PEOPLE (NCT03447678), a first-line phase II pembrolizumab trial, in negative and low PD-L1 advanced NSCLC: clinical outcomes and association with circulating immune biomarkers.

BACKGROUND: The PEOPLE trial aimed to identify new immune biomarkers in negative and low programmed death-ligand 1 (PD-L1) (0%-49%) advanced non-small-cell lung cancer (aNSCLC) patients treated with first-line pembrolizumab. Here we report the main outcomes and the circulating immune biomarkers analysis. PATIENTS AND METHODS: The primary endpoint of this phase II trial was the identification of immune biomarkers associated with progression-free survival (PFS). Overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety were secondary endpoints. Absolute cell counts for 36 subsets belonging to innate and adaptive immunity were determined by multiparametric flow cytometry in peripheral blood at baseline and at first radiologic evaluation. An orthoblique principal components-based clustering approach and multivariable Cox regression model adjusted for clinical variables were used to analyze immune variables and their correlation with clinical endpoints. RESULTS: From May 2018 to October 2020, 65 patients were enrolled. After a median follow-up of 26.4 months, the median PFS was 2.9 months [95% confidence interval (CI) 1.8-5.6 months] and median OS was 12.1 months (95% CI 8.7-17.1 months). The ORR was 21.5%, DCR was 47.7% and median DoR was 14.5 months (95% CI 6.4-24.9 months). Drug-related grade 3-4 adverse events were 9.2%. Higher T cell and natural killer (NK) cell count at baseline and at the first radiologic evaluation were associated with improved PFS, DCR and OS. On the contrary, higher myeloid cell count at baseline or at the first radiologic evaluation was significantly associated with worse OS and DCR. CONCLUSIONS: Circulating immune biomarkers can contribute to predict outcomes in negative and low PD-L1 aNSCLC patients treated with first-line single-agent pembrolizumab.

Neoral versus prograf in simultaneous pancreas-kidney transplantation with portal venous drainage: three-year results of a single-center, open-label, prospective, randomized pilot study.

BACKGROUND: The preferential use of tacrolimus (Prograf) over cyclosporine microemulsion (Neoral) in simultaneous pancreas-kidney transplantation (SPKTx) is mainly based on historical, retrospective studies. We herein report the 3-year results of a single-center, prospective, randomized comparison of the two calcineurin inhibitors in the setting of mycophenolate mofetil (MMF)-based immunosuppression and portal drainage of pancreas allografts. METHODS: Between May 2001 and August 2004, 47 SPKTx recipients who were stratified by recipient sex, were alternatively assigned to treatment with Neoral (n = 22) or Prograf (n = 25). Concurrent immunosuppression included induction treatment with basiliximab and maintenance with MMF and steroids. RESULTS: After a median follow-up of 24.0 months, all patients remained in the study arm into which they were initially enrolled. No pancreas rejection episode was observed. One acute kidney rejection was recorded in the Neoral arm (4.5%) as compared with 7 (28.0%) including one steroid-resistant episode, in the Prograf arm (P = .03). The cumulative incidence of adverse events was 31.8% (n = 7) in the Neoral arm compared with 92.0% (n = 23) in the Prograf arm (P < .0001). One patient died in each study arm. Patient, pancreas, and kidney survivals overlapped at 1- and 3-years posttransplant, namely all 95.4% for the Neoral arm compared with 95.8%, 91.8%, and 95.8%, respectively, for the Prograf arm (P > .05). CONCLUSIONS: We conclude that in MMF-based immunosuppression there is no convincing evidence that Prograf should be preferred to Neoral in SPKTx.

Outcome of 118 pancreas transplants with retroperitoneal portal-enteric drainage.

BACKGROUND: We have recently described a technique for retroperitoneal pancreas transplantation (RPTx) with portal-enteric drainage (PED). Further experience with 118 RPTx is detailed herein. METHODS: Between April 2001 and August 2004, 118 patients underwent RPTx with PED among 125 recipients (94.4%) scheduled for this procedure. Surgical complications and patient and graft survivals were recorded prospectively. RESULTS: After a minimum follow-up period of 3 months (mean 27.8 +/- 13.0 months), 18 recipients (15.2%) required relaparotomy because of bleeding (n = 6; 5.1%), allograft pancreatectomy due to either hyperacute/accelerated rejection (n = 3; 2.5%) or vein thrombosis (n = 3; 2.5%), leak from duodenojejunal anastomosis (n = 2; 1.7%), bleeding and vein thrombectomy (n = 1; 0.8%), or small bowel occlusion due to bezoar (n = 1; 0.8%). One patient had a negative relaparotomy and one underwent two relaparotomies. Most patients with hemorrhage (5/7; 71.4%) were recipients of solitary pancreas grafts managed with heparin infusion. No venous thrombi extended into recipient's superior mesenteric vein. Nonocclusive venous thrombosis was diagnosed with duplex ultrasonography and confirmed at computed tomography in seven patients (5.1%). None of these patients lost graft function. Ten patients (8.5%) were diagnosed with peripancreatic fluid collections, all successfully treated by observation (n = 7) or percutaneous drainage (n = 3). Enteric bleeding occurred in eight recipients (6.8%). Overall, 1-year patient and pancreas survival rates were 97.4% and 92.0%, respectively. CONCLUSIONS: We conclude that RPTx with PED is a technical option that may be included in the repertoire of pancreas transplant surgeons.

Successful solitary pancreas transplantation with portal-enteric drainage following unsuccessful islet cell transplantation.

BACKGROUND: There are no data regarding the outcome of solitary pancreas transplantation (SPT) with portal venous drainage (PVD) following unsuccessful islet transplantation (ITx) after multiple islet injections into the portal vein. We herein describe the outcome of three SPTs with PVD performed after failed ITx. METHODS: Between October 2002 and December 2003, three SPTs with PVD were performed following unsuccessful ITx with multiple intraportal islet injections (mean 2.3 injections: range 2 to 3 injections) in two women and one man, aged 26, 49, and 60 years. Panel reactive antibody titer was 0% in all recipients. Immunosuppression was based on induction with either basiliximab (n = 2) or thymoglobulin (n = 1); maintenance therapy included steroids, mycophenolate mofetil, and tacrolimus. During the recipient operation, the absence of venous hypertension was established by direct measurement of portal pressure, before making the final decision to drain the pancreas into the portal vein. RESULTS: Portal pressures were 16 cm H2O, 14 cm H2O, and 13 cm H2O. Pancreas grafts were reperfused after a period of cold preservation of 638, 695, and 835 minutes, respectively. All grafts showed immediate endocrine function, maintaining their recipients insulin-independent for longest follow-ups of 8, 21, and 23 months, respectively. One recipient developed a nonocclusive venous thrombus that resolved with intravenous heparin infusion. CONCLUSIONS: Our experience showed that unsuccessful ITx with multiple intraportal injections does not necessarily preclude the possibility of subsequent successful SPT with PVD. Further experience is needed to define contraindications and possible complications of SPT with PVD following ITx.

Rescue of kidney and pancreas grafts with complex vascular lesions.

BACKGROUND: The organ shortage mandates that grafts with complex vascular lesions be considered for graft rescue. METHODS: Surgical graft rescue was attempted in 8 patients bearing 8 kidneys and 2 pancreata that showed complex vascular lesions deemed not suitable for interventional radiology procedures. RESULTS: All procedures but 1 were performed under elective conditions. Seven grafts were repaired in situ, while cooling the organ through retrograde venous perfusion, and 3 kidneys were explanted, repaired extracorporeally, and retransplanted. All vascular reconstructions remain patent after a mean follow-up period of 3.3 years (+/-2.1 years). CONCLUSIONS: Careful patient selection, multidisciplinary evaluation, and personalized surgical technique may allow the rescue of kidney and pancreas grafts with complex vascular lesions that, otherwise, would be lost.