth factor alpha (TGF-alpha). In comparison with skin fibroblasts, the cells derived from neurofibroma responded to these growth factors at considerably lower concentrations. Stimulation by EGF at physiological concentrations indicated the possible involvement of EGF in the development of neurofibromas.


Epidermal Merkel cells in psoriatic lesions: immunohistochemical investigations on neuroendocrine antigen expression. Biopsy specimens from lesional psoriatic skin and from normal controls were investigated by immunohistochemistry for the presence of epidermal Merkel cells (MC). MC were defined as epidermal cells expressing simple-type keratins, i.e. nos. 8, 18, and 19. A significant number of MC could be found at the bottom of the rete ridges of psoriatic lesions (about 19.6 MC per square mm skin surface area) and of normal skin (about 14.0 MC per square mm surface area). In contrast to normal skin, MC of psoriatic lesions were positive for synaptophysin (21.7% of simple-type keratin positive epidermal cells, i.e. MC), pancreatic polypeptide (14.8%), somatostatin (7.0%), and chromogranin A (less than 3%). The immunostaining was rather faint though significantly different from normal skin. The findings suggest that in psoriasis, epidermal MC show variations of the expression of neuropeptides compared to normal skin. Since some of the neuropeptides are thought to be involved in hyperproliferation and/or skin immunology, our findings might suggest a functional activity of epidermal MC in psoriatic lesions different from normal controls.


The relationship between eosinophils, OKT6-positive cells and house dust mite (HDM) antigens in naturally occurring lesions of atopic dermatitis. To determine the role of eosinophils in naturally occurring lesions of atopic dermatitis, we observed the distribution of eosinophil cationic protein (ECP) and the relationship between eosinophils, OKT6-positive cells and house dust mite (HDM) antigens. Some specimens showed many EG2-positive stains, although the accumulation of tissue eosinophils was not prominent. EG2 stains were seen not only in eosinophils but also in extracellular granules. Some macrophage-like cells of the dermis showed EG2 stains in the form of phagocytized eosinophil granules. Some EG2-positive eosinophils were in close contact with OKT6-positive cells in the epidermis and dermis. Furthermore, in three patients sensitive to house dust mite (HDM) antigen, HDM antigens invaded the skin with many EG2-positive stains. These results suggest that eosinophils play an active role in the development of eczematous lesions of atopic dermatitis.


Effects of retinoids on endothelial cell proliferation, prostacyclin production and platelet aggregation. In addition to their anti-inflammatory and anti-cancer activities, retinoids have been shown to affect angiogenesis, endothelial proliferation and the process of wound healing. While peripheral vascular occlusion has not been observed as an adverse effect clinically, the effects of retinoids on prostacyclin production in endothelial cells and platelet aggregation are not known. We examined the effects of tretinoin, isotretinoin and etretinate (3.3 x 10(-8) to 3.3 x 10(-5) M) on cytotoxicity by 51Cr-release assay, growth and prostacyclin in bovine carotid endothelial cell cultures, and the aggregation of human platelets induced by ADP. All retinoids showed either no or only small effects on cytotoxicity and human platelet aggregation. Prostacyclin production was not significantly affected except for tretinoin and isotretinoin at 3.3 x 10(-5) M. Endothelial proliferation was affected by all three retinoids in a dose-dependent fashion; for tretinoin and isotretinoin an inhibitory trend was noted as the concentration increased but the reverse was true for etretinate. Retinoids at 3.3 x 10(-5) M induced alterations of typical endothelial morphology; the cells became fibroblastoid. The results of prostacyclin production and platelet aggregation in the present study are consistent with the absence of peripheral vascular occlusion as a side effect clinically.


Organ culture conditions of human hair follicles. Experimental results revealed that although [3H]thymidine uptake in the hair bulb increased time dependently for 12 days under normal culture conditions (95% air-5% CO2 at 37 degrees C), striking morphological changes occurred in the hair bulb cells as demonstrated by histological findings. As such, organ culture conditions applicable to human hair follicles were studied utilizing observations from both histology and DNA synthesis. We found that culture conditions of 95% O2-5% CO2 at 31 degrees C were superior when compared to normal culture conditions for cultures of human hair follicles when attempting to maintain the normal morphology of hair germinative cells. The hair bulb and the germinative cells successfully maintained their normal morphology throughout the 96 and 48 h culture period, respectively. Autoradiographs of [3H]thymidine-labeled follicles showed localization in the germinative cells below Auber's critical line. Hair bulb DNA synthesis increased time dependently for 96 h after culture initiation. Under conditions of 95% O2-5% CO2 at 31 degrees C, the synthesis of DNA in hair germinative cells was observed. Such an organ culture method may prove useful for studies on the human hair growth mechanism.


Production of IL-4, IL-2, IFN-gamma, and TNF-alpha by peripheral blood mononuclear cells of patients with atopic dermatitis. Recently, T cell-derived cytokines have been postulated to be involved in the pathogenesis of atopic dermatitis (AD) since the synthesis of IgE is profoundly regulated by cytokines such as IL-4, IFN-gamma and IL-2. IL-4 enhances the production of IgE and in contrast, IFN-gamma inhibits this IL-4-mediated IgE production. IL-2 also prevents IL-4-induced production of IgE by a different mechanism from IFN-gamma, suggesting that the level of IgE is regulated by the quantitative balance of these antagonizing cytokines. We examined the production of IL-4, IL-2, IFN-gamma and TNF-alpha by PBMC of AD patients and non-AD controls. Although the production of IL-2 and TNF-alpha by AD patients was significantly lower than that of non-AD controls, the production of IL-4 and IFN-gamma did not show significant differences between AD and non-AD individuals. There was no significant correlation between cytokine production and clinical symptoms in AD patients. There was significant positive correlation between IL-4 and IL-2 production, and between IFN-gamma and TNF-alpha production. Serum IL-4 levels showed no significant difference between AD group and non-AD group.


Cloning and sequence analysis of the tyrosinase gene from a patient with tyrosinase-positive oculocutaneous albinism. Tyrosinase is synthesized on membrane-bound ribosomes and transported into melanosomes through smooth endoplasmic reticulum and Golgi apparatus. Melanin polymers are produced only in melanosomes but never in smooth endoplasmic reticulum or Golgi apparatus, indicating that posttranslational modifications of tyrosinase are completed with melanosomes where tyrosinase becomes an active form. Based on a working hypothesis that tyrosinase-positive oculocutaneous albinism is a consequence of the structurally altered tyrosinase due to a point mutation in the gene of its gene coding for a glycosylation site or a membrane-binding site, which leads to the impairment in the posttranslational modification of tyrosinase and its catalytic activity, we have cloned the tyrosinase gene of one patient affected with tyrosinase-positive oculocutaneous albinism and determined its nucleotide sequence. Thus demonstrated all exons' nucleotide sequence of the patient's tyrosinase gene was found to be identical to that of the wild-type gene. The results indicate that the patient's tyrosinase itself is not altered. We therefore propose that the molecular basis for the development of tyrosinase-positive oculocutaneous albinism exists as a defect in other proteins required for the activation of tyrosinase or in other regions of the tyrosinase gene.


Splenic cysts in pediatric patients--a report on 8 cases and review of the literature. 8 cases of splenic cysts are reported: treatment was surgical in 4 large cysts (greater than 5 cm, 3 epidermoids and 1 pseudocyst), and non-operative in 4 small cysts (less than 5 cm, 3 post-traumatic pseudocysts and 1 congenital cyst, probably epidermoid). Follow-up was over a period of 3 months to 7 years. 3 among the 4 post-traumatic pseudocysts were followed up by ultrasound until resolution (3 months to 3 years), and 1 large pseudocyst was operated on due to rupture following benign trauma. 3 large cysts were epidermoid in origin, 1 was electively operated, and 2 were discovered and operated on because of complications (rupture, infection). Only one total splenectomy was performed; surgery preserved the spleen in all other cases; but 1 epidermoid cyst presents now with a recurrence. Based on this experience, we suggest frozen section of the cyst wall during surgery, to decide the type of partial splenectomy to be performed: total cystectomy or marsupialization.


Massive bleeding into the upper gastro-intestinal tract in hereditary chronic calcifying pancreatitis in the child. This report deals with a young girl affected with chronic hereditary calcifying pancreatitis, which gave rise to acute life-threatening arterial bleeding into the upper gastro-intestinal tract. A pancreatic pseudocyst forming in the chronically affected pancreas spontaneously perforated into the stomach, thereby eroding a gastric wall artery. We think it is conceivable that in the future this type of complication in children with pancreatitis and pseudocyst formation might occur more frequently.


Echinococcus granulosus infection of the liver and lung in an 8 1/2-year-old boy. We report on an 8 1/2-year-old boy with an echinococcus granulosus infection of the liver and lung, drawing particular attention to the therapy applied. This therapy consists on the one hand of medicinal treatment with Mebendazol and on the other hand of two subsequent operations with resection of the cysts. The course of the illness is illustrated by means of the most important laboratory parameters; an indication of the present serological diagnostic is also given.


Clinical relevance of Hirschsprung-associated neuronal intestinal dysplasia (HANID). The rate of Hirschsprung-associated neuronal intestinal dysplasia (HANID) is reported to be as high as 20-75% but no report deals with its sequelae. The aim of our study was to evaluate the influence of the retained neuronal dysplastic segment in patients with Hirschsprung's disease (HD). We report on 47 patients with HD including 11 cases with HANID (23%). All 47 children had a Duhamel procedure subsequent to colostomy and in none of the 11 cases with HANID was the neuronal dysplastic segment resected. There was no significant difference of early and late complications in both groups and the results of the mean follow-up of 5 years after the Duhamel procedure show that the patients with HANID did as well as the patients with isolated HD. It is suggested therefore that HANID may be a distinct disease compared to isolated NID and that the NID attained segment may be retained without increased risks or morbidity.


Surgical significance of the duplex kidney with bifid ureter. Between 1974 and 1990 in 16 children (5 boys and 11 girls) with a duplex kidney and bifid ureter surgery was indicated. The mean age of the 15 already operated patients was 7 years (0.3-12 years). 14 had uretero-ureteric reflux, 1 had a stenosis of the ureteric bifurcation, and 1 had a lower pole pelvi-ureteric junction obstruction. An interpyelic anastomosis was performed in 14 and a ureteroneocystostomy "en bloc" in 1. The follow-up was 3-10 years with a mean of 5 years. All 15 patients had normal uroradiological findings, and out of the 9 patients with longer follow-up (more than 3 years) 7 had a significantly diminished infection rate.


Treatment and follow-up of vesico-ureteral reflux in patients with neuropathic bladder. Vesico-ureteral reflux (VUR) is a relatively frequent and severe complication in neuropathic bladder, therefore it must be ruled out in every case, and prevented whenever possible. The Spina Bifida Center of our Institute is presently following 220 patients with neuropathic bladder, who undergo a periodical clinical and instrumental evaluation. Urodynamics has proved essential in detecting risk factors for VUR: small capacity bladders with reduced compliance, increased outlet resistance, and detrusor instability. Forty-eight cases of VUR, 38 of which were severe, were detected in a total of 166 patients reviewed for this paper. All patients with VUR were treated conservatively, attaining complete remission or improvement in 21 cases. Ten underwent surgical treatment owing to recurrent pyelonephritis or pyelo-renal reflux with severe dilatation, despite a standard pharmacological trial.


Blunt injuries to liver, spleen, kidney and pancreas in pediatric patients. 96 children with blunt injuries to liver, spleen, pancreas and kidney were analysed. The aim of this review was to determine the accuracy of radiologic imaging and to define clinical factors present on admission which could be predictive of major injuries resolving only by operation. Two thirds of the lesions could be treated non-operatively. Diagnostic accuracy of ultrasound examination (US) varies between 60 and 90%, depending on the type of the injured organ. Peritoneal lavage was progressively abandoned in favour of US. CT scan has a 100% accuracy in the determination of the type and the extension of the injury. Our review revealed 6 clinical factors present on admission with a statistically significant predictive value for surgical intervention.


Ruptured spleen in children--15-year evolution in therapeutic concepts. This is a 15-year retrospective study of 64 pediatric surgical patients with traumatic rupture of the spleen from 1976 to 1990. The overall mortality was 14% (9/64). All non-survivors had severe multiple traumata and no fatalities were attributable to splenic injury. During the first 5 years of the study, the traditional surgical approach of immediate laparotomy and splenectomy was employed. During the next 5 years we practised laparotomy with subtotal splenectomy and repair. During the final 5 years conservative management with clinical and ultrasonographic monitoring became predominant (1 splenectomy, 4 repair, 23 conservative treatments). Among the 55 survivors, 11 had splenectomy, 14 had splenic repairs and 30 were treated non-operatively. All survivors had excellent outcomes and there was only one complication: a local abscess following splenic repair. Based on a very strict protocol in conservative management, the total amount of transfused blood could be reduced remarkably during the last period. Splenectomized patients received pneumococcal vaccine and prophylactic antibiotic coverage was prescribed for febrile episodes. None of the splenectomized patients experienced septic episodes or increased rates of infection. Based on our experience, ultrasonographically monitored conservative management is the treatment of choice in most patients with splenic injury in childhood.


A rare complication due to sulfuric acid ingestion. The authors present a case of pyloric and duodenal obstruction in an 8-year-old child, resulting from accidental ingestion of sulfuric acid. A marked pyloric and duodenal cicatrizing stenosis resulting from ingestion of sulfuric acid is seen infrequently, especially in pediatric age. Sulfuric acid produces a coagulation necrosis of the gastric mucosa and submucosa, and the process may involve the entire thickness of the gastric wall, with subsequent ulceration and fibrosis. This dynamic pathophysiologic event imposes postponement of surgical intervention because of various time length between ingestion of acid and onset of gastric outlet obstruction (17 days to 5 years). Clinical features included postprandial epigastric distress, repeated non-bilious vomiting, and marked weight loss. The authors also discuss the various surgical procedures that were employed to relieve the obstruction. Notwithstanding a potential risk of malignant evolution, a gastro-jejunostomy is the treatment of choice because of the age of the patient, and good postoperative results are confirmed by barium studies.


Obstetric fractures.

Obstetric fractures. The purpose of this study was to determine the risk factors predisposing to an obstetric fracture, and their long-term outcome. We reviewed 28 obstetric fractures treated in the County of Vaud, Switzerland, between 1976 and 1989. There were 12 fractures of long bones, 10 clavicles and 6 depressed skull fractures. The belief that obstetric fractures occur in large babies or after breech deliveries is no longer valid. The common risk factors of these fractures are obstetric maneuvers during delivery (75% of cases), especially Cesarean sections (35%), prolonged labor (33%), and prematurity (25%). Cephalic presentation (64.2% of cases) is more frequent than breech position (32.1%). Weight, size, age of gestation, age of the mother, parity, gestity, and time of delivery cannot be considered as risk factors for obstetric fractures. For each type of fracture some specific risk factors are pointed out: maneuvers at birth for depressed skull fracture, Cesarean section, breech delivery with assistance and low birth weight for the fractures of long bones. All fractures were treated conservatively, except for skull fractures with a depression of more than 2 cm. Early consolidation is achieved within 2 weeks. Long-term prognosis for obstetric fractures is good without sequelae.


Significance of arthroscopy in children with knee joint injuries. Clinical and arthroscopic findings after knee joint injury were evaluated in 35 children aged 4-15 years. Arthroscopy revealed a rupture of the anterior cruciate ligament in 9 patients; two lesions were only partial. Eight children suffered from patellar dislocation. Eleven patients showed minimal synovial and cartilaginous lesions as the only cause of hemarthrosis, hydrarthrosis and clinical symptoms. Three had chondral lesions due to a dysplastic patella. The clinical diagnosis was confirmed in only 12 of 35 cases. Arthroscopic therapy was performed in 15 and open surgical intervention in 16 patients. Our results show that hemarthrosis and persisting symptoms after a knee trauma in children indicate a severe knee injury. The diagnostic procedure and treatment should be as ambitious as in adults.


Fractures of the sacrum and disk herniation: rare lesions in the pediatric surgical patient? Fractures of the sacrum and lesions of the intervertebral disks are seldom reported in childhood and adolescence. In our report, illustrated by three representative cases that we treated during the past six months, we show that sacrum fractures, not an easy diagnosis, may be more frequent than currently assumed, and that in quite a number of children and adolescents an anterior pelvic fracture may in fact be an unrecognized Malgaigne type pelvic fracture with a posterior fracture plane cutting through the sacrum. They may be accompanied by herniations and/or lacerations of intervertebral disks.


Does lateral bending lead to bowing fracture in an infantile lower arm? In a postmortem study on 50 lower arms of fetuses of the 25th week of gestation and newborn we performed three-point bending experiments to find out the stability of the lower arm after bending to the resulting fracture. Lower arms with intact soft tissue show an elastic behavior when bent from the side until fracture occurs. Applying the loading deflection diagrams we could classify the fractures into three types which differ significantly by means of bending moment, maximal deflection per unit length, and force required.


Operative treatment of solitary bone cysts with tricalcium phosphate ceramic. A 1 to 7 year follow-up. From 1984 to 1990 we treated 18 patients aged 5 to 15 1/2 years with solitary bone cysts of the humerus, the femur and the calcaneus. To fill the defect, tricalcium phosphate (TCP) instead of bone grafting was used. The clinical and radiological long-term results up to seven years postoperatively are reported. In 16 patients TCP was well incorporated without any adverse reaction to the synthetic material. Two patients with a recurrence of the bone cyst were successfully reoperated. We conclude that ceramics are a cheap and easy available substitute for bone grafts in the treatment of solitary bone cysts.


New implantable device for long-term vascular access in children. We report on our experience in the use of a new system of a totally implantable device for repeated vascular access in children, developed in 1989 by Pharmacia and named P.A.S. Port (Peripheral Access System Port). The P.A.S. Port is far smaller than other systems and has been designed for peripheral location in the arm. This avoids unsightly pectoral scars particularly in girls and allows insertion under local anesthesia. It is an interesting alternative to the Port-a-Cath for children older than 5 years of age. It is easily accepted by the patient as well as by the caring team.


Preliminary experiences with the Orbis-Sigma-System as a ventriculo-peritoneal shunt. In the last 3 years an Orbis-Sigma system has been implanted in 40 hydrocephalic children (as a primary shunt in 28 and following another shunt system in 12). Its usefulness was tested by regular clinical examinations, head circumference measurement, ultrasonography or CT and the causes and frequency of shunt revisions. The preliminary results of a mean follow-up time of 1.4 years are discussed.


Liaison psychiatry in pediatric surgery--a promising approach. Liaison psychiatry in pediatric surgery is described and the experiences at the University Children's Hospital in Zurich are reported. The patients seen by the child psychiatrist in surgery are specified and compared with those seen in pediatrics. For the most part the same psychiatric diagnoses were made in both groups with some differences in frequency. It is concluded that liaison psychiatry should be implemented in pediatric surgery, as has long been the case in pediatrics.


Freezing preservation of the mammalian heart explant. III. Tissue dehydration and cryoprotection by polyethylene glycol. Isolated rat hearts perfused with hyperosmotic Krebs-Henseleit buffer containing 60 mmol/L NaCl lose 10% of their tissue water. Perfusion of the rat hearts with Krebs-Henseleit buffer containing polyethylene glycol 8000 caused a concentration-dependent reduction in tissue water. In a study of the effect of different cryoprotectants on cardiac preservation, isolated rat hearts were flushed with a cardioplegic solution (CP-14), or CP-14 with either 50 mmol/L glycerol (CP-15), or 5% polyethylene glycol (CP-16) and frozen at -1.4 degrees C for 5 hours. Thawed hearts were reperfused in working mode to assess function. There was no recovery in CP-14 hearts. Hearts treated with CP-15 recovered 39.3% +/- 2.9% (mean +/- SEM) of control cardiac output. CP-16 boosted the recovery of cardiac output to 54.4% +/- 5.7% (p less than 0.05 vs CP-15). Glycerol significantly reduced tissue ice content; PEG further decreased the ice content to 31.7% +/- 0.6%, which was distinctively lower than that in CP-14 (44.7% +/- 1.1%) and in CP-15 hearts (34.6% +/- 1.1%). Tissue water content of CP-14 and CP-15 hearts was similar (3.83 and 3.87 gm H2O/gm dry weight). Polyethylene glycol reduced the tissue water content to 3.24 +/- 0.04 gm H2O/gm dry (p less than 0.01 vs CP-14 and CP-15 by ANOVA). Thus both glycerol and polyethylene glycol offered cryoprotection to the heart explant by reducing tissue ice formation. Polyethylene glycol was superior to glycerol by dehydrating myocardial tissue and further minimizing freezing damage.


Long-term hypothermic storage of the mammalian heart for transplantation: a comparison of three cardioplegic solutions. We have compared the protective properties of three cardioplegic solutions (St. Thomas' Hospital, University of Wisconsin, and Bretschneider) for the long-term hypothermic preservation of the rat heart. Hearts (n = 8 per group) were excised and arrested by an infusion (10 ml at 4 degrees C) of cardioplegic solution. After 4, 6, or 8 hours of storage at 4 degrees C, they were reperfused in the Langendorff mode for 15 minutes and then in the working mode for 20 minutes. After 4 hours of storage, postischemic cardiac output in the St. Thomas' and Wisconsin groups was 68.8 +/- 4.6 and 63.7 +/- 3.0 ml/min, respectively (NS); nonischemic aerobic control cardiac output was 83.2 +/- 2.6 ml/min. In the Bretschneider group, cardiac output was only 43.4 +/- 3.6 ml/min (p less than 0.05 compared to the other groups). Extending storage to 6 or 8 hours led to further decreases in recovery of function in all groups (cardiac output in the St. Thomas' and Wisconsin groups was 53.7 +/- 3.2 and 52.2 +/- 5.1 ml/min after 6 hours and 39.9 +/- 2.2 and 45.8 +/- 2.5 ml/min after 8 hours, respectively; NS). With the Bretschneider solution the cardiac output was again lower (37.6 +/- 3.0 and 22.3 +/- 4.1 ml/min, respectively). Creatine kinase leakage tended to be greater in the Bretschneider group, but adenosine triphosphate and creatine phosphate contents were well preserved in all groups. In further studies, hearts (n = 8 per group) were infused with the three solutions and stored at 4 degrees C for 8 or 10 hours; they were then heterotopically transplanted into the abdomens of homozygous recipients. After 24 hours of reperfusion, the hearts were excised and taken for ex vivo functional and metabolic studies. Recovery of contractile function was similar in all groups, but the tissue content of adenosine triphosphate tended to be greater in the St. Thomas' and Wisconsin groups (15.0 +/- 1.5 and 14.7 +/- 1.0 mumol/gm dry weight in the 8-hour storage groups and 12.1 +/- 1.2 and 11.7 +/- 0.8 mumol/gm dry weight in the 10-hour storage groups, respectively) than in the Bretschneider groups (12.3 +/- 0.9 and 9.1 +/- 1.6 mumol/gm dry weight, respectively). Creatine phosphate content recovered completely in all groups. We conclude that all three solutions afford similar protection to the hypothermically stored rat heart, but that the St. Thomas' Hospital and University of Wisconsin solutions are marginally superior to the Bretschneider solution.


Improved donor myocardial recovery with a new lazaroid lipid antiperoxidant in the isolated canine heart. U74006F is a new 21-amino steroid (lazaroid) that prevents lipid peroxidation without glucocorticoid or mineralocorticoid side effects. Reperfusion injury has been reduced by the addition of various free radical scavengers and antiperoxidants to the reperfusate. To assess the effect of U74006F on reperfusion of donor hearts subjected to prolonged hypothermic ischemia, 21 isolated canine hearts were divided into three groups: control (group 1), drug (2 mg/kg) injected into the oxygenated blood perfusate immediately before 4 hours of preservation (group 2), and drug (2 mg/kg) injected 1 hour before heart isolation and again 15 minutes before reperfusion (group 3). After control left ventricular function studies (with an intraventricular balloon) and biopsy for high-energy phosphates and dry/wet ratios, the hearts were arrested with cold cardioplegia and cooled for 4 hours then reperfused for 3 hours. Left ventricular work was calculated by systolic and diastolic pressure curves, which showed a better return of function in group 3 hearts (1625, 2150, and 3493 mm Hg/ml in groups 1, 2, and 3, respectively, at 180 minutes of reperfusion; p = 0.02). This was likely the result of improved diastolic compliance in group 3. Dry/wet ratios showed increased tissue edema in all hearts at the end of reperfusion. Although high-energy phosphate concentrations were not different between groups, adenosine was best preserved in group 3 (p = 0.03), suggesting reduced washout of this precursor. In conclusion, administration of U74006F before preservation and reperfusion may be useful for donor heart protection.


Improvement of currently used methods for lung preservation with prostacyclin and University of Wisconsin solution. After 6 hours of cold ischemia the quality of lung preservation was assessed in a canine heart-lung transplant model comparing three clinically used methods for lung preservation: donor core cooling by means of extracorporeal circulation (group I); pulmonary artery flush perfusion with either Euro-Collins solution after prostacyclin application (group II); or University of Wisconsin solution after donor pretreatment with prostacyclin (group III). In all cases St. Thomas Hospital solution was used for myocardial protection. Heterotopic heart and orthotopic left lung allotransplantation was performed in three groups of six mongrel dogs each according to the method of lung preservation. After transplantation cardiorespiratory function was assessed at FiO2 of 0.4 for a maximum of 12 hours. After surgery, significantly improved oxygenation of the donor lung was observed in groups II and III, compared to group I (p less than 0.01). Between groups II and III, no significant differences were found in the oxygenation during the first 5 hours, but in the later postoperative course pO2 values decreased in group II although they remained stable on a higher level during the entire postoperative course in group III (p less than 0.05). University of Wisconsin solution for lung preservation in combination with prostacyclin donor pretreatment provides superior postoperative oxygenation of the transplanted lung compared to currently used clinical standards represented by donor core cooling and Euro-Collins flush perfusion.


Long-term preservation of the heart: the effect of infusion pressure during continuous hypothermic cardioplegia. Continuous hypothermic low-flow infusion of cardioplegic or other preservation solutions has been advocated for extending the maximum duration of storage of donor hearts for transplantation. We report the effect of varying the pressure during continuous infusion of St. Thomas' Hospital cardioplegic solution on functional recovery after long-term storage. Isolated working rat hearts (six per group) were aerobically perfused (20 minutes), and control indexes of cardiac function were measured; hypothermic ischemic arrest was then induced by a 3-minute infusion (60 cm H2O) of cold (7.5 degrees C) St. Thomas' Hospital cardioplegic solution. Hearts were then stored for 8 hours at 7.5 degrees C, either immersed in St. Thomas' Hospital cardioplegic solution (noninfused control) or continuously infused at varying infusion pressures with St. Thomas' Hospital cardioplegic solution, which had been both oxygenated and supplemented by the addition of glucose (11.1 mmol/L). After 8 hours of hypothermic ischemia, the rate of cardioplegic infusion was measured as an index of vascular resistance. The hearts were then reperfused (Langendorff) for 30 minutes during which creatine kinase leakage was measured. The hearts were then converted to working preparations for 20 minutes, and the recovery of contractile function was measured and expressed as a percentage of the preischemic control value. In hearts that had been subjected to continuous infusion at 6, 10, 20, 30, 40, and 60 cm H2O, the recoveries of aortic flow were 0% (p less than 0.05), 38.6% +/- 5.1% (p less than 0.05), 36.2% +/- 3.6% (p less than 0.05), 14.0% +/- 8.0%, 5.8% +/- 2.9%, and 9.9% +/- 4.7%, respectively, and the postischemic leakage of creatine kinase was 98.7 +/- 19.5 (p less than 0.05), 26.2 +/- 4.2, 15.5 +/- 3.4, 30.4 +/- 11.1, 109.8 +/- 21.8 (p less than 0.05), and 136.0 +/- 14.1 (p less than 0.05) IU/30 min/gm dry weight, respectively. In contrast, in noninfused control hearts the recovery of aortic flow was 11.1% +/- 7.5%, and creatine kinase leakage was 58.9 +/- 8.7 IU/30 min/gm dry weight. In conclusion, maximum myocardial preservation was obtained with continuous low-flow hypothermic cardioplegic infusion at pressures between 10 and 20 cm H2O.


Beneficial effect of fluorocarbon reperfusion on postoperative cardiac dysfunction of transplanted heart. Fluosol DA 20% (Fluosol) perfusion was used to protect ischemic donor hearts of mongrel dogs from reperfusion injury. Fifteen orthotopically transplanted hearts, eight in the control group and seven in the Fluosol group, were studied for 3 hours after weaning from cardiopulmonary bypass. Donor hearts were arrested and immersed in 4 degrees C St. Thomas's Hospital Solution for 4 hours. The mean total ischemic time was 323 minutes (range, 298 to 345 minutes). In the Fluosol group, 200 ml of oxygenated Fluosol (37 degrees C; PO2 650 mm Hg; PCO2 35 mm Hg) was infused into the aortic root at approximately 100 ml/min just before aortic unclamping. Coronary sinus blood was analyzed for the MB fraction of creatine kinase, reduced glutathione, and oxidized glutathione. Hemodynamic and biochemical results were obtained at 30 minutes, 1 hour, and 3 hours after bypass. In the control group, during the second 30 minutes of the period after bypass, left ventricular end-diastolic pressure and stroke volume showed progressive deterioration, 54.8% increased (p less than 0.01) and 28.4% decreased (p less than 0.05), respectively. The MB fraction of creatine kinase and oxidized glutathione were increased, and reduced glutathione had declined, from 39.3 to 135.3 IU/L (p less than 0.01), from 28.0 to 33.4 micrograms/ml (p less than 0.05) and from 4.4 to 2.5 micrograms/ml (p less than 0.01), respectively. These parameters failed to recover during the next 2 hours, and massive mitochondrial degeneration was observed by electron microscopy. In the Fluosol group, these parameters maintained their baseline values, and electron microscopy showed well-preserved mitochondria. The data suggested that, in the control group, initial mitochondrial dysfunction was profound, persistent for at least 3 hours, and associated with membrane hyperpermeability, leading to cardiac dysfunction. Oxygenated Fluosol perfusion better preserved cardiac and mitochondrial function.


Donor-heart evaluation by monitoring the left ventricular pressure-volume relationship: clinical observations. Fourteen donor hearts were assessed by measurement of dopamine requirement, basic hemodynamic parameters (for example, systolic blood pressure), and the left ventricular pressure-volume relationship. The latter function was measured by a combination microtipped manometer/conductance catheter placed in the left ventricle through the ascending aorta. With an isoproterenol dose 24 hours after transplantation as the measure of cardiac performance, multiple linear regression analysis indicated that the ratio of arterial elastance (Ea) to left ventricular end-systolic elastance (Ees), ventriculoarterial coupling (Ea/Ees), and myocardial ischemic time were good predictors of posttransplantation cardiac performance. Dopamine requirement and basic hemodynamic data were not. Twelve implanted hearts showed an Ea/Ees of less than 1.0 and showed good early (less than 24 hours) and late function. Two hearts considered on clinical grounds to be unsuitable for transplantation showed an Ea/Ees of more than 1.0. The data suggest that measurement of the left ventricular pressure-volume relationship would appear to be a clinically useful predictor of donor-heart performance after transplantation.


Bench coronary angiography: a potentially useful method to assess coronary artery disease in the older donor heart without catheterization laboratory angiography. To assess the diagnostic accuracy of ex vivo coronary artery arteriography, 12 sheep hearts were harvested, after random multiple coronary occlusions were created. The hearts were radiographed either in the flat (n = 6) or upright suspended (n = 6) position with the aorta cross-clamped. The aortic root was cannulated with an 18-gauge needle and flushed with cold normal saline solution. Five milliliters of iodinated contrast media was injected under constant hand pressure, and angiographic views were taken with a conventional, portable x-ray machine. The aortic root was then immediately flushed with normal saline solution under constant pressure to minimize contrast contact with the vascular endothelium. Total elapsed time including film development was 7 to 10 minutes. In hearts that were radiographed lying flat, a ventriculogram was obtained because of aortic incompetence. In hearts suspended in the upright position, normal coronary anatomy and previously placed coronary occlusions were easily detected in every heart that was read blindly by angiographers. To assess the effects of the contrast media on ventricular performance, five rabbit hearts were harvested and mounted on a Langendorff apparatus for functional analysis at controlled left ventricle volumes. Diastolic and systolic left ventricular pressures were unaffected by the dye injection. This simple and rapid method to evaluate coronary anatomy of the donor heart could be potentially useful in the assessment of older donor hearts in the operating room, thus increasing the volume of donor hearts available for transplantation.


Successful heart transplantation with cardiac allografts exposed to carbon monoxide poisoning. The procurement of cardiac allografts from brain-dead donors who have suffered acute carbon monoxide poisoning has, in the past, been considered inadvisable. Two patients have recently undergone successful transplantation at our institution with cardiac allografts from donors who had suffered acute carbon monoxide poisoning. Carbon monoxide poisoning is not a contraindication to cardiac allograft procurement in the setting of clinical and objective evidence of satisfactory cardiac function.


Effects of terminal cardioplegia with leukocyte-depleted blood on heart grafts preserved for 24 hours. Canine hearts immersed in modified Collins solution were transplanted heterotopically (n = 23) and orthotopically (n = 15) to evaluate the effect of terminal warm-blood cardioplegia with or without leukocyte depletion. As the index for graft function, preload recruitable stroke work was measured in both series before harvesting (control) and after transplantation (percentage). The heterotopic hearts were divided into four groups (group 1 to 4) according to the preservation method; hearts were preserved for 3 hours in group 1 and for 24 hours in groups 2, 3, and 4. Simple terminal warm-blood cardioplegia was applied in group 3, and terminal warm-blood cardioplegia with leukocyte depletion was used in group 4. In the orthotopic series, five hearts were transplanted soon after harvesting (group 5) to simulate on-site transplantation, and the remaining ten hearts were transplanted after 24 hours of hypothermic preservation without and with terminal warm-blood cardioplegia with leukocyte depletion (groups 6 and 7, respectively). Among the heterotopic transplants, the percentage of preload recruitable stroke work was highest in group 4 (91% +/- 6%, 51% +/- 4%, 83% +/- 10%, 140% +/- 11% in groups 1, 2, 3 and 4, respectively). All orthotopic transplants in groups 5 and 7 were weaned from cardiopulmonary bypass without inotropic support and without significant differences in cardiac function between groups 5 and 7 (percentage of preload recruitable stroke work, 99% +/- 10% versus 102% +/- 2%; cardiac output, 122 +/- 10 versus 140 +/- 22 ml/kg/min). No orthotopic transplants in group 6 could be weaned from cardiopulmonary bypass, even with inotropic support.(ABSTRACT TRUNCATED AT 250 WORDS)


Donor cardiectomy for other transplantation centers. Inadequate supply of donor hearts is the greatest limitation to wider utilization of heart transplantation. We performed donor cardiectomy for other transplantation centers in three cases. The donor heart functioned well in all cases, and the recipients were all discharged. Donor cardiectomy for other transplantation centers allows utilization of hearts that might otherwise be lost for transplantation.


Influence of recipient and donor gender on outcome after heart transplantation. To investigate the effect of recipient and donor genders on the outcome after heart transplantation, a retrospective survey was undertaken of 356 patients (366 transplants: 316 males, 40 females) undergoing transplantation between January 1979 and December 31, 1989, at Papworth Hospital. Ninety-three organs came from female donors; 263 organs came from males. Twelve females (30%; 95% confidence interval 16% to 44%) and 51 males (16%; 95% confidence interval 12% to 20%) died in the early postoperative period (within 90 days of operation). To date, two females (5%) and 51 males (16%) have died in the late postoperative period. Comparison between recipient genders showed no statistically significant difference in early mortality rates from any cause or in actuarial survival overall, although fatal acute rejection was significantly more common in female recipients (7 of 40 female recipients versus 19 of 316 male recipients). The higher incidence of fatal rejection among female recipients was related to the higher proportion of female donors in this group, because recipients of female donor grafts had significantly higher mortality rates, particularly in the early postoperative period and as a result of acute rejection, than did recipients of organs from male donors. Death from rejection after the first 3 months and death from infection were not gender-related. Recipients of grafts from female donors did not suffer significantly more early morbidity, such as rejection and infection, or late morbidity in the form of coronary artery disease. Acute rejection episodes were more common in female recipients.(ABSTRACT TRUNCATED AT 250 WORDS)


Influence on survival after heart transplantation of contraindications seen in transplant recipients. Fifty-seven patients underwent heart transplantation at our hospital between April 1986 and April 1991. In an attempt to assess the result of and the influence of contraindications seen in transplant recipients before transplantation on the outcome after transplantation, we have analyzed six of these "relative" contraindications: (1) age over 55 years (21% of patients); (2) pulmonary hypertension (pulmonary vascular resistance of more than 5 Wood units, and/or transpulmonary gradient of more than 12 mm Hg; 26% of patients); (3) renal failure (serum creatinine level of more than 2 mg/dl, and/or creatinine clearance of less than 35 ml/min; 11% of patients); (4) active infection (9% of patients); (5) diabetes mellitus (7% of patients); and (6) critical/unstable clinical condition before transplantation (25% of patients). An overall "risk score," obtained by adding one point for each contraindication, was also analyzed. Risk score was 0 (the "ideal" recipient) in 38% of patients, 1 in 25% of patients; 2 in 23% of patients; and 3 or more in 14% of patients. Actuarial survival was significantly lower for patients over 55 years of age (45% versus 68% at 18 months; p less than 0.05), for patients with elevated pulmonary vascular resistance (38% versus 72%; p less than 0.01), and for patients with kidney failure (16% versus 70%; p less than 0.01). On the contrary, survival at 18 months was not significantly different for patients with or without diabetes mellitus (50% versus 63%; not significant [NS]), active infection (60% versus 63%; NS), or critical/unstable condition (45% versus 69%; p less than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)


Utility of prostaglandin E1 in the pretransplantation evaluation of heart failure patients with significant pulmonary hypertension. Patients with chronic heart failure frequently have pulmonary hypertension. Because severe preoperative pulmonary hypertension predicts a poor outcome after orthotopic transplantation, pulmonary vasoreactivity is evaluated frequently in the pretransplantation screening of heart failure patients. We prospectively evaluated the utility of the direct pulmonary vasodilator, prostaglandin E1, and compared it to the nonspecific vasodilators, nitroglycerin and sodium nitroprusside, in the evaluation of pulmonary hypertension in 39 heart transplantation candidates. Prostaglandin E1 significantly lowered pulmonary artery pressure, transpulmonary pressure gradient, and pulmonary vascular resistance. An adequate pulmonary vasodilator response (defined as a decline in transpulmonary pressure gradient to less than 15 mm Hg) occurred in 31 patients (79%). In a subgroup of nine patients also tested with nitroglycerin, greater reductions (p less than 0.01) in both transpulmonary pressure gradient and pulmonary vascular resistance occurred with prostaglandin E1, compared to nitroglycerin. Five of six patients who did not respond to nitroglycerin responded to prostaglandin E1. In another subgroup of 12 patients who were also evaluated with sodium nitroprusside, prostaglandin E1 produced a larger decline (p less than 0.05) in transpulmonary pressure gradient and pulmonary vascular resistance than did sodium nitroprusside. Six of eight patients who did not respond to sodium nitroprusside responded to prostaglandin E1. Based on pulmonary vasodilator response to prostaglandin E1, 27 patients were accepted on the transplantation waiting list, and eight patients underwent orthotopic transplantation. Postoperatively, acute right ventricular failure of the donor heart developed in none of these patients. Significant hemodynamic improvement occurred by 24 hours and persisted through 4 weeks of postoperative follow-up in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)


Prostaglandin E1 reduces the frequency of rejection after heart transplantation. This retrospective study was carried out to evaluate the effect of prostaglandin E1 on the frequency of rejection in 36 heart transplant recipients who survived orthotopic heart transplantation for 60 days or longer. The therapy for both groups was the same except group 1 (n = 12) was given PGE1 for 6 to 14 days. Indication for the PGE1 was right ventricular mismatch or failure. The prostaglandin administration started during the transplantation procedure. The dosage was 28 to 64 ng/kg/min and was tapered down from 14.7 to 32 ng later. No major side effects related to PGE1 have been observed. During the first 60 days after heart transplantation, in the group treated with prostaglandin, rejection grade 2 or higher was evident in 0.91 biopsies/patient versus 2.2 in nontreated patients, (p less than 0.05). A prolonged interval free from rejection (p less than 0.05) was observed in the patients treated with prostaglandin.


Reversal of acute fulminant lymphocytic myocarditis with combined technology of OKT3 monoclonal antibody and mechanical circulatory support. Reported is a case of acute fulminant lymphocytic myocarditis with profound circulatory compromise that was successfully reversed by treatment with OKT3 monoclonal antibody. The patient was supported with biventricular assist devices while being treated with the monoclonal antibody. The patient had remarkable recovery of ventricular function, which allowed for the removal of the device after 8 days of support. This case shows the success of combined technologies of monoclonal antibody and mechanical circulatory support to treat a potentially fatal disease process.


Methotrexate for the treatment of patients with multiple episodes of acute cardiac allograft rejection. Of 142 cardiac allograft recipients who underwent transplantation from December 1985 to January 1991, four women and seven men (mean age, 41 +/- 14 years) required multiple (10.5 +/- 3.3) courses of antirejection treatment over a total follow-up period of 30 +/- 15 months. The underlying heart disease was cardiomyopathy in six patients and coronary disease in five patients. These patients were treated with methotrexate (10 mg/wk for 6 weeks). Rejection treatment before methotrexate therapy included six courses of OKT3, one course of antithymocyte globulin, 33 courses of high-dose steroids, and 45 courses of low-dose steroids for the entire group. The average number of rejection treatments per patient before methotrexate therapy was 8.7 +/- 3.5 treatments or 0.90 +/- 0.51 treatments per month of follow-up. After methotrexate therapy the average number of rejection treatments fell to 1.7 +/- 1.1 treatments or 0.11 +/- 0.08 treatments per month of follow-up (p = 0.0002). Seven patients responded to a single course of methotrexate therapy; three patients required two courses (second course, 20 mg/wk for 6 weeks), and one patient required three courses of methotrexate therapy. The only complication associated with methotrexate therapy was one patient in whom cytomegalovirus interstitial pneumonitis developed while on therapy. Methotrexate was well tolerated and appeared to be effective in halting repeated episodes of rejection in this subset of patients who have had multiple episodes of acute rejection.


Photochemotherapy in human heart transplant recipients at high risk for fatal rejection. Heart transplant recipients in whom high levels of lymphocytotoxic antibodies directed towards a spectrum of histocompatibility antigens develop frequently represent difficult management problems. Recipients of multiple transplants and multiparous females generally form higher levels of panel reactive antibodies, which have been associated with fatal rejection episodes and accelerated graft atherosclerosis. In this study, two multiple transplant patients with preexistent high levels of panel reactive antibodies and two multiparous women who were considered at risk of sensitization were treated with a new form of immunotherapy termed photochemotherapy in addition to conventional immunosuppression. High levels of panel reactive antibodies have been reduced, and patients have suffered few rejection episodes and no infectious complications. This preliminary experience shows that the addition of photochemotherapy to conventional regimens may improve the clinical course of hypersensitized transplant patients without additional immunosuppressive risk.


Evolution of untreated mild rejection in heart transplant recipients. To elucidate whether mild rejection requires treatment, we retrospectively examined the spontaneous natural history of this histologic feature without an increase of immunosuppression. During a 4-year period, 55 heart transplantations were performed in 54 patients on whom 958 endomyocardial biopsies were performed. Among these biopsies, 162 specimens showed features of mild rejection. We studied the results of subsequent biopsies performed 7 to 10 days later, without any change in immunosuppression. These revealed regression of lesions to minimal rejection in 51 cases (31%), the same histologic feature in 82 cases (51%), or progression to moderate or severe rejection in 29 cases (18%). In 82% of these cases, therefore, no aggravation of histologic feature was observed. We separated the cases in which current-study biopsies showed mild rejection into three groups according to the result of the most recent biopsy, that is, minimal, mild, or moderate-severe rejection. The percentage of good outcome was not modified by the nature of the previous biopsy specimen: 84%, if minimal rejection was preceding the study biopsy; 82%, in the cases of mild rejection; and 77%, for moderate or severe rejection. We did not find significant differences in this evolution between patients with fewer or more than two moderate or severe acute rejections in the first 4-month period after heart transplantation (respectively, 15% or 24% progression to moderate or severe acute rejection after nontreated mild rejection).(ABSTRACT TRUNCATED AT 250 WORDS)


Asymmetric intramyocardial lymphocytic accumulation during acute rejection in rat heart and heart-lung transplantation. Lymphocytic accumulation in different areas of the myocardium during different phases of acute rejection were studied in rat heterotopic cardiac and cardiopulmonary allograft and isograft transplantation models. Indium 111-labeled syngeneic lymphocytes were injected 1 to 7 days after transplantation, and accumulation of the labeled cells in the graft was determined 24 hours later. The cardiac graft was divided into three segments: right ventricular (RV) free wall, epicardial portion of the left ventricle (LV) plus RV septum, and endocardial portion of the LV. In the subsequent heart-lung transplantation group, the LV epicardial portion plus RV septum segment was subdivided into LV epicardial portion and RV septum. Lymphocytic accumulation in each segment was compared between three groups according to the day the animal was killed after transplantation: days 2, 3 (group 1), days 4, 5 (group 2), and days 6, 7, 8 (group 3). Lymphocytic accumulation caused by rejection in group 1 and group 2 of both the cardiac and cardiopulmonary allografts showed significantly different intramyocardial distribution (p less than 0.01). Lymphocytic accumulation was consistently highest in RV free wall and lowest in LV endocardial portion. In group 3 specimens, lymphocytic accumulation was symmetrical in both the cardiac and cardiopulmonary allografts. In the cardiac allograft, the lymphocytic accumulation increased sharply on day 4 then declined to a nadir. This transient increase was not so pronounced in the cardiopulmonary allografts. The significantly decreased intramyocardial lymphocytic accumulation in group 2 of the cardiopulmonary allografts when compared with the cardiac allografts (p less than 0.01) is compatible with the clinical observation of a lower incidence of acute heart rejection in heart-lung transplant recipients. These data show an asymmetric accumulation of lymphocytes during acute heart rejection, which is due to increased lymphocytic affinity for the RV free wall.


Ventricular dysrhythmia and heterotopic heart transplantation. Heterotopic heart transplantation is an alternative option in end-stage heart disease. We present a patient with a heterotopic allograft that maintained hemodynamics at the period of a malignant ventricular dysrhythmia and supports the notion that these otherwise lethal dysrhythmias of the native heart may not carry the same risk of sudden heart death in patients with heterotopic heart transplantation.


Ventricular fibrillation during acute rejection after heart transplantation. The case of a 46-year-old patient who underwent orthotopic heart transplantation for treatment of end-stage heart failure as a result of ischemic heart disease is reported. Four months after transplantation a grade II rejection episode was complicated by ventricular fibrillation. Lidocaine and procainamide intravenously did not effectively prevent recurrence. An increase of antirejection therapy in combination with flecainide acetate effectively prevented further episodes of ventricular fibrillation. This case demonstrates that recurrent ventricular fibrillation can be a complication of acute rejection.


Pacing requirements after orthotopic heart transplantation: incidence and related factors. To assess the incidence of severe bradyarrhythmia and pacing requirements after orthotopic heart transplantation, as well as the possible causal mechanisms, we have reviewed our experience on 52 consecutive transplant patients. The overall incidence of bradyarrhythmia requiring pacing for at least 24 hours after transplantation was 27% (14 patients). The conditions of three of them required pacing for less than 1 week; the conditions of the other 11 patients (21%) required pacing for more than 1 week. Normal sinus rhythm resumed in all but four patients within 3 weeks; a permanent pacemaker was implanted in these four patients (7.6% of all 52 patients and 28% of patients requiring temporary pacing). Late complete heart block associated with acute rejection developed in two patients whose conditions required implantation of a permanent pacemaker. The age and sex of the recipient and donor were similar for patients with or without bradyarrhythmia. The percentage of patients with or without bradyarrhythmias taking amiodarone before transplantation (57% and 46%, respectively), total ischemic time (133 +/- 33 and 123 +/- 37 minutes, respectively), and cardiopulmonary bypass time (117 +/- 17 and 132 +/- 65 minutes, respectively) were not significantly different for either group of patients. The initial temperature of cardioplegic solution for organ storage and the preimplantation myocardial temperature were, however, significantly lower in patients whose conditions required pacing immediately after transplantation than in those whose conditions did not require pacing (5.3 +/- 1.7 degrees C versus 6.5 +/- 1.5 degrees C, p less than 0.05, and 3.9 +/- 1.6 degrees C versus 5.7 +/- 2.6 degrees C, p less than 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)


Successful use of the total artificial heart as a bridge to transplantation with no mediastinitis. High rates of infection, especially mediastinitis, have been reported with the use of the total artificial heart (TAH), thereby limiting its usefulness. We have used the TAH as a bridge to transplantation with only minor infectious complications and a zero incidence of mediastinitis. Between February 1988 and August 1990, the TAH was inserted at Loyola University Medical Center in 19 patients, ages 16 to 64 years (mean, 44 years). Seventeen patients (89%) underwent transplantation within 1 to 34 days (mean, 9.8 days). Of the patients who did not undergo transplantation, one was brain dead and the other died of bleeding diathesis. Early (30-day) deaths occurred in two patients (11.7%): acute rejection at 18 days and multiple cerebral infarcts at 14 days. Three late deaths (17.6%) occurred: one patient, cytomegalovirus and pneumocystis pneumonia at 4 months; one patient, bronchopneumonia and multisystem failure at 9 months; and one patient, chronic rejection at 14 months. Minor infectious complications during the TAH implantation included Enterobacter pneumonia treated with antibiotics and positive sputum cultures (Escherichia coli; Candida), with no clinical evidence of infection in two patients. No cases of mediastinitis occurred either while the TAH was implanted or after transplantation. All patients were on antibiotics while the device was in place. Our experience with the TAH shows this to be an excellent device for successful bridging of patients for heart transplantation. We have had minimal infectious complications and none directly attributed to the use of this device. This device should continue to be used safely as a bridge to transplantation.


Bladder cancer.

Bladder cancer. In the search for sensitive and specific tumor markers for bladder carcinoma, expression of various oncogenes and gene products (such as c-erb B-2, p53) and epidermal growth factor receptor merits particular attention. Although the results are not yet conclusive, important predictive markers are about to emerge from ongoing studies in this field. Bacillus Calmette-Guerrin treatment in superficial bladder cancer is probably the most successful immunotherapy in humans. But there is still a large knowledge deficit in the issues of optimal dose schedule and mechanisms of action. Although promising results of neoadjuvant chemotherapy in patients with invasive bladder cancers are reported, we must be cautious about changing our conventional approach until the results of large scale, controlled, randomized studies evaluating the survival are published.


Successful double bridge to transplantation with the Thoratec ventricular assist device. A 34-year-old woman was successfully bridged to heart transplantation after 5 days of biventricular support on the Thoratec system. Acute graft failure necessitated immediate replacement of biventricular support, which continued for 12 days until successful retransplantation occurred. Uneventful recovery led to discharge from the hospital on postoperative day 18.


Nocardia otitidiscaviarum (caviae) infection in a heart transplant patient presented as having a thigh abscess (Madura thigh). The first case of disseminated infection with Nocardia otitidiscaviarum in a heart transplant patient is reported. The clinical spectrum and treatment of infections with N. otitidiscaviarum is discussed, including our patient's apparent response to imipenem/cilastatin.


Recent advances in epidemiology of head and neck cancer. Cancer of the oral cavity is an important contributor to the overall international cancer burden, especially in the developing countries. Smoking cessation, moderation of alcohol consumption, and increased consumption of fruits, and probably vegetables, have been identified by epidemiologic studies as three actions that could lead to the prevention of approximately three fourths of cases in Western countries. Similar effects could be brought about in developing countries through cessation of cigarette smoking and, where appropriate, betel quid chewing and increased consumption of fruits and vegetables. Since this disease is increasing in frequency in many countries, it is important to implement these health education messages. A similar situation holds true for larynx cancer. Clearly many head and neck cancers are preventable and it is worth repeating that prevention should become an epidemiologic priority. There are exciting prospects of effective chemoprevention opportunities in head and neck cancer, with a number of compounds having activity. Further developments in this important area are awaited.


Experimental head and neck oncology.

Experimental head and neck oncology. The field of experimental head and neck oncology continues to expand in both scope and meaningful observations. During the past year, research has focused intensively on factors responsible for disease development, genetic alterations that contribute to cancer progression, tumor growth factors and their modulation, and the biologic and clinical significance of cell-surface antigen expression. In the field of carcinogenesis, various dietary components that either promote or inhibit head and neck cancer development have been identified. Clinical trials that utilize various vitamins and their precursors such as beta-carotene have been reported. Genetic studies have demonstrated that head and neck cancers are heterogeneous in their oncogene expression; potentially, a reflection of the differential effect of various environmental carcinogenic exposures. Finally, the relationship between modulation of normally occurring cell-surface antigens and tumor aggressiveness has been demonstrated by several investigators throughout the past year. Significantly, animal models and human clinical trials have demonstrated that modulation of cell surface components by biologic agents alters the behavior of head and neck cancer and its relationship to the host.


Dactylaria infection of a human being: pulmonary disease in a heart transplant recipient. We describe a case of pulmonary abscess caused by Dactylaria constricta in a heart transplant recipient. A 30-year-old man with a 1-month history of fever and cough was found by computed tomographic scan to have a cavitary lesion in the lingular segment in the upper lobe of his left lung. Culture of a needle biopsy specimen yielded a pure culture of D. constricta. The patient was successfully treated with systemic amphotericin B therapy, which resulted in resolution of the clinical symptoms and of the cavitary lesion.


Pathology of squamous carcinomas of the head and neck. Recent publications have been critically reviewed to illustrate some of the newer approaches that may eventually provide more precise prognostic information from tumor biopsies. Examples include changes in expression of various surface antigens, DNA ploidy, and alterations at the level of molecular genetics, eg, gene amplification. Other molecular changes in tumor tissue, such as point mutations and loss of normal tumor suppressor genes, are also giving clues to underlying carcinogenic mechanisms.


Hemodynamically significant suture line obstruction immediately after heart transplantation. Mechanical complications after heart transplantation are uncommon. We describe a case of hemodynamically significant suture line obstruction that was recognized immediately after heart transplantation using transesophageal echocardiography. Transesophageal echocardiography has proved to be a powerful tool in recognizing mechanical complications in the early posttransplant period.


Head and neck cancer surgery.

Head and neck cancer surgery. This review presents several areas of current interest in head and neck oncology including endoscopic and conservation management of early laryngeal cancer, intraoperative radiotherapy, and microvascular reconstruction techniques. Endoscopic treatment of early laryngeal cancer using the CO2 laser has been shown to be effective in several recent studies, and improved laryngeal reconstruction techniques following conservation laryngeal surgery have resulted in improved functional results. Intraoperative radiotherapy for head and neck carcinoma has received more attention recently, with encouraging results for the treatment of advanced and recurrent skull base and head and neck tumors. New techniques of free flap reconstruction following surgery for head and neck cancer continue to result in improved rehabilitation.


Chemotherapy in head and neck cancer.

Chemotherapy in head and neck cancer. The role of chemotherapy in the management of patients with head and neck cancer continues to evolve. Single-agent methotrexate or cisplatin, or the combination of cisplatin and infusional fluorouracil can be considered standard therapy for patients with recurrent disease. Neoadjuvant chemotherapy is being actively pursued. Although enhanced survival has not yet been demonstrated, the goal of organ preservation has been achieved for patients with laryngeal cancer. Because of the high incidence of locoregional failure, concomitant chemoradiotherapy is also under investigation. This treatment approach has already been suggested to result in prolonged survival in randomized studies and holds promise for the future.


Radiotherapy, hyperthermia, and phototherapy for central nervous system tumors. Many new modalities and increasing data have become available in the treatment of brain tumors. We will review the growing experience with newer treatment modalities such as brachytherapy, radiosurgery, hyperthermia, and photodynamic therapy.


Surgery, radiation therapy, and chemotherapy for metastatic tumors to the brain. Recent literature has confirmed patient age, Karnofsky status, and the extent of extracerebral tumor as independent prognostic variables in patients with cerebral metastases. In a good-risk population, surgery followed by radiation therapy is superior to radiation alone for treatment of patients with solitary metastases. Stereotactic radiosurgery is feasible in the same select patient population, but questions regarding the extent of delayed toxicity, tumor response, and the impact on quality of life and longevity remain to be answered. Studies of external beam radiation therapy for patients with brain metastases have shown that 1) misonidazole does not improve the response rate, quality of life, or duration of survival, 2) 5 Gy for six fractions and 3 Gy for 10 fractions produce similar results, and 3) reirradiation at doses of 25 Gy for tumors progressing after initial radiation may be feasible in a selected population of patients. Chemotherapy can affect regression of brain metastases in patients with small cell lung and breast carcinoma, as well as melanoma, but the overall contribution to the quality and duration of the patient's life compared with radiation alone is unknown. Intracarotid chemotherapy is feasible for patients with brain metastases, but substantial toxicity precludes its use outside of an investigational setting. Brain metastases remain an important cause of morbidity and mortality for patients with cancer, but the majority of patients still succumb to widespread systemic disease. The goal of treatment of brain metastases should be palliation with minimal infringement upon the patient's quality of life.


Immunotherapy and monoclonal antibody therapies. High-grade malignancies of the central nervous system continue to be refractory to multimodality therapy. Immunotherapy with monoclonal antibodies, biologic response modifiers (eg, interleukin-2), and autologous, activated lymphocytes offer the potential for more selective therapy. Current research is likely to help overcome obstacles inherent in current monoclonal antibody therapy, including cross-reactivity with normal tissues, impermeability of the blood-brain barrier, and immunogenicity of murine-derived monoclonal antibodies. Treatment with adoptive cellular therapy and biologic response modifiers has been limited by low killing activity and specificity of the activated lymphocytes, limited infiltration of implanted cells, and the toxicity associated with systemically administered biologic response modifiers. Improved specificity and killing efficacy of activated lymphocytes will allow integration of cellular immunotherapy into the treatment of central nervous system malignancies.


[Pneumonia caused by non-opportunistic bacteria in patients infected with HIV. Incidence and evaluation of a non-invasive approach]. Pneumonia due to pathogenic bacteria is common in HIV infected patients. However, a global overview has not been yet performed and also the effectiveness of a non-invasive approach has not been tested. An open study was conducted in 1989 including all HIV infected patients with a presumptive or definite diagnosis of bacterial pneumonia. Fiberoptic bronchoscopy procedures were used only in patients with a difficult diagnosis and/or problems in their clinical evolution. Clinical and biological data were compared among different etiologic groups, and their evolution was also recorded in relation with the use of non-invasive procedures. Among a total of 302 admissions of HIV infected patients, 113 developed a primary or secondary respiratory tract infection. Forty-three of those were bacterial pneumonia episodes. Etiologic diagnosis was achieved with non invasive methods in 18 cases (42%). Blood cultures were the most effective method used. Streptococcus pneumoniae was the most frequently identified microorganisms (9 cases, 21%). The identification of other bacteria was linked with more severe forms of disease regarding immunologic (leukopenia, p less than 0.001; T4 lymphopenia, p less than 0.05), and respiratory parameters (hypoxemia, p less than 0.05). Two deaths were directly related with pneumonia of known etiology. Bacterial pneumonia is the most frequent respiratory infection in HIV infected patients. An initial non-invasive approach yields a reasonable percentage of etiologic diagnosis and is not related with a poorer outcome.


[Serological diagnosis of pulmonary tuberculosis using ELISA and the A60 antigen]. Study of the utility of a serologic technic in the clinic diagnostic of the pulmonary tuberculosis. An indirect enzyme-linked immunosorbent assay (ELISA) for detecting serum antibodies (IgG) against the antigen A60 has been applied to 170 tuberculosis patients (151 adults and 19 children) and 35 healthy children not protected with BCG. The ELISA results obtained with tuberculosis patients were: 84.8% positive IgG in adults and 21.1% in children. The percentage of serologically positive cases in healthy children against the antigen A60 was 11.5%. All the results were statistically significant (p less than 0.01). This test can be successfully applied as a support technique in the diagnosis of pulmonary tuberculosis in adults, it will be necessary to know the endemic situation in each community analysed.