Histopathological tumour response scoring in resected pancreatic cancer following neoadjuvant therapy: international interobserver study (ISGPP-1).

BACKGROUND: Most tumour response scoring systems for resected pancreatic cancer after neoadjuvant therapy score tumour regression. However, whether treatment-induced changes, including tumour regression, can be identified reliably on haematoxylin and eosin-stained slides remains unclear. Moreover, no large study of the interobserver agreement of current tumour response scoring systems for pancreatic cancer exists. This study aimed to investigate whether gastrointestinal/pancreatic pathologists can reliably identify treatment effect on tumour by histology, and to determine the interobserver agreement for current tumour response scoring systems. METHODS: Overall, 23 gastrointestinal/pancreatic pathologists reviewed digital haematoxylin and eosin-stained slides of pancreatic cancer or treated tumour bed. The accuracy in identifying the treatment effect was investigated in 60 patients (30 treatment-naive, 30 after neoadjuvant therapy (NAT)). The interobserver agreement for the College of American Pathologists (CAP) and MD Anderson Cancer Center (MDACC) tumour response scoring systems was assessed in 50 patients using intraclass correlation coefficients (ICCs). An ICC value below 0.50 indicated poor reliability, 0.50 or more and less than 0.75 indicated moderate reliability, 0.75 or more and below 0.90 indicated good reliability, and above 0.90 indicated excellent reliability. RESULTS: The sensitivity and specificity for identifying NAT effect were 76.2 and 49.0 per cent respectively. After NAT in 50 patients, ICC values for both tumour response scoring systems were moderate: 0.66 for CAP and 0.71 for MDACC. CONCLUSION: Identification of the effect of NAT in resected pancreatic cancer proved unreliable, and interobserver agreement for the current tumour response scoring systems was suboptimal. These findings support the recently published International Study Group of Pancreatic Pathologists recommendations to score residual tumour burden rather than tumour regression after NAT.

Phase II study of gemcitabine and erlotinib as adjuvant therapy for patients with resected pancreatic cancer.

BACKGROUND: There is currently no consensus about the most effective adjuvant therapy for adenocarcinoma of the pancreas. Both gemcitabine and erlotinib have been demonstrated to improve survival in patients with metastatic disease. This study was designed to evaluate the efficacy of gemcitabine and erlotinib as adjuvant therapy, and to explore potential biomarkers associated with response. METHODS: An institutional review board-approved single-center phase II trial of adjuvant biweekly fixed-dose rate gemcitabine (1500 mg/m(2)) and daily erlotinib (150 mg/day) for 4 months followed by maintenance erlotinib (150 mg/day) over 8 months was initiated. Primary end point was recurrence-free survival (RFS). Epidermal growth factor receptor (EGFR) expression in the resected tumors was assessed by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). RESULTS: The study completed planned accrual of 25 patients. Median follow-up was 18.2 (range 11.6-23.5) months. Recurrences were observed in 17 subjects (68%). Median RFS was 14.0 months (95% confidence interval [95% CI], 8.2-24.5) with 1-year and 2-year RFS of 56% (95% CI, 35-73) and 26% (95% CI, 6-52), respectively. Median overall survival was not reached. Estimated 1-year and 2-year overall survival was 84% (95% CI, 63-94) and 53% (95% CI, 22-76), respectively. Nine patients (36%) had a grade 3 event and only 1 (4%) had a grade 4 (neutropenia). Most toxicities were dermatologic, gastrointestinal, and constitutional. There were nonsignificant trends to longer RFS and lower recurrence rates while receiving therapy in subjects with fluorescence in situ hybridization-positive tumors and greater immunohistochemistry expression. CONCLUSIONS: Our phase II results suggest that adjuvant gemcitabine and erlotinib is a promising regimen that merits further investigation.

Percutaneous ablation of VX2 carcinoma-induced liver tumors with use of ethanol versus acetic acid: pilot study in a rabbit model.

PURPOSE: Acetic acid has been employed as a chemical ablation agent for liver tumors because of its superior diffusion characteristics compared with ethanol and the resulting requirement for smaller volumes and fewer injection sessions. Early tissue changes were compared after injection of acetic acid and ethanol in a rabbit model of hepatocellular carcinoma. MATERIALS AND METHODS: VX2 tumors were created in the left lobe of the liver in 11 male New Zealand White rabbits. Each animal underwent a midline minilaparotomy to expose the tumor-laden left lobe, followed by injection of 1.0 mL of 100% ethanol (n = 5) or 50% acetic acid (n = 6) with use of a 20-gauge infusion needle. Animals were killed 30 minutes after surgery; explanted livers were sectioned and examined for gross and microscopic changes. RESULTS: Injection of each agent produced rapid diffusion through tumor and surrounding hepatic parenchyma, with immediate protein precipitation manifested by blanching as a result of coagulation effect. The sizes of coagulation zones, expressed as mean products of the maximum perpendicular diameters of tumoral diffusion, were 13.0 cm(2) +/- 9.4 and 1.3 cm(2) +/- 1.8 for acetic acid and ethanol, respectively (P =.049). No differences in histologic changes were seen between agents. CONCLUSIONS: In this animal model, acetic acid produced significantly larger zones of tumor coagulation compared with ethanol when injected into VX2 carcinoma in equal volumes. Further evaluation is necessary before these findings can be extrapolated to a clinical setting.

Dexamethasone inhibits early regenerative response of rat liver after cold preservation and transplantation.

Regeneration is crucial for the recovery of hepatic mass following liver transplantation. Glucocorticoids, immunosuppressive and antiinflammatory agents commonly used in transplantation, are known to inhibit the expression of specific cytokines and growth factors. Some of these proteins, namely tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6), play a critical role in the initiation of liver regeneration. Following cold preservation and reperfusion of the transplanted liver, the normal recovery process is marked by increased expression of TNF-alpha and IL-6, followed by activation of cytokine-responsive transcription factors and progression of the cell cycle resulting in hepatocyte proliferation. We hypothesized that glucocorticoids may influence the repair mechanisms initiated after extended cold preservation and transplantation. Using a rat orthotopic liver transplant model, recipient animals were treated with dexamethasone at the time of transplantation of liver grafts with prolonged cold storage (16 hours). Treatment with dexamethasone suppressed and delayed the expression of TNF-alpha and IL-6 compared with animals receiving no treatment and attenuated downstream nuclear factor kappaB (NF-kappaB), signal transduction and activator of transcription 3 (STAT3), and activation protein 1 (AP-1) activation. This suppression was accompanied by poor cell-cycle progression, delayed cyclin D1 nuclear transposition, and impaired hepatocyte proliferation by BrdU uptake. Histologically, the liver grafts in treated animals demonstrated more injury than controls, which appeared to be necrosis, rather than apoptosis. In conclusion, these data provide evidence that the administration of glucocorticoids at the time of transplantation inhibits the initiation of the regenerative process and may have a deleterious effect on the recovery of liver grafts requiring significant regeneration. This may be particularly relevant for transplantation of partial liver grafts in the living donor setting.

Interleukin-6 from intrahepatic cells of bone marrow origin is required for normal murine liver regeneration.

Interleukin-6 (IL-6) is required for normal liver regeneration, but the specific cellular source of this growth factor is unknown. We investigated whether this signal originates from the resident macrophage, the Kupffer cell. Using a murine model of bone marrow transplantation, we replaced recipient bone marrow-derived cells, including Kupffer cells, with cells of donor genetic phenotype. Recipients deficient in IL-6 (IL-6(-/-)) were lethally irradiated, then rescued with 10(7) donor bone marrow cells capable of expressing IL-6 (IL-6(+/+)). Conversely, IL-6(+/+) recipients received IL-6(-/-) marrow. Successful engraftment was measured by the presence of the Y chromosome SRY locus in the livers of female recipients receiving male marrow, in situ IL-6 expression by Kupffer cells, and up-regulation of IL-6 in splenocytes after activation with lipopolysaccharide (LPS). Kupffer cell isolation in IL-6(-/-) females receiving IL-6(+/+) male marrow clearly showed the presence of the SRY locus and IL-6 disrupted allele, whereas males receiving female marrow demonstrated no SRY or IL-6 signals, confirming the extent of replacement. Replacement of these cells in IL-6(-/-) mice with IL-6(+/+) bone marrow successfully restored the regenerative response after partial hepatectomy (PHx) as indicated by signal transduction and activator of transcription 3 (STAT3) activation and hepatocyte DNA replication. Alternatively, complete replacement of Kupffer cells in IL-6(+/+) mice by transplantation with IL-6(-/-) cells significantly inhibited liver regeneration and was partially restored by administration of IL-6. This investigation demonstrates a paracrine mechanism by which cells of bone marrow origin, most likely Kupffer cells, regulate the regenerative capacity of the hepatocyte through IL-6 expression.