Panagiotis Samaras

Golgi phosphoprotein 2 (GOLPH2) expression in liver tumors and its value as a serum marker in hepatocellular carcinomas.

Hepatocellular carcinomas (HCCs) and bile duct carcinomas (BDCs) have a poor prognosis. Therefore, surveillance strategies including sensitive and specific serum markers for early detection are needed. Recently, Golgi Phosphoprotein 2 (GOLPH2) has been proposed as a serum marker for HCC, but GOLPH2 expression data in liver tissues was not available. Using tissue microarrays and immunohistochemistry, we semiquantitatively analyzed GOLPH2 protein expression in patients with HCC (n = 170), benign liver tumors (n = 22), BDC (n = 114) and normal liver tissue (n = 105). A newly designed sandwich enzyme‐linked immunoassay (ELISA) was used to analyze GOLPH2 levels in the sera of patients with HCC (n = 62), hepatitis C virus (HCV) (n = 29), BDC (n = 10), and healthy control persons (n = 12). By immunohistochemistry 121/170 (71%) of HCC showed strong GOLPH2 expression, which was significantly associated with a higher tumor grade (P = 0.01). A total of 97/114 (85%) BDCs showed a strong GOLPH2 expression which proved to be an independent prognostic factor for overall survival (P < 0.05). Serum levels of GOLPH2 measured by ELISA were significantly elevated in patients with HCC with underlying HCV infection (median 18 mg/L, P < 0.05) and patients with BDC (median = 14.5 mg/L, P < 0.01) in comparison to healthy controls (median 4 mg/L). Conclusion: GOLPH2 protein is highly expressed in tissues of HCC and BDC. GOLPH2 protein levels are detectable and quantifiable in sera by ELISA. In patients with hepatitis C, serial ELISA measurements in the course of the disease appear to be a promising complementary serum marker in the surveillance of HCC. GOLPH2 should be further evaluated as a serum tumor marker in BDC on a larger scale. (HEPATOLOGY 2009.)

Continuous Sunitinib treatment in patients with advanced hepatocellular carcinoma: a Swiss Group for Clinical Cancer Research (SAKK) and Swiss Association for the Study of the Liver (SASL) multicenter phase II trial (SAKK 77/06).

BACKGROUND Sunitinib (SU) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity. The objective of this trial was to demonstrate antitumor activity of continuous SU treatment in patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS Key eligibility criteria included unresectable or metastatic HCC, no prior systemic anticancer treatment, measurable disease, and Child-Pugh class A or mild Child-Pugh class B liver dysfunction. Patients received 37.5 mg SU daily until progression or unacceptable toxicity. The primary endpoint was progression-free survival at 12 weeks (PFS12). RESULTS Forty-five patients were enrolled. The median age was 63 years; 89% had Child-Pugh class A disease and 47% had distant metastases. PFS12 was rated successful in 15 patients (33%; 95% confidence interval, 20%-47%). Over the whole trial period, one complete response and a 40% rate of stable disease as the best response were achieved. The median PFS duration, disease stabilization duration, time to progression, and overall survival time were 1.5, 2.9, 1.5, and 9.3 months, respectively. Grade 3 and 4 adverse events were infrequent. None of the 33 deaths were considered drug related. CONCLUSION Continuous SU treatment with 37.5 mg daily is feasible and has moderate activity in patients with advanced HCC and mild to moderately impaired liver dysfunction. Under this trial design (>13 PFS12 successes), the therapy is considered promising. This is the first trial describing the clinical effects of continuous dosing of SU in HCC patients on a schedule that is used in an ongoing, randomized, phase III trial in comparison with the current treatment standard, sorafenib (ClinicalTrials.gov identifier, NCT00699374).

Quantitative computed tomography liver perfusion imaging using dynamic spiral scanning with variable pitch: feasibility and initial results in patients with cancer metastases.

Purpose:To assess the feasibility and image quality of computed tomography (CT) liver perfusion imaging using an adaptive 4D spiral-mode, developed to extend the z-axis coverage, and to report initial qualitative and quantitative results in patients with cancer metastases. Materials and Methods:A total of 21 patients with liver metastases of various origins underwent CT perfusion imaging (100 kV and 150 mAs/rot) using a 4D spiral-mode with single-source 64-slice CT (n = 7) with a scan range of 6.7cm (protocol A: 16 cycles, 46.5 seconds examination time), or dual-source 128-slice CT with a scan range of 14.8 cm (protocol B: 16 cycles, 46.5 seconds examination time, n = 7; protocol C: 12 cycles, 51.0 seconds examination time, n = 7). Ability to suspend respiration during perfusion imaging was monitored. Two independent readers assessed image quality on a 4-point scale, both before and after motion correction, and performed a qualitative (ie, arterial enhancement pattern and enhancement change over time) and quantitative perfusion (ie, arterial liver perfusion [ALP]; portal-venous perfusion [PVP]; hepatic perfusion index [HPI]) analysis. Results:Of 21 patients, 7 (33%) could suspend respiration throughout the perfusion study and 14 (67%) resumed shallow breathing during the perfusion scan. The 21 patients had a total of 88 metastases. The scan range of protocol A covered at least 1 metastasis in all patients (total 20/34 [58.8%] metastases). The scan range of protocol B and C covered 53 of 54 (98.1%) metastases, whereas one metastasis in segment VIII was only partially imaged. Image quality was diagnostic both before and after motion correction, whereas being significantly better after motion correction (P < 0.001). Qualitative perfusion analysis of 67 metastases revealed diffuse arterial enhancement in 3 (4.5%), sparse enhancement in 11 (16.4%), peripheral-nodular enhancement in 9 (13.4%), rim-like enhancement in 15 (22.4%), and none in 29 (43.3%) metastases. Enhancement over time of 67 metastases showed a centripetal progression in 6 (8.9%), sustained portal phase in 16 (23.9%), wash-out in 16 (23.9%), and none in 29 (43.3%) metastases. Quantitative perfusion analysis revealed significantly higher arterial liver perfusion and HPI in metastases and metastasis borders than in adjacent normal liver tissue (P < 0.001 each). Portal-venous perfusion was significantly lower in metastases and metastasis borders than in normal liver tissue (P < 0.001). There were no significant differences in image quality and qualitative perfusion analysis between the 3 protocols (P = n.s.). Calculated effective radiation doses were 13.4 mSv for protocol A, 30.7 mSv for protocol B, and 23.0 mSv for protocol C. Conclusion:CT perfusion imaging of the liver using the 4D spiral-mode is feasible with diagnostic image quality, and enables the reliable qualitative and quantitative analysis of the normal and metastatic liver parenchyma. Radiation dose issues must be considered when determining the scan range, number of cycles, and scan duration of the perfusion CT protocol.

Gemcitabine depletes regulatory T‐cells in human and mice and enhances triggering of vaccine‐specific cytotoxic T‐cells

Particle‐mediated epidermal delivery (PMED) is a potent genetic vaccination method. However, a recent report found PMED only poorly and infrequently triggered antigen‐specific cytotoxic T‐cells in cancer patients. Here, we show that injection of the chemotherapeutic drug Gemcitabine in mice results in improvement of the efficacy of subsequent PMED vaccination against NY‐ESO‐1. We found in mice and in cancer patients that administration of Gemcitabine induces a transient reduction in the percentage of regulatory T‐cells among CD4‐positive cells. The higher relative sensitivity of regulatory T‐cells compared to other CD4‐positive T‐cells toward cytostatic drugs can be linked to the higher frequency of proliferating cells in the regulatory compartment compared to the nonregulatory CD4‐compartment in healthy people and cancer patients. Thus, by affecting regulatory T‐cells more than other lymphocyte subsets, chemotherapeutic agents can create a transient hyperimmunoreactive window. Such a window would provide an ideal timepoint to administer a vaccine expected to induce a therapeutically relevant anticancer cytotoxic T‐cell response.

Infectious Port Complications Are More Frequent in Younger Patients with Hematologic Malignancies than in Solid Tumor Patients

Background: We assessed longevity and complications of totally implantable venous access devices in oncology patients. Methods: 197 patients received a total of 201 port devices via the subclavian vein for delivery of chemotherapy between January 1, 2005, and December 31, 2006. We reviewed the patient charts for port-related complications and risk factors until July 31, 2007. Results:A total of 47,781 catheter days were analyzed (median, 175 days; range, 1–831). Forty-six different complications occurred (0.96 complications/1,000 catheter days). The only risk factor significantly associated with a higher complication rate was younger age. Older patients had a lower risk for developing complications with a risk reduction of 2.4% for each year. There were no differences regarding underlying tumor, gender, access side, method of placement (subclavian/cephalic vein) or implanting team (thoracic versus visceral surgery). A trend was seen for shorter port longevity in hematologic patients compared to oncologic patients (p = 0.059). The former developed significantly more port-associated infections than solid tumor patients [11/53 cases (21%) versus 2/148 cases (1.4%); p < 0.0001]. Conclusions: Port-associated infections were mostly observed in younger patients with hematologic neoplasms. Prospective trials should be performed to evaluate the benefit of a prophylactic antimicrobial lock in these selected patients.

Quantitative perfusion analysis of malignant liver tumors: dynamic computed tomography and contrast-enhanced ultrasound.

Objective:To prospectively analyze the correlation between quantitative parameters of perfusion derived from dynamic contrast-enhanced CT (DCE-CT) and contrast-enhanced ultrasound (DCE-US) in patients with malignant liver tumors. Materials and Methods:Thirty patients (mean age: 59.4 ± 12.3 years) with primary malignant liver tumors or hepatic metastases of various origin underwent DCE-CT (4D spiral mode, scan range, 14.8 cm; 15 scans; cycle time, 3 seconds) and DCE-US (low mechanical index, <0.1, 2.4 mL microbubbles). DCE-CT and DCE-US images were evaluated by 2 radiologists regarding quantitative perfusion parameters including arterial liver perfusion (ALP), portal-venous perfusion (PVP), and total perfusion (P = ALP + PVP) from DCE-CT, as well as blood inflow velocity (B) and the normalized slope within the calculation range (CVan) from DCE-US. Results:Quantitative assessment was possible with DCE-CT in 12/30 (40%) patients before and in all patients after automated motion correction. With DCE-US, quantitative assessment could not be performed in 9/30 (30.0%) patients due to respiratory motion. Interreader agreements for quantitative perfusion analysis were good with DCE-CT (r = 0.640–0.892, each P < 0.001) and DCE-US (r = 0.761–0.909, each P < 0.001). Moderate significant correlations were found between the perfusion parameters from DCE-CT (P, ALP) and DCE-US (B, CVan) (r = 0.446–0.621, each P < 0.05). No significant correlations were found between PVP from CT and perfusion parameters from DCE-US (B, CVan; each P = nonsignificant). Conclusions:Quantitative evaluation of DCE-CT data was feasible in all patients after automated motion correction, whereas DCE-US data could not be quantitatively evaluated in 30% of patients due to respiratory motion and lack of motion correction software. Quantitative arterial perfusion analysis showed moderate significant correlations for blood flow parameters among modalities.

Hodgkin’s lymphoma in remission after first-line therapy: which patients need FDG–PET/CT for follow-up?

BACKGROUND The purpose of the study was to evaluate the impact of 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET)/computed tomography (CT) during follow-up of patients with Hodgkins lymphoma. PATIENTS AND METHODS Patients in complete remission or an unconfirmed complete remission after first-line therapy who received FDG-PET/CT during their follow-up were analyzed retrospectively. Confirmatory biopsy was mandatory in case of recurrence. RESULTS Overall, 134 patients were analyzed. Forty-two (31.3%) patients had a recurrence. The positive predictive value of FDG-PET/CT was 0.98. Single-factor analysis identified morphological residual mass [P = 0.0005, hazard ratio (HR) 3.4, 95% confidence interval (CI) 1.7-6.6] and symptoms (P < 0.0001, HR 4.9, 95% CI 2.4-9.9) as significant risk factors for relapse. By multivariate analysis, morphological residual mass was the only significant risk factor for early follow-up (<24 months) (P = 0.0019, HR 7.6, 95% CI 2.1-27.3). Advanced stage (P = 0.0426, HR 3.6, 95% CI 1.1-12.3) and the presence of symptoms (P = 0.0009, HR = 14.6, 95% CI 3.0-69.7) were found to be significant risk factors for later follow-up (>24 months). CONCLUSIONS Asymptomatic patients without morphological residues and an early stage of disease do not need a routine FDG-PET/CT for follow-up. Asymptomatic patients with morphological residues should receive routine follow-up FDG-PET/CT for the first 24 months. Only patients with advanced initial stage do need a routine follow-up FDG-PET/CT beyond 24 months.

Risk-adapted FDG–PET/CT-based follow-up in patients with diffuse large B-cell lymphoma after first-line therapy

BACKGROUND The purpose of this study was to evaluate the impact of 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) during follow-up of patients with diffuse large B-cell lymphoma (DLBCL) being in complete remission or unconfirmed complete remission after first-line therapy. PATIENTS AND METHODS DLBCL patients receiving FDG-PET/CT during follow-up were analyzed retrospectively. Confirmatory biopsy was mandatory in cases of suspected disease recurrence. RESULTS Seventy-five patients were analyzed and 23 (30%) had disease recurrence. The positive predictive value (PPV) of FDG-PET/CT was 0.85. Patients >60 years [P = 0.036, hazard ratio (HR) = 3.82, 95% confidence interval (CI) 1.02-7.77] and patients with symptoms indicative of a relapse (P = 0.015; HR = 4.1; 95% CI 1.20-14.03) had a significantly higher risk for relapse. A risk score on the basis of signs of relapse, age >60 years, or a combination of these factors identified patients at high risk for recurrence (P = 0.041). CONCLUSIONS FDG-PET/CT detects recurrent DLBCL after first-line therapy with high PPV. However, it should not be used routinely and if only in selected high-risk patients to reduce radiation burden and costs. On the basis of our retrospective data, FDG-PET/CT during follow-up is indicated for patients <60 years with clinical signs of relapse and in patients >60 years with and without clinical signs of relapse.

A Pooled Analysis of Sequential Therapies with Sorafenib and Sunitinib in Metastatic Renal Cell Carcinoma

Objective: To evaluate the optimal sequence for the receptor tyrosine kinase inhibitors (rTKIs) sorafenib and sunitinib in metastatic renal cell cancer. Methods: We performed a retrospective analysis of patients who had received sequential therapy with both rTKIs and integrated these results into a pooled analysis of available data from other publications. Differences in median progression-free survival (PFS) for first- (PFS1) and second-line treatment (PFS2), and for the combined PFS (PFS1 plus PFS2) were examined using weighted linear regression. Results: In the pooled analysis encompassing 853 patients, the median combined PFS for first-line sunitinib and 2nd-line sorafenib (SuSo) was 12.1 months compared with 15.4 months for the reverse sequence (SoSu; 95% CI for difference 1.45–5.12, p = 0.0013). Regarding first-line treatment, no significant difference in PFS1 was noted regardless of which drug was initially used (0.62 months average increase on sorafenib, 95% CI for difference –1.01 to 2.26, p = 0.43). In second-line treatment, sunitinib showed a significantly longer PFS2 than sorafenib (average increase 2.66 months, 95% CI 1.02–4.3, p = 0.003). Conclusion: The SoSu sequence translates into a longer combined PFS compared to the SuSo sequence. Predominantly the superiority of sunitinib regarding PFS2 contributed to the longer combined PFS in sequential use.

Daily Pomegranate Intake Has No Impact on PSA Levels in Patients with Advanced Prostate Cancer - Results of a Phase IIb Randomized Controlled Trial.

Pomegranate has been shown to prolong PSA doubling time in early prostate cancer, but no data from a placebo controlled trial has been published yet. The objective of this study was to prospectively evaluate the impact of pomegranate juice in patients with prostate cancer. We conducted a phase IIb, double blinded, randomized placebo controlled trial in patients with histologically confirmed prostate cancer. Only patients with a PSA value ≥ 5ng/ml were included. The subjects consumed 500 ml of pomegranate juice or 500 ml of placebo beverage every day for a 4 week period. Thereafter, all patients received 250 ml of the pomegranate juice daily for another 4 weeks. PSA values were taken at baseline, day 14, 28 and on day 56. The primary endpoint was the detection of a significant difference in PSA serum levels between the groups after one month of treatment. Pain scores and adherence to intervention were recorded using patient diaries. 102 patients were enrolled. The majority of patients had castration resistant prostate cancer (68%). 98 received either pomegranate juice or placebo between October 2008 and May 2011. Adherence to protocol was good, with 94 patients (96%) completing the first period and 87 patients (89%) completing both periods. No grade 3 or higher toxicities occurred within the study. No differences were detected between the two groups with regard to PSA kinetics and pain scores. Consumption of pomegranate juice as an adjunct intervention in men with advanced prostate cancer does not result in significant PSA declines compared to placebo.