Skin-sparing mastectomy. Oncologic and reconstructive considerations

OBJECTIVE: The authors compared skin-sparing mastectomy and traditional mastectomy both followed by immediate reconstruction in the treatment of breast cancer. SUMMARY BACKGROUND DATA: Skin-sparing mastectomy is used increasingly in the treatment of breast cancer to improve the aesthetic results of immediate reconstruction. The oncologic and reconstructive outcomes of this procedure have never been analyzed closely. METHODS: Institutional experience with 435 consecutive patients who underwent total mastectomy and immediate reconstruction from January 1989 through December 1994 was examined. Mastectomies were stratified into skin-sparing (SSM) and non-skin-sparing (non-SSM) types. RESULTS: Three hundred twenty-seven SSMs and 188 non-SSMs were performed. The mean follow-up was 41.3 months (SSM, 37.5 months, non-SSM, 48.2 months). Local recurrences from invasive cancer occurred after 4.8% of SSMs versus 9.5% of non-SSMs. Sixty-five percent of patients who underwent SSMs had nothing performed on the opposite breast versus 45% in the group of patients who underwent non-SSM (p = 0.0002). Native skin flap necrosis occurred in 10.7% of patients who underwent SSMs versus 11.2% of patients who underwent non-SSMs. CONCLUSIONS: Skin-sparing mastectomy facilitates immediate breast reconstruction by reducing remedial surgery on the opposite breast. Native skin flap necrosis is not increased over that seen with non-SSM. Skin-sparing mastectomies can be used in the treatment of invasive cancer without compromising local control.     

Phylogenetic relationships among tick subfamilies (Ixodida: Ixodidae: Argasidae) based on the 18S nuclear rDNA gene

A null mutation was introduced into the mouse desmin gene by homologous recombination. The desmin knockout mice (Des -/-) develop normally and are fertile. However, defects were observed after birth in skeletal, smooth, and cardiac muscles (Li, Z., E. Colucci-Guyon, M. Pincon-Raymond, M. Mericskay, S. Pournin, D. Paulin, and C. Babinet. 1996. Dev. Biol. 175:362-366; Milner, D.J., G. Weitzer, D. Tran, A. Bradley, and Y. Capetanaki. 1996. J. Cell Biol. 134:1255- 1270). In the present study we have carried out a detailed analysis of somitogenesis, muscle formation, maturation, degeneration, and regeneration in Des -/- mice. Our results demonstrate that all early stages of muscle differentiation and cell fusion occur normally. However, after birth, modifications were observed essentially in weight-bearing muscles such as the soleus or continually used muscles such as the diaphragm and the heart. In the absence of desmin, mice were weaker and fatigued more easily. The lack of desmin renders these fibers more susceptible to damage during contraction. We observed a process of degeneration of myofibers, accompanied by macrophage infiltration, and followed by a process of regeneration. These cycles of degeneration and regeneration resulted in a relative increase in slow myosin heavy chain (MHC) and decrease in fast MHC. Interestingly, this second wave of myofibrillogenesis during regeneration was often aberrant and showed signs of disorganization. Subsarcolemmal accumulation of mitochondria were also observed in these muscles. The lack of desmin was not compensated by an upregulation of vimentin in these mice either during development or regeneration. Absence of desmin filaments within the sarcomere does not interfere with primary muscle formation or regeneration. However, myofibrillogenesis in regenerating fibers is often abortive, indicating that desmin may be implicated in this repair process. The results presented here show that desmin is essential to maintain the structural integrity of highly solicited skeletal muscle.     

DNA damage distribution in the human brain as shown by in situ end labeling; area-specific differences in aging and Alzheimer disease in the absence of apoptotic morphology

DNA damage has been proposed to underlie neuronal degeneration in aging and Alzheimer disease (AD). To determine the histological distribution of DNA damage, in situ end labeling (ISEL) was applied as a marker for DNA breaks on 4 differentially affected brain areas. Occipital cortex showed considerable variation between cortical layers and between patients. Temporal cortex displayed little ISEL-labeling in controls, and in AD, surprisingly. In the hippocampus, which is strongly affected in AD, many ISEL-positive nuclei and glialike cells were found in AD as compared with controls. The hypothalamic supraoptic and paraventricular nuclei showed little DNA-damage, whereas the nucleus basalis was often, but not always, labeled by ISEL. In contrast to others, no apoptotic morphology was observed, only necrotic morphology. Our results in relation to postmortem delay indicate that, area dependent, increased DNA vulnerability may occur in AD. Furthermore, the distribution of DNA damage in cortex differs from that of plaques and tangles, suggesting that these 3 phenomena are, in principle, independent. Whether the enhanced level of hippocampal DNA breaks in AD underlies, or rather is a consequence of, previous degenerative changes in this brain area remains to be established.     

Reduction of hospital resources utilization in vascular surgery: a four-year experience

PURPOSE: Managed care whether through risk or through capitated contracts results in reduction in resources, reduced length of hospital stay, and reduced utilization of hospital resources (collectively referred to as resource reductions). These resource reductions will become even more noticeable as a greater proportion of Medicare patients who need vascular operations select a managed-care senior product. We examined the results of a 4-year experience with resource management in an academic vascular surgery practice during which best practice plans were developed and implemented. METHODS: We analyzed hospital cost data, which included both total hospital and intensive care unit length of stay, average units per operation for laboratory, pharmacy, and radiology services and operating room and direct hospital costs for 257 carotid endarterectomies performed over fiscal years (FY) 1994, 1995, 1996, and 1997 (6 month data) and 175 infrainguinal bypass procedures performed during the same period. RESULTS: For carotid endarterectomy, length of stay decreased 66% over the 4-year period to an average of 2.07 days in FY97. Both radiology and pharmacy utilization were reduced after the first year of institution of best practice plans (56% and 32% respectively) with 4-year total reductions of 86% and 55% by FY97. The most notable changes included elimination of routine postoperative laboratory testing, use of aspirin rather than low-molecular-weight dextran, emphasis on oral rather than intravenous vasoactive drugs, and routine use of duplex scanning alone rather than angiography for diagnosis after FY94-95. The length of operating room time for carotid endarterectomy remained relatively constant from FY94 to FY97. As a result of these multiple factors, our study showed a 30% decrease in total average direct hospital costs for carotid endarterectomy from $9974 to $7002 in this 4-year period. Infrainguinal bypass graft procedures showed a progressive decrease in total cost of 28% for patients without complications to $15,186 but remained unchanged for those with complications. Laboratory use, pharmacy use, and radiology use were not significantly different. CONCLUSIONS: Case management for patients undergoing carotid endarterectomy and infrainguinal bypass grafting involving an integrated team of vascular surgeons, surgical house staff, a dedicated vascular nurse, and a social work case manager resulted in dramatic reductions both in length of stay and hospital resource utilization. As these costs decreased, operating room expenses assumed increasing importance. Operating room costs account for 60% of the direct costs of carotid endarterectomy and a comparable percentage for uncomplicated infrainguinal bypass grafting. Further substantial reductions in direct hospital costs will depend primarily on reductions in operating room costs, particularly those related to length of time in the operating room.     

Incisional hernia recurrence following "vest-over-pants" or vertical Mayo repair of primary hernias of the midline

A series of 68 primary midline incisional hernias with a vertical Mayo repair was evaluated retrospectively. Patients without documented hernia recurrence following this repair were invited for physical examination. Life-table methods were used for statistical analysis. The 1-, 3-, 5-, and 10-year cumulative recurrence rates were 35%, 46%, 48%, and 54%, respectively. Also, generally accepted risk factors were studied. Multivariate analysis identified the size of the hernia (p = 0.02) and the use of steroids (p = 0.04) as the most important independent risk factors of first time recurrent incisional hernia. Considering the high recurrence rates found, the results of this study strongly suggest that the vest-over-pants repair should no longer be used for closure of midline incisional hernias.     

Efficacy of systemic administration of irinotecan against neuroblastoma xenografts

4-Hydroxytamoxifen is a major metabolite of the antiestrogenic drug tamoxifen used in the treatment of women with breast cancer. 4-Hydroxytamoxifen is broken down by a horseradish peroxidase/H2O2 system very much more rapidly than tamoxifen and causes much greater DNA damage determined by 32P-postlabelling. EPR spin trapping of 4-hydroxytamoxifen reaction products in the presence of the free radical trap 5,5-dimethyl-1-pyrroline N-oxide, together with glutathione as a hydrogen donor, resulted in the generation of a species with the characteristics of the glutathione thiyl radical (aN approximately 15.3 G, aH approximately 16.2 G). Support for the creation of thiyl radicals comes from the close to stoichiometric time dependent formation of glutathione disulfide concomitant with the loss of glutathione. Similar results were obtained using 4-hydroxytoremifene but no radical formation or glutathione loss could be detected using 3-hydroxytamoxifen (droloxifene). On-line LC-ESI MS analysis of the incubation products from 4-hydroxytamoxifen has identified three products with a protonated molecular mass of 773, consistent with the formation of dimers of 4-hydroxytamoxifen. The role that radical mechanisms have in the carcinogenic effects of tamoxifen in the endometrium or other target organs of women taking this drug remains to be established.     

Synthesis and antiprotozoal activities of some new triazine derivatives including a new antitrypanosomal agent: SIPI-1029

Two series of compounds, 1,2-dihydro-2,2-dimethyl-4, 6-diamino-1-(omega-haloalkyloxy)-s-triazines and O, O'-bis (4, 6-diamino-1, 2-dihydro-2, 2-disubstituted-s-triazin-l-yl) alkanediols were synthesized and tested against Plasmodium berghei and Trypanosoma evansi in mice. Most title compounds showed good antimalarial activity and compounds IIc-e showed good antitrypanosomal effect. After further studies on pharmacology, toxicology, pharmacokinetics and efficacy on infected cattles compound IIe (SIPI-1029, T-46) was shown to be a new highly active antitrypanosomal agent with low toxicity and long half life in plasma.     

MCP-1 protects mice in lethal endotoxemia

The overzealous production of proinflammatory cytokines in sepsis can result in shock, multiorgan dysfunction, and even death. In this study, we assessed the role of monocyte chemoattractant protein-1 (MCP-1) as a mediator of sepsis in endotoxin-challenged mice. Intraperitoneal administration of LPS to CD-1 mice induced a substantial time-dependent increase in MCP-1 in plasma, lung, and liver. The passive immunization of mice with rabbit antimurine MCP-1 antiserum 2 h before endotoxin administration resulted in a striking increase in LPS-induced mortality from 10% in control animals to 65% in anti-MCP-1-treated animals. Importantly, the administration of anti-MCP-1 antibodies to endotoxin-challenged mice resulted in increases in peak TNF-alpha and IL-12 levels, and also in a trend toward decreased serum levels of IL-10. Conversely, the administration of recombinant murine MCP-1 intraperitoneally significantly protected mice from endotoxin-induced lethality, and resulted in an increase in IL-10 levels, a decrease in IL-12 levels, and a trend toward decreased levels of TNF. In conclusion, our findings indicate that MCP-1 is a protective cytokine expressed in murine endotoxemia, and does so by shifting the balance in favor of antiinflammatory cytokine expression in endotoxin-challenged animals.     

Direct and indirect association of the small GTPase ran with nuclear pore proteins and soluble transport factors: studies in Xenopus laevis egg extracts

Ran is a small GTPase that is required for protein import, mRNA export, and the maintenance of nuclear structures. To gain a better understanding of Ran's role in the nucleus, we have sought to use Xenopus egg extracts for the purification and characterization of proteins from egg extracts bound with a high affinity to a glutathione-S-transferase-Ran fusion protein (GST-Ran). We found that GST-Ran associates specifically with at least 10 extract proteins. We determined the identifies of six Ran-interacting proteins (Rips), and found that they include RanBP2/Nup358, Nup153, Importin beta, hsc70, RCC1, and RanBP1. On the basis of peptide sequence, a seventh Rip (p88) seems to be similar but not identical to Fug1/RanGAP1, the mammalian Ran-GTPase-activating protein. Gel filtration analysis of endogenous extract proteins suggests that Importin beta acts as a primary GTP-Ran effector. Both Ran and Importin beta are coimmunoprecipitated by anti-p340RanBP2 antibodies in the presence of nonhydrolyzable GTP analogues, suggesting that Ran-Importin beta complexes interact with p340RanBP2. Two other Rips, p18 and p88, are coprecipitated with p340RanBP2 in a nucleotide-independent manner. Analysis of the Ran-GTPase pathway in Xenopus extracts allows the examination of interactions between Ran-associated proteins under conditions that resemble in vivo conditions more closely than in assays with purified components, and it thereby allows additional insights into the molecular mechanism of nuclear transport.