Predictive Power of the NSQIP Risk Calculator for Early Post-Operative Outcomes After Whipple: Experience from a Regional Center in Northern Ontario.

BACKGROUND: NSQIP Risk Calculator was developed to allow surgeons to inform their patients about their individual risks for surgery. Its ability to predict complication rates and length of stay (LOS) has made it an appealing tool for both patients and surgeons. However, the NSQIP Risk Calculator has been criticized for its generality and lack of detail towards surgical subspecialties, including the hepatopancreaticobiliary (HPB) surgery. We wish to determine whether the NSQIP Risk Calculator is predictive of post-operative complications and LOS with respect to Whipple's resections for our patient population. As well, we wish to identify strategies to optimize early surgical outcomes in patients with pancreatic cancer. METHODS: We conducted a retrospective review of patients who underwent elective Whipple's procedure for benign or malignant pancreatic head lesions at Health Sciences North (Sudbury, Ontario), a tertiary care center, from February 2014 to August 2016. Comparisons of LOS and post-operative complications between NSQIP-predicted and actual ones were carried out. NSQIP-predicted complications rates were obtained using the NSQIP Risk Calculator through pre-defined preoperative risk factors. Clinical outcomes examined, at 30 days post-operation, included pneumonia, cardiac events, surgical site infection (SSI), urinary tract infection (UTI), venous thromboembolism (VTE), renal failure, readmission, and reoperation for procedural complications. As well, mortality, disposition to nursing or rehabilitation facilities, and LOS were assessed. RESULTS: A total of 40 patients underwent Whipple's procedure at our center from February 2014 to August 2016. The average age was 68 (50-85), and there were 22 males and 18 females. The majority of patients had independent baseline functional status (39/40) with minimal pre-operative comorbidities. The overall post-operative morbidity was 47.5% (19/40). The rate of serious complication was 17.5% with four Clavien grade II, two grade III, and one grade V complications. One mortality occurred within 30 days after surgery. NSQIP Risk Calculator was predictive for the majority of post-surgical complication types, including pneumonia, SSI, VTE, reoperation, readmission, and disposition to rehabilitation or nursing home. Our center appears to have a higher rate of UTI than NSQIP predicted (O/E = 3.9), as well, the rate of cardiac complication (O/E = 3.1) also appears to be higher at our center. With respect to readmission rates (O/E = 0.6) and renal failure (O/E = 0), NSQIP provided overestimated rates. The average LOS was 11.9 ± 0.9 days, which was not significantly different from the average LOS of 11.5 ± 0.3 days predicted by NSQIP (p = 0.3). Overall, 80% of discharges occurred less than or within 3 days of that predicted by NSQIP. CONCLUSION: NSQIP Risk Calculator is predictive of post-operative complications and LOS for patients who have undergone Whipple's at our center. A more HPB-focused NSQIP calculator may accurately project post-operative complication in the pre-operative period. Nevertheless, the generic NSQIP has allowed us to examine our existing practice of post-operative care and has paved way to reduce cardiac and urinary complications in the future.

Treatment with a short course of LF 15-0195 and continuous cyclosporin A attenuates acute xenograft rejection in a rat-to-mouse cardiac transplantation model.

Searching for a novel immunosuppressive agent to effectively prevent acute vascular rejection (AVR) is essential for success in clinical xenotransplantation. We previously reported that Lewis rat hearts transplanted into BALB/c mice developed typical AVR in 6 days. The present study was undertaken to determine the efficacy of LF 15-0195, a new immunosuppressive analog of 15-deoxyspergualin in the prevention of AVR in a rat-to-mouse cardiac xenograft model. We transplanted 2-week old Lewis rat hearts into BALB/c mice. Four groups were included in this study: untreated recipients and cyclosporin A (CsA) treated recipients were controls; LF 15-0195 treated recipients or LF 15-0195 combined with CsA treated recipients were experimental groups. Mouse recipients received either LF 15-0195 2 mg/kg subcutaneously from day-1 to post-operative day 14, or CsA 15 mg/kg subcutaneously daily, from day 0 to endpoint rejection, or the two drugs in combination. We observed that high dose CsA did not inhibit AVR and the graft was rejected in 11.3 +/- 1.9 days. Graft histology and immunohistology showed typical AVR, characterized by interstitial hemorrhage, intravascular fibrin deposition, thrombosis, and massive deposition of anti-rat immunoglobulin G (IgG) and immunoglobulin M (IgM). Serum xenoreactive antibodies (xAbs) were markedly elevated in these animals as well. In contrast, we observed that treatment with LF 15-0195 alone significantly prolonged graft survival to 19.3 +/- 0.7 days. Notably, xAbs were significantly decreased and the rejection pattern of these grafts was cell-mediated rejection (CMR), instead of AVR. When CsA was combined with LF 15-0195, the graft mean survival time was further increased to 58.5 +/- 17.3 days. Antibody production and T-cell infiltration were significantly inhibited at the terminal stages of graft survival and pathology showed striking attenuation of both AVR and CMR. Sequential studies on days 6 and 14 demonstrated that LF 15-0195 either alone or combined with CsA completely inhibited antibody production. However, intragraft infiltration by Mac-1 positive cells including natural killer cells, macrophages and granulocytes in LF 15-0195 treated recipients was similar to that of untreated recipients. We conclude that LF 15-0195 effectively prevented AVR by markedly inhibiting the production of anti-donor IgG xAbs. Also, treatment with short course LF 15-0195 and continuous CsA significantly reduced T-cell infiltration. Studies to test this therapy in inhibiting AVR in a pig-to-non-human primate xenotransplantation model are underway.

Attenuation of acute xenograft rejection by short-term treatment with LF15-0195 and monoclonal antibody against CD45RB in a rat-to-mouse cardiac transplantation model.

BACKGROUND: We previously reported that Lewis rat hearts transplanted into BALB/c mice developed typical acute vascular rejection (AVR). The present study was undertaken to determine the efficacy of LF15-0195, a new analogue of 15-deoxyspergualin, in the prevention of AVR and to determine whether a combination of LF15-0195 and CD45RB monoclonal antibody (mAb) would have a synergistic effect in prolonging xenograft survival. METHODS: We transplanted 2-week-old Lewis rat hearts into BALB/c mice, followed by experimental immunosuppressive regimens. Control groups were either untreated or treated with mAb monotherapy (100 microg/mouse, days -1 to 7, intravenously). Experimental groups were either treated with LF15-0195 (2 mg/kg, days -1 to 14, subcutaneously) or with LF15-0195 combined with mAb at monotherapeutic doses. RESULTS: Heart xenografts in both untreated and mAb-treated BALB/c recipients were rejected at 6.0+/-0.7 days and 8.5+/-1.3 days, respectively, with typical features of AVR, characterized by hemorrhage, fibrin deposition, thrombosis, and massive accumulations of anti-rat IgG and IgM. Serum xenoreactive antibodies (xAbs) were also markedly elevated in these animals. In contrast, LF15-0195 monotherapy significantly prolonged graft survival to 19.3+/-0.7 days. Notably, xAbs were significantly decreased and graft rejection was of a cell-mediated nature instead of AVR. When mAb was combined with LF15-0195, graft survival was further increased to 65.2+/-9.1 days. Antibody production and T-cell infiltration were significantly inhibited at terminal stages of graft survival. Sequential studies on days 6 and 14 demonstrated that LF15-0195, either alone or combined with mAb, completely inhibited antibody production. However, intragraft infiltration by Mac-1+ cells in LF15-0195-treated recipients was similar to that of untreated recipients. CONCLUSIONS: LF15-0195 effectively attenuated AVR by markedly inhibiting antidonor xAb production. Treatment with a combination of LF15-0195 and CD45RB mAb also significantly reduced T-cell infiltration and should be studied further to evaluate its efficacy in nonhuman primate subjects.