The impact of a new hepatopancreatobiliary surgery program on the management of pancreatic cancer at Health Sciences North

Background: Centralization of specialist services to urban centres presents a challenge to patients living in rural communities. The hepatopancreatobiliary surgery (HPB) program at Health Sciences North (HSN) is the tenth and newest HPB centre by Cancer Care Ontario and presents a unique opportunity to evaluate the barriers to delivering HPB cancer care to patients in northern Ontario. Methods: We retrospectively reviewed the cases of patients referred to the Northeastern Ontario Cancer Centre and HSN with a pancreatic cancer diagnosis between 2009 and 2015. July 2013 marked the inception of the HPB surgical program. Our primary outcome was time to HPB surgical consultation. Secondary outcomes included distance of travel and time to curative intent operation. Results: Our population consisted of 207 patients (98 pre-HPB v. 109 post-HPB). Median time to consultation with an HPB surgeon was decreased in the post-HPB group (43 v. 11 d, p < 0.001). An increased proportion of patients with pancreatic malignancies in the post-HPB group received HPB surgical consultations (34% v. 74%, p < 0.001), with decreased median distance travelled to surgical consultation (411 v. 79 km, p < 0.001). Time to curative intent operation or medical oncology consultation did not significantly increase. Conclusion: A new HPB program appears to have facilitated the proportion of patients with pancreatic malignancies at HSN receiving an HPB surgical consultation. Patients received complex surgeries, closer to their home regions. It is anticipated that these changes may affect overall outcomes and patient satisfaction and will be the focus of future investigations.

Contexte: La concentration des services spécialisés dans les centres urbains pose un défi pour les patients des communautés rurales. Le programme de chirurgie hépatopancréatobiliaire (HPB) d'Horizon Santé-Nord (HSN) est le 10e et plus récent centre HPB d'Action Cancer Ontario; il offre une occasion unique d'évaluer les obstacles à la prestation des soins oncologiques HPB aux patients du Nord de l'Ontario. Méthodes: Nous avons passé en revue de manière rétrospective les cas adressés au Centre de cancérologie du Nord-Est de l'Ontario et à HSN pour un diagnostic de cancer du pancréas entre 2009 et 2015. Le programme chirurgical HPB a été lancé en juillet 2013. Notre principal paramètre était le délai d'obtention d'une consultation pour une chirurgie HPB. Les paramètres secondaires incluaient la distance à parcourir et le délai d'obtention d'une intervention à visée curative. Résultats: Notre population comportait 207 patients (98 pré-HPB c. 109 post-HPB). Le délai médian d'obtention de la consultation en chirurgie HPB a diminué dans le groupe post-HPB (43 j c. 11 j, p < 0,001). Une proportion plus grande de patients atteints de cancer du pancréas dans le groupe post-HPB a obtenu une consultation pour chirurgie HPB (34 % c. 74 %, p < 0,001), et une diminution de la distance médiane à parcourir pour se rendre à la consultation a été constatée (411 km c. 79 km, p < 0,001). Le délai d'obtention de la chirurgie à visée curative ou de la consultation en oncologie médicale n'a pas augmenté significativement. Conclusion: Le nouveau programme HPB semble avoir permis d'accroître la proportion de patients atteints de cancer du pancréas ayant pu bénéficier d'une consultation pour chirurgie HPB. Les patients ont pu subir des chirurgies complexes plus près de chez eux. On prévoit que ces modifications auront une incidence sur les paramètres globaux et la satisfaction des patients et qu'elles feront l'objet d'études.

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.

Diagnostic Accuracy of a Qualitative Fecal Immunochemical Test Varies With Location of Neoplasia But Not Number of Specimens.

BACKGROUND & AIMS: We compared the accuracy of a qualitative fecal immunochemical test (FIT) in identifying patients with proximal vs distal advanced neoplasia and evaluated whether analysis of 2 specimens performed better than analysis of 1 specimen. Distal advanced neoplasia was defined as colorectal cancer (CRC), any colorectal adenoma ≥10 mm in diameter, high-grade dysplasia, or a lesion with villous or tubulovillous histologic characteristics in a location distal to the splenic flexure, including the descending colon, the rectosigmoid, and the rectum. METHODS: We collected data from 5343 subjects (50-70 years old) who received 2 FITs (Hemosure; cutoff value, 10 µg hemoglobin/g feces) before colonoscopy in an invitational CRC screening program in Hong Kong from 2008 through 2012. We calculated the FIT's sensitivity, specificity, positive predictive value (PPV), and negative predictive value in detecting colorectal neoplasia. RESULTS: Of the participants, 13.6%, 12.2%, and 6.0% had distal, proximal, and synchronous distal or proximal neoplasia, respectively. Advanced neoplasia was detected in 291 subjects (5.4%); 22 (0.4%) had CRC. FIT detected distal advanced adenoma with 39.7% sensitivity (95% confidence interval [CI], 32.0%-48.0%) vs proximal advanced adenoma with 25.0% sensitivity (95% CI, 17.3%-34.6%; P = .014), distal advanced neoplasia with 40.0% sensitivity (95% CI, 32.5%-47.9%) vs proximal advanced neoplasia with 27.9% sensitivity (95% CI, 20.0%-37.4%; P = .039), and any distal adenoma ≥10 mm, irrespective of other lesion characteristics, with 39.5% sensitivity (95% CI, 31.0%-48.7%) vs. proximal adenoma with 25.3% sensitivity (95% CI, 16.5%-36.6%; P = .038). The specificity of FIT in detecting CRC was similar between the proximal and distal colon. FIT detected distal lesions with higher PPV than proximal lesions. One FIT detected advanced neoplasia with 31.8% sensitivity (95% CI, 25.9%-38.4%) and 92.4% specificity (95% CI, 91.6%-93.2%), whereas 2 FITs detected advanced neoplasia with 34.1% sensitivity (95% CI, 28.0%-40.8%; P = .617) and 91.9% specificity (95% CI, 91.0%-92.7%; P = .327). FIT detected distal advanced neoplasia with greater sensitivity and higher PPV than proximal advanced neoplasia. CONCLUSIONS: In an analysis of data from subjects who underwent CRC screening in Hong Kong, FIT detected distal advanced neoplasia with higher sensitivity than proximal advanced neoplasia. Analysis of 1 vs 2 specimens by FIT identified advanced neoplasia with similar test characteristics.

Donation after cardiac death pediatric en bloc renal transplantation.

PURPOSE: Use of small pediatric kidneys obtained from extremely young donors after cardiac death has been limited. This potential organ source remains under used by transplant teams. MATERIALS AND METHODS: We reviewed all renal transplants at our institution from 2000 to 2013 to identify recipients of an en bloc pair of kidneys from deceased pediatric donors younger than 4 years. The outcomes of donation after cardiac death en bloc allografts were compared with neurological determination of death en bloc allografts. RESULTS: A total of 21 recipients of en bloc renal allografts were identified, of which 4 organ pairs were obtained through donation after cardiac death. Mean ± SD donor age was 20.6 ± 11.6 months and weight was 12.4 ± 3.7 kg. Delayed allograft function occurred in 2 of 4 recipients of allografts obtained from donation after cardiac death en bloc and 3 of 17 recipients of allografts from neurological determination of death en bloc. One year after transplantation mean ± SD glomerular filtration rates were similar, at 80.7 ± 15.3 and 85.7 ± 33.4 ml/minute/1.73 m(2) in the cardiac and neurological allograft groups, respectively (difference not significant). Surgical complications occurred in 3 patients, and no allograft was lost to thrombosis. CONCLUSIONS: We report successful transplantation of a small cohort of pediatric en bloc kidneys obtained through donation after cardiac death from donors younger than 4 years. Outcomes at 1 year are comparable to those in neurological determination of death en bloc allograft recipients.

Prediction of proximal advanced neoplasia: a comparison of four existing sigmoidoscopy-based strategies in a Chinese population.

OBJECTIVE: To compare the performance of existing sigmoidoscopy-based strategies in predicting advanced proximal neoplasia (APN) in an asymptomatic Chinese cohort. DESIGN: We included all screening participants aged 50-70 years who received colonoscopy between 2008 and 2014 in Hong Kong. Sigmoidoscopy yield was estimated from the colonoscopic findings based on the: (1) UK flexible sigmoidoscopy; (2) Screening for COlon REctum (SCORE); (3) NORwegian Colorectal Cancer Prevention (NORCCAP) trials and (4) US clinical index based on age, gender and distal findings. The sensitivity, specificity, the number of subjects needed to screen (NNS) and the number of subjects needed to refer (NNR) for colonoscopy to detect one APN were evaluated. Binary logistic regression modelling identified the distal findings associated with APN. RESULTS: From 5879 eligible subjects, 132 (2.2%) had APN. The US strategy achieved the highest sensitivity for APN detection (42.0%) and the UK criteria attained the highest specificity (96%). The US criteria led to the lowest NNS (92 vs 103-267) and the UK criteria required the least NNR (12 vs 16-21). Using the US strategy, the rates of APN detected were 1.4% (low-risk group), 2.2% (intermediate risk) and 5.9% (high risk). The c-statistics of the UK, SCORE, NORCCAP and the US criteria were 0.55±0.03; 0.59±0.03; 0.59±0.03 and 0.62±0.05 respectively. CONCLUSIONS: The US criteria had the highest sensitivity for detection of APN and lowest NNS and the UK score had the highest specificity and the lowest NNR. The performance of all these four criteria to predict APN is limited, highlighting an urgent need to devise a novel APN prediction system for Asian subjects.

Should prior FIT results be incorporated as an additional variable to estimate risk of colorectal neoplasia? A prospective study of 5,813 screening colonoscopies.

BACKGROUND: Recent studies showed that previous negative results from faecal immunochemical tests (FITs) for colorectal cancer (CRC) screening was associated with lower risk of advanced neoplasia (AN). We evaluated whether prior FIT results should be included to estimate the risk of AN in 2008-2012. METHODS: A community-based screening practice recruited 5,813 asymptomatic residents aged 50 to 70 years in Hong Kong for CRC screening. We included study participants who had (1). positive FIT with subsequent colonoscopy workup (FIT+ group; n = 356); (2). negative FIT in three consecutive years and received a colonoscopy (FIT- group; n = 857); (3). received colonoscopy without FIT (colonoscopy group; n = 473); and (4). received both colonoscopy and FIT at the same time (combined group; n = 4,127). One binary logistic regression model evaluated whether prior FIT results were associated with colonoscopy findings of AN. RESULTS: The proportion of participants having AN/CRC was 18.0% (FIT+), 5.5% (FIT-), 8.0% (colonoscopy group), and 4.3% (combined group), respectively. When compared with the colonoscopy group, those in the FIT- group were not significantly more or less likely to have AN/CRC (AOR = 0.77, 95% C.I. = 0.51 to 1.18, p = 0.230). Having one (AOR = 0.73, 95% C.I. 0.48-1.12, p = 0.151) or three consecutive negative FIT result (AOR = 0.98, 95% C.I. 0.60-1.62, p = 0.944) were not associated with lower risks of AN/CRC. Subjects in the FIT+ group was 3.32-fold (95% C.I. 2.07 to 5.32, p < 0.001) more likely to have AN/CRC. CONCLUSIONS: These findings indicated that subjects with negative FIT findings could be risk stratified similarly as those who had not previously received FIT.

Comparison of short- and long-term outcomes after early versus late liver retransplantation: a single-center experience.

BACKGROUND: As the survival of patients after liver transplantation (LT) improves, the requirement of liver retransplantation (reLT) for late graft failure has grown. Although some have reported that the short-term outcome of late reLT was comparable with that of early reLT, it remains unknown whether long-term survival of late reLT is inferior to that of early reLT patients. MATERIALS AND METHODS: We reviewed early (<6 mo after primary LT) and late (≥6 mo after primary LT) reLT cases performed between January 2000 and December 2010. RESULTS: Sixteen early and 32 late reLT cases were analyzed. There was no significant difference regarding the number of units of red blood cells transfused during the transplantation between the groups, whereas operative time was significantly longer in the late reLT cases. Graft loss within 3 mo after early and late reLT was 18.6% and 15.6%, respectively. Patient and graft survival rates after 1, 3, 5, and 10 y in the late reLT group were 80.6%, 73.3%, 73.3%, and 67.7% and 80.7%, 69.1%, 63.3%, and 54.3%, respectively, whereas those in the early reLT group were 75.0%, 75.0%, 64.3%, and 64.3% and 81.3%, 75.0%, 64.3%, and 32.1%, respectively. There was no significant difference in patient or graft survival rates between the groups (P = 0.91 and 0.91, respectively). CONCLUSIONS: Acceptable short- and long-term survival were provided in early and late reLT. The time between the primary LT and reLT does not seem to play significant role in the prognosis of reLT in the long term.

Short- and long-term outcomes of third liver transplantation at single centre.

PURPOSE: Although three or more liver transplantation (LT)s in the same patient arouse not only medical but also ethical issues in the context of organ shortage, it is a fact that additional liver retransplantation (reLT) is the only lifesaving treatment option for those with graft failure after a second LT. However, little is known regarding the risks and benefits associated with a third LT. METHODS: We analyzed fifteen cases of third LT and 48 of second LT performed between January 2000 and December 2010. Clinical outcomes were compared with those of second LT cases performed during the same period. RESULTS: Model for end-stage liver disease (MELD) scores at transplant was similar between the two groups. As for surgical aspects, there was no significant difference in operative time or number of units of red blood cells transfused during the transplant procedures between the groups. Patient and graft survival after the third LT at 1, 3, and 10 years were 66.7, 51.9, and 44.4 %, and 66.7, 51.9, and 29.6 %, respectively. There was no significant difference in patient or graft survival between the groups. However, graft loss within 3 months after the third LT was significantly higher than that of second LT patients. CONCLUSION: Third LT cases showed acceptable short- and long-term outcomes that were not significantly inferior to those of a second LT. Careful patient care especially in the early phase after a third LT may be essential to improve the outcome.

Management of appendicitis in a femoral hernia.

Appendicitis in a femoral hernia is a rare occurrence often diagnosed intraoperatively. We present a case where the incarcerated appendicitis required division of the inguinal ligament for reduction. Appendectomy was carried out and because of contamination a primary McVay procedure was done to repair the femoral hernia. The patient tolerated the surgery and was discharged shortly.

Tenecteplase for ST-elevation myocardial infarction in a patient treated with drotrecogin alfa (activated) for severe sepsis: a case report.

INTRODUCTION: Drotrecogin alfa (activated) (DrotAA), an activated protein C, promotes fibrinolysis in patients with severe sepsis. There are no reported cases or studies that address the diagnosis and treatment of myocardial infarction in septic patients treated with DrotAA. CASE PRESENTATION: A 59-year-old Caucasian man with septic shock secondary to community-acquired pneumonia treated with DrotAA, subsequently developed an ST-elevation myocardial infarction 12 hours after starting DrotAA. DrotAA was stopped and the patient was given tenecteplase thrombolysis resulting in complete resolution of ST-elevation and no adverse bleeding events. DrotAA was restarted to complete the 96-hour course. The sepsis resolved and the patient was discharged from hospital. CONCLUSION: In patients with severe sepsis or septic shock complicated by myocardial infarction, it is difficult to determine if the myocardial infarction is an isolated event or caused by the sepsis process. The efficacy and safety of tenecteplase thrombolysis in septic patients treated with DrotAA need further study.

LF 15-0195, a novel immunosuppressive agent prevents rejection and induces operational tolerance in a mouse cardiac allograft model.

BACKGROUND: LF 15-0195 (LF) is a new analogue of 15-deoxyspergualin (DSG) that is less toxic and more potent than DSG. The present study was undertaken to determine (1). the dose response of LF monotherapy, (2). its ability to induce tolerance, and (3) its interaction with cyclosporine (CsA), FK 506 (FK), and rapamycin (RAPA). METHODS: Varying doses of LF were administered to determine dose-dependent effects on graft survival in a C57BL/6 to BALB/c heterotopic heart allograft mouse model. Transplanting-donor and third-party skin grafts into long-term survivors were used to assess the tolerance status. CsA, FK, and RAPA were combined with LF to determine their interactive effects on graft survival. RESULTS: The efficacy and toxicity of LF was dose dependent. High-dose LF monotherapy (>2 mg/kg) induced donor-specific operational tolerance, but it was associated with high mortality. Simultaneous administration of high-dose calcineurin inhibitors (CsA FK) prevented tolerance induced by LF. In contrast, a short course of LF combined with a subtherapeutic dose of CsA FK achieved indefinite survival of C57/BL6 cardiac allografts. RAPA and LF had a synergistic effect in induction of tolerance. CONCLUSIONS: The efficacy and toxicity of LF were dose dependent. A short course of LF significantly reduced the requirement of CsA or FK to prevent rejection. RAPA and LF had synergy in induction of tolerance. These data indicate that LF may be a promising agent that warrants further studies in nonhuman primate models of transplantation.

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.

Monotherapy with LF 15-0195, an analogue of 15-deoxyspergualin, significantly prolongs renal allograft survival in monkeys.

BACKGROUND: LF 15-0195 is a novel, more potent, and less toxic analogue of 15-deoxyspergualin, an antibiotic used as an immunosuppressive agent to prevent rejection of organ transplants. This study was undertaken to determine whether LF 15-0195 monotherapy would prevent renal allograft rejection in a nonhuman primate model. METHODS: In the study groups, recipients received LF 15-0195 monotherapy at doses of 0.065 mg/kg per day (group 2, n=4), 0.13 mg/kg per day (group 3, n=4), or 0.2 mg/kg per day (group 4, n=4), administered subcutaneously, on postoperative days 0 to 14. RESULTS: Group 1 consisted of untreated control recipients, all of which developed advanced graft rejection after surviving for an average of 6.5+/-0.6 days. LF 15-0195 treatment significantly prolonged graft survival in groups 2, 3, and 4, to 20+/-20 days, 49+/-5 days, and 39+/-4 days, respectively. Animals in groups 3 and 4 demonstrated no evidence of rejection during LF 15-0195 treatments. The animals maintained stable renal function for 2 weeks after LF 15-0195 withdrawal but gradually developed rejection at 5 to 6 weeks. Pathologic studies demonstrated that vascular graft rejection was attenuated in LF 15-0195-treated allografts, compared with control specimens. These groups also demonstrated transient reductions in lymphocyte counts during treatment, which returned to normal levels 2 weeks after LF 15-0195 withdrawal. Total serum concentrations of IgM and IgG decreased by a mean of 20.4% and a mean of 31.4%, respectively, at the end of LF 15-0195 treatment (postoperative day 14). LF 15-0195 did not significantly alter thrombocyte counts or hemoglobin levels. Necropsy studies showed no evidence of drug toxicity in the heart, liver, spleen, intestines, stomach, or colon. CONCLUSIONS: LF 15-0195 monotherapy significantly prolonged renal allograft survival in monkeys. These encouraging data suggest that this novel agent may be of future value in clinical transplantation.