Pts In Grp Research Articles

Timing of PD-L1 Blockade with Durvalumab May Affect Outcomes of CD19 CAR-T Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma

Introduction CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy has shown high overall response rates (ORRs) in patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL); however, CD19 CAR-T cells fail to elicit a complete response (CR) in a considerable proportion of pts. PD-L1 expression in the tumor microenvironment could impair the efficacy of CAR-T cell therapy. PD-1/PD-L1 pathway blockade may enhance the function and antitumor activity of CAR-T cells. Here, we report the analysis of a phase I dose-finding study (NCT02706405) of combination therapy with CD19-targeted 4-1BB-costimulated CAR-T cells (JCAR014) and escalating doses of durvalumab (durva), an anti-PD-L1 monoclonal antibody, in adults with R/R LBCL. Methods Pts were treated in 1 of 2 groups. All pts received lymphodepletion (LD) with cyclophosphamide (Cy) and fludarabine (Flu) followed by JCAR014 infusion. Pts in group 1 (Grp 1) received the first dose of durva (225 mg or 750 mg) after JCAR014 infusion. Pts in group 2 (Grp 2) received the first dose of durva (7.5 mg, 22.5 mg, 75 mg, 225 mg, or 750 mg) 1 day prior to JCAR014 infusion. Up to 10 doses of durva were administered at 4-week intervals after JCAR014 at the highest identified safe dose until toxicity or disease progression. Adverse events (AEs) were graded by CTCAE 4.03, except for cytokine release syndrome (CRS), which was graded according to Lee 2014 consensus criteria. Response was reported according to PET/CT 2014 Lugano criteria. Results Between 01/23/2017 and 07/02/2020, 34 pts were screened, 32 underwent leukapheresis, and 29 were enrolled and received LD and JCAR014. Eleven pts were treated in Grp 1 and 18 in Grp 2 (Table 1). All pts received 2 x 106 JCAR014 cells/kg, except for the first 2 pts treated on the study who received 7 x 105 cells/kg. The most common AEs of any grade related to LD and JCAR014 with or without durva were CRS (41%), neutropenia (21%), neurotoxicity (17%), and hypogammaglobulinemia (17%). The incidences of any grade and grade ≥ 3 CRS and neurotoxicity were similar between Grp 1 and Grp 2 (Table 2A). Patients in Grp 2 had later onset of CRS after JCAR014 infusion compared with Grp 1 (median of 6 vs. 4 days, P = .05) and shorter duration of CRS (median of 3 vs. 8 days, P = .08). Among the 27 pts evaluable for dose-limiting toxicity (DLT), 2 (7%) had DLT: 1 pt with grade 4 CRS in Grp 2 (durva 225 mg) and 1 pt with prolonged grade 3 neurotoxicity in Grp 2 (durva 750 mg). No maximum-tolerated dose of durva was identified. In pts evaluable for response (n = 26), the ORR and the CR rate at 3 months were 35% (95% CI, 17-56) and 27% (95% CI, 14-46). We retrospectively compared the response rates of LBCL pts treated with JCAR014 in combination with durva (NCT02706405) with LBCL pts who received the same Cy/Flu lymphodepletion regimen and JCAR014 dose (2 x 106 cells/kg) without durva (JCAR014 alone cohort) on our previous phase I/II clinical trial (NCT01865617). There was a trend towards lower ORR (P = .08) and CR rate (P = .09) in pts treated with JCAR014 in combination with durva compared with those treated in the JCAR014 alone cohort (Table 2B). There were no significant differences in ORR and CR rate between patients in Grp 1 and those who received JCAR014 alone. However, despite a trend towards lower tumor burden, pts in Grp 2 (first durva before JCAR014) had lower ORR (P = .07) and CR rate (P = .03) compared with those treated in the JCAR014 alone cohort, and a trend towards lower CR rate compared with those treated in Grp 1 (first durva after JCAR014; P = .16). Patients treated with JCAR014 alone had significantly shorter time to CAR-T cell peak counts in blood compared with patients treated with JCAR014 in combination with durva (median of 8 vs. 14 days, P = .01). We did not observe significant differences in peak CAR-T cell expansion, area under the curve (AUC) from day 0 to 28 after JCAR014 infusion, and day 28 CAR-T cell counts by qPCR between the cohorts. Conclusion The combination of JCAR014 with durva for the treatment of adult pts with LBCL was safe. Our findings suggest that the timing of initiation of durva therapy is a key variable that may affect outcomes. To our knowledge, this is the first report suggesting that PD-L1 blockade may impact toxicity and antitumor response in pts with LBCL undergoing CD19 CAR-T cell therapy. Additional studies will be required to determine the optimal approach for combining CD19 CAR-T cell therapy with PD-1/PD-L1 pathway blockade in LBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract P1-18-37: Treatment patterns and outcomes associated with sequential and non-sequential use of CDK4 and 6i for HR+, HER2- MBC in the real world

Abstract Background: Cyclin-dependent kinase 4 and 6 inhibitors (CDK4 & 6i) provide significant benefit for patients (pts) with HR+, HER2- MBC, however, clinical questions remain regarding the optimal sequence (seq) of treatments (tx). Prior analyses of real world (rw) abemaciclib indicate up to 50% of pts have had prior palbociclib or ribociclib for MBC and published studies regarding seq and non-seq tx outcomes have had limited sample sizes. To our knowledge, the current study represents the largest rw analysis of CDK4 & 6i tx seq to date. Methods: US electronic medical records were retrospectively analyzed from the ConcertAI Oncology Dataset. Pts received abemaciclib and ≥ 1 other systemic tx line for HR+, HER2- MBC; the study period was 11/1995 (date of first MBC dx in dataset) to 10/2020 (end of follow-up). Tx sequences were identified and grouped to enable outcomes analyses. Data for 4 select groups (grp) are presented: grp 1 (1L CDK4 & 6i to 2L CDK4 & 6i), grp 2 (1L CDK4 & 6i to 2L non-CDK4 & 6i), grp 3 (2L CDK4 & 6i to 3L CDK4 & 6i), grp 4 (2L CDK4 & 6i to 3L non- CDK4 & 6i). Progression-free survival (PFS) from regimen start date to disease progression or death was analyzed by line using Kaplan-Meier method; pts were censored on the start date of the subsequent tx or end of follow-up if a progression event was not reported. Pts were characterized as having primary or secondary endocrine resistance per ESMO guidelines, if applicable. Pt characteristics at initiation of 1st CDK4 & 6i and median PFS are summarized descriptively. Results: Of 690pts, the majority were white (n=555, 80%), had a median age of 61yrs (range 26-86) and were treated in community oncology practices (80%) in southern US (47%). Most pt characteristics between grp 1 vs grp 2 were not statistically different except for pts participating in clinical trials [grp 1 (n=3; 2%) vs grp 2 (n=12; 13%)]. Pts in grp 4 were younger than grp 3, with a median age of 60 and 67yrs, respectively (p<0.05). In the overall cohort, the most prevalent tx seq grp was 1L CDK4 & 6i followed by 2L CDK4 & 6i (n=165). There was significant treatment regimen heterogeneity across all grps, with the most frequent being 1L palbociclib/AI followed by 2L abemaciclib/fulvestrant received by 26 (16%) pts. Abemaciclib was prevalent in 1L (n=92; 13%), 2L (n= 204; 30%), 3L (n=122; 18%), ≥4L (n=344; 50%). Pts receiving seq CDK4 & 6i experienced a substantial PFS benefit in the subsequent line (grp 1: 17mo; grp 3: 11mo), while pts in non-seq grps experienced a numerically lower PFS from the non-CDK4 & 6i tx in the subsequent line (grp 2: 8mo; grp 4: 8mo). Median PFS for each grp is described in Table 1. Results of cox proportional hazards models will be presented. Conclusions: Seq CDK4 & 6i appears to deliver substantial 2L PFS in pts who had a meaningful PFS on 1L CDK4 & 6i. These results appear consistent for pts receiving 3L CDK4 & 6i who had a meaningful PFS to 2L CDK4 & 6i. While most pts received 1L CDK4 & 6i to 2L CDK4 & 6i, there was marked tx heterogeneity across all seqs in this predominantly community oncology sample, reinforcing the continued lack of consensus on this topic. While these results are hypothesis generating, these data serve as further rationale for additional prospective and retrospective studies evaluating the potential utilization and outcomes of CDK4 & 6i, after progression on a previous CDK4 & 6i. Table 1.Grp 11L CDK4 & 6i to 2L CDK4 & 6i n=165Grp 21L CDK4 & 6ito 2L non-CDK4 & 6i n=94Grp 32L CDK4 & 6i to 3L CDK4 & 6i n=115Grp 42L CDK4 & 6i to 3L non-CDK4 & 6i n=121Line 1No. of Events/Pts78/16572/94Median (m)18.459.8095% CI[15.0, 23.2][6.4, 14.2]Line 2No. of Events/Pts55/16540/9455/11587/121Median (m)17.308.3917.308.2995% CI[9.8, 33.4][5.9, 10.5][12.1, 21.0][6.2, 9.9]Line 3No. of Events/Pts46/11557/121Median (m)11.227.8695% CI[6.8, 14.0][5.5, 11.3] Citation Format: Kevin M Kalinsky, Megan Kruse, Emily Nash Smyth, Claudia M Guimaraes, Santosh Gautam, Alnecia R Nisbett, Maxine D Fisher, Zhanglin Lin Cui, Lee Bowman. Treatment patterns and outcomes associated with sequential and non-sequential use of CDK4 and 6i for HR+, HER2- MBC in the real world [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-37.

Comparison of intra-articular injection of local anaesthetic Ropivacaine versus Ropivacaine+Ketorolac and Ropivacaine+Tramadol for post-operative pain relief in knee and hip arthroplasty surgeries under spinal anaesthesia

Local anaesthetic infiltration in knee and hip arthroplasty is employed as a part of multi-model analgesia to reduce opiate consumption and help in early ambulation of elderly people It reduces post-operative pain effectively and thus reduces complications like Deep vein thrombosis, pulmonary embolism, pneumonia and even myocardial infection. Addition of ketorolac or Tramadol further prolongs the duration of analgesia. To compare the local anaesthetic infiltration of Ropivacaine alone and Ropivacaine with Ketorolac and Ropivacaine with tramadol for postoperative pain relief in knee and hip arthroplasty. Randomize double-blind study was conducted on 60 patients undergoing knee or hip arthroplasty under spinal anaesthesia. Group A patients received wound infiltration with Inj. Ropivacaine0.75% 50ml (5-7 mg/kg), Group B patients received Inj. Ropivacaine 0.75% 50 ml+1ml Inj. Ketorolac(30 mg) and Group C patients received Inj Ropivacaine 0.75% 50 ml+ Inj Tramadol 2ml (100mg), all diluted with NS to make 100 ml infiltration. Post-operative pain scores, time of first rescue analgesia (FRA), hemodynamic parameters and total rescue analgesic consumed in 24 hrs. as Inj Diclofenac and Tramadol was assessed and any untoward incidences like nausea, vomiting, knee swelling & Hypotension etc. were noted. The VA Score was significantly lower in Grp C as compared to Grp B and A in first 4-6 hrs. as tramadol and ketorolac significantly prolongs the duration of analgesia. VA score in Grp Cis 3.8+_0.52, as compared to 4.02 ± 1.58 in Grp B and 5.7 ± 1.014 in Grp A. which was statistically significant (P value 0.0141). The time of first rescue analgesia (FRA) was also prolonged by 2.2 hrs. in Grp C as compared to Grp B and C which is statistically significant. (P value 0.003). The total rescue analgesia in 24 hrs. given as Inj Diclofenac and Inj Tramadol was significantly lower in Grp C as compared to Grp B and A. No of pts requiring rescue analgesia was also less 45% in Grp C as compared to 50% and 95% in Grp B and A respectively. 25% pts in Grp C has excellent pain relief as compared to 20% in Grp B and 10% in Grp A. No untoward effect like nausea vomiting is noted in any patient, only 3 pts in Grp A and 2 pts in Grp B required bl transfusion. Local infiltration of Ropivacaine provides good analgesia. Addition of tramadol or Ketorolac prolongs the analgesic effect of Ropivacaine and lowers the VAS significantly and improves patient satisfaction score. It also decreases post-operative 24hrs NSAID or opioid consumption.

Is second-line targeted therapy beneficial in patients (pts) with differentiated thyroid cancer (DTC) after first-line sorafenib (SOR) failure?

e17016 Background: SOR has demonstrated efficacy in phase II trials but responses are not durable. 2nd line therapy is used in clinical practice however there are no data showing clinical benefit with this approach. We sought to determine if 2nd line targeted therapy was beneficial after SOR failure. Methods: Adult pts with DTC treated with 1st line SOR for >3 months were included. We compared overall survival (OS) in pts who received only 1st line SOR (grp 1) with pts treated with 2nd line therapy after 1st line SOR failure (grp 2). OS was defined as time after SOR failure until death. SOR failure was defined as discontinuation due to progression or intolerable toxicity. Results: We identified 62 DTC pts from 2006-2012 who were treated with 1st line SOR. 10 pts in grp 1 were excluded due to missing data, secondary unrelated cancers and <3 mo on SOR. We included 52 pts: 31 in grp 1 and 21 in grp 2. Baseline characteristics were similar between groups (Table). FTC was more frequent in grp 2. 2nd therapy included sunitinib, pazopanib, vemurafenib, and other investigational drugs. Median time on treatment with 2nd line therapy was 14.5 mo. Median OS in grp 1 and grp 2 was 6 and 50 mo, respectively (p=0.002). After excluding pts for death <3 mo after SOR end, median OS was 20 and 50 mo; there was a trend toward significance (p=0.07). Response and updated analysis will be reported at the meeting. Conclusions: Our study shows that pts receiving 2nd line therapy after SOR failure had a long OS despite more pts with FTC in this group. Acknowledging the limitations of a retrospective study, we conclude that in DTC pts, salvage targeted therapy after SOR failure appears to be beneficial and a promising strategy. [Table: see text]

Effect of axillary dissection for occult detected sentinel nodes metastases on survival: NSABP B-32.

80 Background: In NSABP B-32 trial 5,611 women with invasive breast cancer were randomly assigned to sentinel lymph node biopsy (SLNB) plus axillary dissection (Group [Grp] 1) or SLNB alone (Grp 2). There was no significant difference in OS or DFS reported between the two groups. Initial permanent pathologic assessment of the SLNs at participating sites was designed to identify all macrometastases >2 mm and consisted of slicing the SLNs at approximately 2.0 mm intervals, embedding all slices in paraffin tissue blocks, and examining one hematoxylin and eosin stained slide from each block. Routine use of IHC or sectioning of deeper levels was prohibited. SLN paraffin tissue blocks from cases with pathologically negative SLNs were later evaluated centrally for occult metastases deeper in the blocks. This study evaluates group outcomes related to occult metastases. Methods: Routine and cytokeratin IHC stains were used at two widely spaced additional levels. Using this technique, occult metastases were detected in 15.9% of the patients (pts) with initially negative SLNs (616 / 3884 cases). Of the 616 cases, 431 (69.8%) had isolated tumor-cell clusters, 171 (27.9%) had micrometastases, and 14 (2.3%) had macrometastases (Weaver D, et al: N Engl J Med, 2011). Results: 316 (16.4%) of 1924 pts had occult metastases in Grp 1 and 300 (15.3%) of 1960 in Grp 2. Non-sentinel node status was available in 312/316 pts in Grp 1; 23 (7.4%) had positive non-sentinel nodes. In pts with occult metastases, there were no significant differences in OS or DFS between groups (Grp 2 vs. Grp 1 OS HR: 0.89, p=0.62; DFS HR: 0.79, p=0.16). There were no significant differences in OS or DFS between the groups in pts who were negative for occult metastases (Grp 2 vs. 1 OS HR:1.25, p=0.07; DFS HR: 1.11, p=0.22). Conclusions: A more detailed assessment of the SLNs with deeper sectioning and IHC staining detected a significant level of occult metastases in clinically node negative pts. However, no benefit was seen by the addition of axillary dissection in pts with occult SLN metastases. Supported by NCI: U10-CA-12027, U10-CA-37377, U10-CA-69974, U10-CA-69651, and ARRA ROI CA 74137

A Phase I, Dose Escalation Study of Lapatinib in Combination with Carboplatin, Paclitaxel, with or without Trastuzumab in Patients with Metastatic Breast Cancer: An Update.

Abstract Background: Lapatinib is a selective and highly potent dual, competitive inhibitor of erbB1 and erbB2 tyrosine kinases with clinical activity in erbB2-positive metastatic breast cancer (MBC). The combination of carboplatin, paclitaxel, and trastuzumab has been shown to have significant clinical activity in MBC as well as in the adjuvant setting. Given the synergy of dual inhibition with trastuzumab and lapatinib observed in both the preclinical and clinical settings, the feasibility, safety, and early clinical activity of paclitaxel, carboplatin, lapatinib with or without trastuzumab in patients (pts) with MBC was assessed.Methods: MBC pts previously untreated with trastuzumab or cytotoxic chemotherapy for metastatic or locally recurrent disease were enrolled into either Group (Grp) A (erbB2 positive) or B (erbB2 positive or negative). Escalating doses of lapatinib (planned range of 750-1500 mg/d) were administered in combination with (Grp A) or without (Grp B) trastuzumab (4 mg/kg followed by weekly 2 mg/kg infusions). Paclitaxel (80 mg/m2) and carboplatin (AUC 2 mg/ml*min) were administered on days 1, 8, 15 with cycles repeated every 28 days. Starting doses of lapatinib were 750 mg in Grp A and 1000 mg in Grp B (Dose Level 0). A standard 3 + 3 Phase I design was used to determine the optimally tolerated regimen (OTR) dose level.Results: Twenty-seven pts (Grp A n=15, Grp B n=12) have been enrolled in the study (median age 45 yrs, range 27-74). A median of 5 cycles (range 1-21) in Grp A and 5.5 (range 2-15) in Grp B have been administered. Drug-related toxicities were reported in 14 pts (93%) in Grp A and 11 pts (92%) in Grp B. In Grp A, drug-related grade 3 toxicities ≥ 10% include neutropenia (47%), diarrhea (33%), and rash (20%). Two drug-related grade 4 toxicities were reported (urinary tract infection and hypocalcemia). In Grp B, drug-related grade 3 toxicities ≥ 10% include diarrhea (17%), fatigue (17%), and rash (17%). Drug-related grade 4 toxicity (neutropenia) occurred in 3 pts in Grp B. In Grp A, there were two patients with dose-limiting toxicity (DLT) (Gr 3 diarrhea, Gr 3 rash) at lapatinib 1000 mg (Dose Level +1). The OTR (Dose Level 0) was identified as lapatinib 750 mg, paclitaxel 80 mg/m2, carboplatin AUC 2, and trastuzumab 2 mg/kg. In Grp B, two patients had DLT (one with Gr 4 neutropenia, one with Gr 3 rash and hypokalemia) at Dose Level 0 (lapatinib 1000 mg). At Dose Level -1 (paclitaxel reduced to 70 mg/m2), one pt had a DLT (Gr 4 neutropenia) and this dose level will be expanded to 6 pts. Clinical activity to date in Grp A (12 pts) includes 2 CR, 8 PR, and 1 SD and in Grp B (11 pts) 5 PR and 5 SD. Two pts in Grp B were ErbB2+, both had PR. Response assessments were not available for 4 pts (3 pts were awaiting response assessment and 1 pt was removed from the study prior to response assessment due to toxicity (neutropenia, catheter infection)).Conclusions: Lapatinib may be administered safely in combination with carboplatin, paclitaxel, with or without trastuzumab at known effective doses. Clinical activity has been observed. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3097.

A phase I, dose escalation study of lapatinib in combination with carboplatin, paclitaxel, with and without trastuzumab in patients with metastatic breast cancer.

Abstract Abstract #3121 Background: Lapatinib is a selective and highly potent dual, competitive inhibitor of erbB1 and erbB2 tyrosine kinases with clinical activity in erbB2-positive metastatic breast cancer (MBC). The combination of carboplatin, paclitaxel, and trastuzumab has been shown to have significant clinical activity in MBC as well as in the adjuvant setting. Given the synergy of dual inhibition with trastuzumab and lapatinib observed in both the preclinical and clinical settings, we assessed the feasibility, safety, and early clinical activity of paclitaxel, carboplatin, lapatinib with and without trastuzumab in patients (pts) with MBC.
 Methods: MBC pts previously untreated with trastuzumab or cytotoxic chemotherapy for metastatic or locally recurrent disease were enrolled into either Group (Grp) A (erbB2 positive) or B (erbB2 positive or negative). Escalating doses of lapatinib (planned range of 750-1500 mg/d) were administered in combination with (Grp A) or without (Grp B) trastuzumab (4 mg/kg followed by weekly 2 mg/kg infusions). Paclitaxel (80 mg/m2) and carboplatin (AUC 2 mg/ml*min) were administered on days 1, 8, 15 with cycles repeated every 28 days. Starting doses of lapatinib were 750 mg in Grp A and 1000 mg in Grp B. A standard 3 + 3 Phase I design is being used until the optimally tolerated regimen (OTR) dose level is determined. An additional 14 - 17 pts will be enrolled into each grp at the OTR dose level to further assess safety and tolerability.
 Results: Fourteen pts (Grp A n=8, Grp B n=6) have been enrolled in the study (median age 42 yrs, range 27-66). A median of 5.5 cycles (range 4-17) in Grp A and 3.5 (range 1-7) in Grp B have been administered. All pts had at least one adverse event (AE). In Grp A, grade 3 toxicities include neutropenia (50%), diarrhea (38%), rash (25%), vomiting (13%), hypokalemia (13%), and syncope (13%). No grade 4 toxicities were reported. In Grp B, grade 3 toxicities include fatigue (33%), hyponatremia (17%), menorrhagia (17%), dermatitis (17%), and rash (17%). One pt (in Grp B) had grade 4 neutropenia. No febrile neutropenia was observed. In Grp A, there was one DLT (Gr 3 diarrhea) at lapatinib 1000 mg. In Grp B, one DLT (Gr 4 neutropenia) at lapatinib 1000 mg has been observed. Clinical activity to date includes 8/8 objective responses in Grp A, (1 CR, 7 PR) and 2/6 objective responses (2 PR) in Grp B (all pts in Grp B were erbB2 negative). Dose escalation continues in both grps.
 Conclusions: Lapatinib may be administered safely in combination with carboplatin, paclitaxel, with and without trastuzumab at known effective doses for each. Clinical activity has been observed. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3121.

Increased risk of CMV infection in heart transplant patients on mycophenolate mofetil

plantation (grp II, n58). Methods: Patients receiving HCV positive allografts between July 1994 to Dec. 1999 were reviewed. The HCV RNA level, seroconversion of anti-HCV antibody, hepatic enzymes, correlation of liver dysfunction and cause of death were examined. Survival and transplant coronary artery disease (TCAD) free rate were compared with age matched patients transplanted in the same period (n5 392). Results: The recipients consisted of 17 males and 1 female, with median age 54 yrs for grp I and 66 for grp II; 2 pts in grp II who were pretransplant HCV positive were also retransplants. Hospital mortality rate was 1/10 in grp I and 2/8 in grp II(total517 %), all from multiple organ failure. All survivors were HCV negative prior to transplant. At a median follow up of 26.5 months, 6/15 survivors (40 %) were infected with detectable viremia. Three(20 %) seroconverted after 1-13 months and two, one per grp, developed HCV related liver dysfunction. One from grp I developed fibrosing cholestatic hepatitis and expired. Actuarial 3 yr survival in those discharged is 56% and 84% for grp I and II. Freedom from rejection (.grade 3) was 40% for grp I and 100% for grp II. TCAD accounted for 2 late deaths in persistently seronegative but viremic pts in grp I and none in grp II. Overall 3-year TCAD free rate was 87% for the 15 patients discharged. Conclusions: (1) Under TDI, hepatitis C transmission using donor heart as the reservoir is moderate with seroconversion lower. (2) Limited use of such donors is justified in selected patients. (3) Seroconversion and risk for hepatic disease may be reduced by tailoring immunosuppression particularly if they are at low risk of rejection.

INCREASED HEPATITIS C VIREMIA IN CHOLESTATIC HEPATITIS C FOLLOWING ORTHOTOPIC LIVER TRANSPLANTATION. IS THE PATHOGENECITY OF THE SYNDROME RELATED TO VIRAL CYTOPATHIC MECHANISMS?

410 Introduction: Progressive cholestatic jaundice in hepatitis C (HCV) patients (pts) following orthotopic liver transplantation (OLTx) is associated with significant morbidity and mortality. The pathogenesis of this syndrome is not known. The aim of this study was to retrospectively compare pts with HCV who developed jaundice post transplant to a matched group of controls who had an uneventful clinical course. Patient and Methods: Cholestatic jaundice was defined as having a serum bilirubin >5.0mg/dL for more than one month, except for three patients who died within one month and were included in the analysis. Other causes such as acute rejection, biliary obstruction, vascular compromise, and viral diseases other than HCV were excluded. Twenty one (10%) of 212 pts transplanted for HCV cirrhosis had cholestatic hepatitis (Grp I). These pts were matched with 21 HCV pts who underwent OLTx but did not develop cholestasis (Grp II). Matching was random and blinded without knowledge of viral load. The two groups were matched for: age, sex, crossmatch, and timing of transplantation. Grp I consisted of 21 pts (11 females/10 males) with median age of 44 years(33-63 years). Grp II consisted of 21 pts (11 females/10 males) with median age 47 years (37-61 years). The positive lymphocytic cytotoxic crossmatch was also similar between the two groups (Grp I n=2, Grp II n=3). Serum HCV-RNA levels were measured by signal amplification of Chiron (Emeryville, CA) and converted into log scale. HCV-RNA levels for Grp I were measured pre transplant, at onset of jaundice, monthly during jaundice, and at the end of jaundice or death. Grp II HCV-RNA levels were measured at similar times after transplant (in terms of post-op days). Results: The duration of jaundice ranged from 9 to 468 days (median 99 days). Follow-up is provided through December 1997 and is similar among the two groups. Grp I (median 281 days, range 44-1114 days) and Grp II (median 246 days, range 29-1212 days). There was a statistically significant difference in serum HCV-RNA levels at all time points (Grp I vs Grp II): pre-op 6.41±0.661 vs 5.79±0.557 (p=0.007), onset of jaundice 7.47±0.767 vs 6.64±0.888 (p=0.004), during jaundice 7.62±0.338 vs 6.92±0.717 (p=0.0007), and at end of the event of jaundice 7.43±0.685 vs 6.76±1.001 (p=0.04). Cirrhosis was evident in five pts in Grp 1 and in no pts in Grp II (p=0.02). Genotyping was available on 7 pts in Grp 1: 1a n = 5, 1b n = 1, and mixed n = 1. Grp I had an 86% mortality rate (18/21) and Grp II a 10% mortality (2/21),(p=0.00000002). The causes of death in Grp I were: recurrent HCV n = 13, chronic rejection n = 2, sepsis n = 3. The causes of death in Grp II were: chronic rejection n = 1, and cardiac tamponade n = 1. Conclusions: 1) Cholestatic jaundice post-OLTx occurred in (10%) of pts and was associated with significant mortality. 2) Hepatitis C viremia was significantly higher at various times in pts with cholestasis. 3) Pathogenetic mechanisms may involve virus related cytopathic effects.

1026-87 Long-term Changes in Defibrillation Thresholds Using Two Nonthoracotomy Lead Systems and a Biphasic Waveform

We implanted nonthoracotomy defibrillators in consecutive pts with sustained ventricular arrhythmias. A Ventritex Cadence (V-l00C) device using a bipbasic waveform was implanted in all pts. The first 21 systems (Grp l) consisted of a CPI (BT-1 0) endocardial lead at the RV apex for sensing and pacing, with a CPI(C-l0) spring electrode at the SVC/HRA junction and a large CPI patch (L67) implanted subcutaneously in the left axillary region for defibrillation. A single lead defibrillation system (CPI Endotak C, Model #0064) was implanted in 27 pts (Grp II). Mean age was 61 ± 12 years and LVEF was 37 ± 16%, Three successful shocks for sustained VF were required to define the defibrillation threshold (DFT). Implantation occurred if thresholds were ≤ 650 V Adequate DFTs were initially obtained in all pts. DFTs (Volts) at implantation (IMPL), predischarge (PREDC), 1 month (MO), 6 MO, and 1 year (YR) were: IMPL PREDC 1 MO 8 MO 1 YR N = 48 48 42 22 4 Group I 562 ± 63 576 ± 68 580 ± 54 571 ± 58 538 ± 48 Group II 471 ± 84 494 ± 101 511 ± 74 525 ± 79 - There was no significant change in DFT for Grp I, comparing IMPL to PREDC, PREDC to 1 MO, 1 MO to 6 MO, or 6 MO to 1 YR (p = NS). In contrast, there was a significant increase in DFT in Grp II comparing 1M PL to PREDC (p = 0.01) and PREDC to 1 MO (p = 0.01). There was no significant increase between 1 MO and 6 MO, but the number of pts was small. DFTs at IMPL were significantly lower in Grp II than in Grp I (p = < 0.01). DFTs in Grp II increased by 50 V in 7 pts, 100 V in 3 pts, 200 V in 1 pt and 250 V in 1 pt. Two pts in Grp I and 1 pt in Grp II required lead revision before discharge, due to the increase in DFT. Unlike a nonthoracotomy patch/lead system, an increase in DFT was noted on follow-up using a single lead Endotak system and device which delivers a biphasic waveform. However, DFTs at IMPL were relatively low using this single lead system and lead revision was rarely required. Because significant increases in DFTs may continue to occur after discharge, close follow-up is recommended.