Nodal and systemic recurrence following observation of a positive sentinel lymph node in melanoma.

BACKGROUND: Two RCTs found no survival benefit for completion lymphadenectomy after positive sentinel lymph node biopsy compared with observation with ultrasound in patients with melanoma. Recurrence patterns and regional control are not well described for patients undergoing observation alone. METHODS: All patients with a positive sentinel node biopsy who did not have immediate completion lymphadenectomy were identified from a single-institution database (1995-2018). First recurrences were classified as node only, local and in-transit (LCIT) only, LCIT and nodal, or systemic. Regional control and factors associated with recurrence survival were analysed. RESULTS: Median follow-up was 33 months. Of 370 patients, 158 (42·7 per cent) had a recurrence. The sites of first recurrence were node only (13·2 per cent), LCIT only (11·9 per cent), LCIT and nodal (3·5 per cent), and systemic (13·8 per cent). The 3-year postrecurrence melanoma-specific survival rate was 73 (95 per cent c.i. 54 to 86) per cent for patients with node-only first recurrence, and 51 (31 to 68) per cent for those with initial systemic recurrence. In multivariable analysis, ulceration in the primary lesion (hazard ratio (HR) 2·53, 95 per cent c.i. 1·27 to 5·04), disease-free interval 12 months or less (HR 2·38, 1·28 to 4·35), and systemic (HR 2·57, 1·16 to 5·65) or LCIT and nodal (HR 2·94, 1·11 to 7·79) first recurrence were associated significantly with decreased postrecurrence survival. Maintenance of regional control required therapeutic lymphadenectomy in 13·0 per cent of patients during follow-up. CONCLUSION: Observation after a positive sentinel lymph node biopsy is associated with good regional control, permits assessment of the time to and pattern of recurrence, and spares lymphadenectomy-related morbidity in patients with melanoma.

CTLA-4 up-regulation plays a role in tolerance mediated by CD45.

Cytolytic T lymphocyte-associated antigen 4 (CTLA-4) is a critical down-regulatory molecule in T cells that plays a major role in peripheral tolerance. Although the CD45 protein tyrosine phosphatase is a potent immunomodulatory target, the mechanisms by which antibody against CD45RB isoforms (anti-CD45RB) induces allograft tolerance remain unclear. We show here that anti-CD45RB treatment alters CD45 isoform expression on T cells, which is associated with rapid up-regulation of CTLA-4 expression. These effects appear specific and occur without up-regulation of other activation markers. Administration of a blocking monoclonal antibody to CTLA-4 at the time of transplantation prevents anti-CD45RB therapy from prolonging islet allograft survival. In addition, treatment with cyclosporin A blocks anti-CD45RB-induced CTLA-4 expression and promotes acute rejection. These data suggest that anti-CD45RB acts through mechanisms that include CTLA-4 up-regulation and demonstrate a link between CD45 and CTLA-4 that depends on calcineurin-mediated signaling. They demonstrate also that CTLA-4 expression may be specifically targeted to enhance allograft acceptance.

Differential increase in cerebral cortical glucose oxidative metabolism during rat postnatal development is greater in vivo than in vitro.

The steady-state rate of glucose oxidation through the mitochondrial TCA cycle (V(TCA)) was measured in acid extracts of 10- and 30-day-old cerebral cortex of rats receiving [1-13C]glucose intravenously and in neocortical slices superfused in vitro with the same isotope. TCA cycle flux was determined for each age group based on metabolic modeling analysis of the isotopic turnover of cortical glutamate and lactate. The sensitivity of the calculated rates to assumed parameters in the model were also assessed. Between 10 and 30 postnatal days, V(TCA) increased by 4.3-fold (from 0.46 to 2.0 micromol g(-1) min(-1)) in the cortex in vivo, whereas only a 2-fold (from 0.17 to 0.34 micromol g(-1) min(-1)) increase was observed in neocortical slices. The much greater increase in glucose oxidative metabolism of the cortex measured in vivo over that measured in vitro as the cortex matures suggests that function-related energy demands increase during development, a process that is deficient in the slice as a result of deafferentiation and other mechanisms.

Targeting signal 1 through CD45RB synergizes with CD40 ligand blockade and promotes long term engraftment and tolerance in stringent transplant models.

The induction and maintenance of allograft tolerance is a daunting challenge. Although combined blockade of CD28 and CD40 ligand (CD40L)-costimulatory pathways prevents allograft rejection in some murine models, this strategy is unable to sustain engraftment in the most immunogenic allograft and strain combinations. By targeting T cell activation signals 1 and 2 with the novel combination of anti-CD45RB and anti-CD40L, we now demonstrate potent enhancement of engraftment in C57BL/6 recipients that are relatively resistant to costimulatory blockade. This combination significantly augments the induction of tolerance to islet allografts and dramatically prolongs primary skin allograft survival. Compared with either agent alone, anti-CD45RB plus anti-CD40L inhibits periislet infiltration by CD8 cells, B cells, and monocytes; inhibits Th1 cytokines; and increases Th2 cytokine expression within the graft. These data indicate that interference with activation signals one and two may provide synergy essential for prolonged engraftment in situations where costimulatory blockade is only partially effective.

Recovery of unused operating room supplies for overseas orthopedic surgery.

Recovery of surplus operating room (OR) materials may contribute needed supplies to volunteer overseas surgical efforts. However, recovery often generates supplies that are highly heterogeneous in nature. In order to evaluate the nature and quantity of supplies useful to orthopedic surgical missions, the present investigation evaluated the material generated from 381 consecutive orthopedic cases performed during three 3-month assessment periods over 3 years. The amount of recovered material varied markedly within and among procedure types as well as surgeons. Nevertheless, the long-term, OR-wide recovery program at Yale-New Haven Hospital has provided a highly reliable source of usable materials over the 4-year life of the program.

Focused versus operating room-wide recovery of unused supplies for overseas reconstructive surgery.

Proliferation of programs that recover surplus operating room supplies may effectively address the needs of volunteer overseas surgical efforts. However, these programs tend to garner supplies highly heterogeneous in nature. In order to evaluate the nature and quantity of supplies generated by plastic and reconstructive procedures, we extrapolated the inventory of 71 consecutive cases from our 33,000-case database. Additionally, we examined the recovery of 7 specific supplies from all cases performed at Yale-New Haven Hospital over a 3-year period. Though consistency is unlikely when only plastic and reconstructive surgical cases are examined, operating room-wide recovery may be a reliable source of usable materials.

Intraoperative cardiac output monitoring: comparison of impedance cardiography and thermodilution.

Impedance cardiography (IC) is a noninvasive, simple to use method of cardiac output (CO) determination. A prospective evaluation of IC monitoring was performed in 50 patients undergoing noncardiac surgery. IC CO measurements (NC-COM3-Revision 7, BoMed Manufacturing) were compared to simultaneous measurements of thermodilution (TD) CO to assess the validity of this technique for intraoperative cardiac monitoring. Adequate impedance signals could not be obtained in 7 of the 50 patients. IC CO measurements were highly correlated to TD CO (P < .005), with a correlation coefficient r = 0.84. Bias analysis, however, indicated clinically significant disagreement between the two techniques. IC CO tended to underestimate TD CO (mean bias = -0.41 L/min) and the SD of the bias was 1.0 L/min (95% level of agreement 1.6 to -2.4 L/min). Trending data showed IC to accurately track the direction of TD CO changes but to underestimate their magnitude (r = 0.60, intercept -0.7 L/min, slope 0.47). Factors that may have impaired the performance of IC in this study include the high prevalence of cardiac disease in the study population and electrical noise in the operative setting. Further development of IC appears warranted if it is to prove useful as an intraoperative cardiac monitor.

Case-by-case assessment of recoverable materials for overseas donation from 1318 surgical procedures.

OBJECTIVE: To provide a mechanism for addressing the need for consistency and projection in overseas donation of surgical supplies, we conducted a case-by-case inventory of unused materials recovered from all surgical procedures in our facility over a 2.5-month period. DESIGN: Unused surgical supplies were recovered in coded bags from individual cases and inventoried. SETTING: Inpatient operating rooms at Yale-New Haven Hospital. MAIN OUTCOME MEASURE: The weight and dollar value of recovered materials were tallied for each case type; these were then extrapolated according to the frequency with which each procedure is performed in the United States to provide an estimate of the impact of a nationwide recovery program. RESULTS: The value of supplies recovered ranged from $1 (bone marrow transplant) to greater than $40 (liver and vulva/perineum procedures). By extrapolation to case-specific data from the National Hospital Discharge Survey (1990), we estimate that a nationwide recovery program could yield more than $193 million in charitable material and reduce operating room waste by more than 1.7 million kilograms (1948 tons). CONCLUSIONS: Consistency and organization would contribute greatly to efforts to alleviate existing medical supply needs in the developing world. This case-by-case assessment should enable participating centers to project more effectively the outcome of such collections and allow the coordination of efforts. Though unlikely to be adopted by all operating theaters in the United States, the potential charitable contributions from a nationwide recovery program are significant.