Tumor necrosis factor alpha (TNF alpha), a primary mediator of systemic responses to sepsis and infection, can be injurious to the organism when present in excessive quantities. Here we report that two types of naturally occurring soluble TNF receptors (sTNFR-I and sTNFR-II) circulate in human experimental endotoxemia and in critically ill patients and demonstrate that they neutralize TNF alpha-induced cytotoxicity and immunoreactivity in vitro. Utilizing immunoassays that discriminate between total sTNFR-I and sTNFR-I not bound to TNF alpha, we show that sTNFR-I-TNF alpha complexes may circulate even in the absence of detectable free TNF alpha. To investigate the therapeutic possibilities of sTNFR-I, recombinant protein was administered to nonhuman primates with lethal bacteremia and found to attenuate hemodynamic collapse and cytokine induction. We conclude that soluble receptors for TNF alpha are inducible in inflammation and circulate at levels sufficient to block the in vitro cytotoxicity associated with TNF alpha levels observed in nonlethal infection. Administration of sTNFR-I can prevent the adverse pathologic sequelae caused by the exaggerated TNF alpha production observed in lethal sepsis.

The DCIS nomogram integrates 10 clinicopathologic variables to provide an individualized risk estimate of IBTR in a woman with DCIS treated with BCS. This tool may assist in individual decision making regarding various treatment options and help avoid over- and undertreatment of noninvasive breast cancer.

Background In breast cancer patients with nodal metastases at presentation, false-negative rates <10% have been demonstrated for sentinel node biopsy (SLNB) after neoadjuvant chemotherapy (NAC) when ≥3 negative sentinel nodes (SLNs) are retrieved, but the frequency with which axillary dissection (ALND) can be avoided is uncertain. Methods Among 534 prospectively identified consecutive patients with clinical stage II–III cancer receiving NAC from 11/2013–11/2015, all biopsy-proven node-positive (N+) cases were identified. Patients who were clinically node-negative post-NAC were SLNB-eligible. ALND was indicated for failed mapping, <3 SLNs retrieved, or positive SLNs. Results Of 288 N+ patients, 195 completed surgery. 132/195 (68%) were SLNB-eligible. Of these, median age was 50yrs, 73(55%) were ER+, 21(16%) ER−/HER2+, 38(29%) triple negative. SLNB was deferred intraoperatively in 4 cases. Among 128 SLNB attempts, ≥3 SLNs were retrieved in 110 (86%), 1–2 SLNs in 15(12%), 3 (2%) failed mapping. ALND was indicated in 66 cases: 54(82%) for positive SLNs, 9(14%) for <3 negative SLNs, 3(4%) for failed mapping. 17% with <3 negative SLNs retrieved had persistent disease. 62/128 (48%) had SLNB alone with ≥3 SLNs retrieved. Among 195 N+ patients completing surgery, nodal pathologic complete response (pCR) was achieved in 49%, ranging from 21% in ER+/HER2− to 97% in ER−/HER2+ cases, and was significantly more common than breast pCR in ER+/HER2− and triple-negative cases. Conclusions Nearly 70% of N+ patients were SLNB-eligible post-NAC. ALND was avoided in 48%, supporting the role of NAC in reducing the need for ALND among patients presenting with nodal metastases.

The present study was undertaken to evaluate the extent to which an endogenous interleukin-1 (IL-1) response contributes to the hemodynamic and metabolic consequences of sublethal endotoxemia or lethal Gram-negative septic shock. Young, healthy baboons received either a sublethal dose oflipopolysaccharide (LPS) or an LDIoo of live Escherichia coli bacteria, and one half of the animals in each group were continuously infused with IL-1 receptor antagonist (IL-ira). Plasma IL-/1# was not detected in this model of endotoxemia. Administration of ILira had only minimal effects on the modest hemodynamic and metabolic responses to sublethal endotoxemia, and did not attenuate the plasma cytokine response. In contrast, high circulating levels of IL-1iB (range 300800 pg/ml) were seen during lethal E. coli septic shock. IL-ira treatment significantly attenuated the decrease in mean arterial blood pressure (MAP) (from -72±8 to -43±6 mm Hg, P < 0.05) and cardiac output (from -0.81±0.17 to -0.48±0.15 liter/min; P < 0.05), and significantly improved survival from 43 to 100% at 24 h (P < 0.05). The plasma I-i1d and IL-6 responses to lethal E. coli septic shock were also significantly diminished by IL-ira treatment (P < 0.05), whereas tumor necrosis factor-a (TNFa) concentrations were unaffected. We conclude that an exaggerated systemic IL-1,6 response is characteristic of lethal E. coli septic shock, and contributes significantly to the hemodynamic and metabolic consequences of E. coli septic shock. IL-ira can significantly attenuate the cytokine cascade and improve survival. (J. Clin. Invest. 1992. 89:1551-1557.) Key words: tumor necrosis factor * interleukin-6 * interleukin-8 * lipopolysaccharide