Occult Liver Metastases Research Articles

Conversion surgery for BRCA-mutated pancreatic ductal adenocarcinoma with liver metastasis treated with platinum-based chemotherapy followed by olaparib

BackgroundWith recent dramatic developments in chemotherapy, attempts to incorporate surgery into the multidisciplinary treatment of unresectable pancreatic ductal adenocarcinoma with metastasis (UR-M PDAC) have emerged. Maintenance therapy with olaparib after chemotherapy including a platinum-based regimen, which inhibits the poly ADP-ribose polymerase (PARP) involved in DNA repair, was approved for UR-M PDAC with positive BRCA mutations.Case presentationA 47-year-old male patient with a high carbohydrate antigen 19-9 (CA19-9) level was diagnosed with PDAC in the pancreatic tail. Staging laparoscopy revealed occult liver metastasis. Because BRCA2 mutation was confirmed, triple combination chemotherapy with SOXIRI (S-1/oxaliplatin/irinotecan) was introduced and continued for 16 weeks, followed by 14 weeks of olaparib. After that, CA19-9 was normalized, and no obvious liver metastases of any size could be seen on imaging studies during chemotherapy. Since staging laparoscopy after chemotherapy proved that the liver metastasis had disappeared, laparoscopic distal pancreatectomy was performed, and curative resection was completed. After adjuvant chemotherapy with olaparib for 12 months, the patient is alive 36 months from his initial diagnosis and 27 months postoperatively without recurrence.ConclusionWe report a case of PDAC with liver metastasis and BRCA mutation-positivity who underwent conversion surgery and achieved long-term survival after irinotecan-based chemotherapy followed by maintenance therapy with olaparib.

MRI with DWI improves detection of liver metastasis and selection of surgical candidates with pancreatic cancer: a systematic review and meta-analysis.

To perform a systematic review and meta-analysis to evaluate if magnetic resonance imaging (MRI) with diffusion weighted imaging (DWI) adds value compared to contrast-enhanced computed tomography (CECT) alone in the preoperative evaluation of pancreatic cancer. MEDLINE, EMBASE, and Cochrane databases were searched for relevant published studies through October 2022. Studies met eligibility criteria if they evaluated the per-patient diagnostic performance of MRI with DWI in the preoperative evaluation of newly diagnosed pancreatic cancer compared to CECT. Our primary outcome was the number needed to treat (NNT) to prevent one futile surgery using MRI with DWI, defined as those in which CECT was negative and MRI with DWI was positive for liver metastasis (i.e., surgical intervention in metastatic disease missed by CECT). The secondary outcomes were to determine the diagnostic performance and the NNT of MRI with DWI to change management in pancreatic cancer. Nine studies met the inclusion criteria with a total of 1121 patients, of whom 172 had liver metastasis (15.3%). The proportion of futile surgeries reduced by MRI with DWI was 6.0% (95% CI, 3.0-11.6%), yielding an NNT of 16.6. The proportion of cases that MRI with DWI changed management was 18.1% (95% CI, 9.9-30.7), corresponding to an NNT of 5.5. The per-patient sensitivity and specificity of MRI were 92.4% (95% CI, 87.4-95.6%) and 97.3% (95% CI, 96.0-98.1). MRI with DWI may prevent futile surgeries in pancreatic cancer by improving the detection of occult liver metastasis on preoperative CECT with an NNT of 16.6. MRI with DWI complements the standard preoperative CECT evaluation for liver metastasis in pancreatic cancer, improving the selection of surgical candidates and preventing unnecessary surgeries. • The NNT of MRI with DWI to prevent potential futile surgeries due to occult liver metastasis on CECT, defined as those in which CECT was negative and MRI with DWI was positive for liver metastasis, in patients with pancreatic cancer was 16.6. • The higher performance of MRI with DWI to detect liver metastasis occult on CECT can be attributed to an increased detection of subcentimeter liver metastasis.

Oncologic resection of pancreatic cancer with isolated liver metastasis: Favorable outcomes in select patients.

Patients with pancreatic ductal adenocarcinoma (PDAC) and liver metastasis are treated with palliative chemotherapy, whereas similar patients with metastatic colorectal cancer are considered for aggressive surgery. Using an institutional database, PDAC patients undergoing liver resection for isolated metastasis were identified. Their overall survival (OS), treatment factors, and clinicopathological variables associated with survival were also evaluated. Forty-seven patients underwent curative-intent surgery for metastatic PDAC to the liver between 2000 and 2019. Median OS was 21.9months from diagnosis. Fourteen patients underwent unplanned resection of radiographically occult liver metastasis during pancreatectomy with median OS of 8.7months. On the other hand, 29 patients received systemic chemotherapy followed by planned resection; this cohort had the most favorable prognosis following aggressive surgery with median OS being 38.1months from diagnosis and 24.1months from surgery. Preoperative chemotherapy (HR=7.1; p= .002) and moderate to well differentiation of the primary tumor (HR=3.7; p= .003) were associated with prolonged survival in multivariate analysis, whereas lymph node metastases, response to preoperative therapy, number of liver metastasis, and extent of liver surgery were not. In select patients with PDAC and isolated liver metastasis, curative-intent surgery can result in meaningful survival. This aggressive approach seems most beneficial in patients following induction chemotherapy.

Survival impact of occult liver metastasis and peritoneal dissemination compared with radiologically defined distant organ metastasis in pancreatic ductal adenocarcinoma

BackgroundCharacteristics and prognoses of patients with occult metastases (OM) of pancreatic ductal adenocarcinoma (PDAC) compared with radiologically defined metastases (RM) have been rarely reported. ObjectiveWe aimed to clarify the prognosis of OM compared with RM and to establish a treatment strategy for PDAC patients with OM. MethodsThis single-institution, retrospective study evaluated patients with unresectable PDAC between 2008 and 2018. OM was defined as abdominal metastasis that was detected by staging laparoscopy or open laparotomy but not in the initial assessment of radiological images. ResultsOM and RM were identified in 135 and 112 patients, respectively. Eastern Cooperative Oncology Group Performance Status (ECOG PS), neutrophil to lymphocyte ratio (NLR), tumor diameter, and rate of local unresectability were significantly lower in the OM group. Median overall survival (OS) of OM was significantly better than that of RM (13.0 vs 8.9 months, p < 0.001). In multivariate analysis of OS, ECOG PS ≥ 1 (HR 1.64, p = 0.009), NLR ≥5 (HR 1.97, p = 0.004), carbohydrate antigen (CA) 19–9 ≥1000 (HR 1.68, p = 0.001), tumor diameter ≥40 mm (HR 1.40, p = 0.027), conversion surgery (HR 0.12, p < 0.001), and multiple lines of chemotherapy (HR 0.38, p < 0.001) were independent predictors. However, type of metastasis (OM vs RM) not an independent predictor (HR 1.10, p = 0.590). ConclusionThe prognosis of PDAC with OM was relatively better than that with RM, but general and nutritional statuses, primary tumor size and CA19-9, conversion surgery and multiple lines of chemotherapy were independent predictors but not tumor burden.

Intraperitoneal Paclitaxel Treatment for Patients with Pancreatic Ductal Adenocarcinoma with Peritoneal Dissemination Provides a Survival Benefit.

Simple SummaryPancreatic ductal adenocarcinoma (PDAC) with peritoneal dissemination is a highly lethal disease. Recently, promising activity of intraperitoneal chemotherapy with paclitaxel (i.p.-PTX) has been observed in patients with peritoneal dissemination. We conducted a retrospective comparative study to evaluate the clinical efficacy of i.p.-PTX combined with systemic chemotherapy versus standard systemic chemotherapy in PDAC patients with peritoneal dissemination. The median survival time was 10.2 months for patients in the standard therapy group and 17.9 months in the i.p.-PTX group; the difference between groups was statistically significant (p = 0.006). We have performed surgical resection (defined as conversion surgery) to responders to treatment. Conversion surgery was planned for 26% in the i.p.-PTX group and 8% in the standard therapy group. The median survival time (27.4 months) from initial treatment in patients who underwent conversion surgery was significantly longer than that in patients who did not undergo conversion surgery (11.3 months, p < 0.0001). Implementation of the i.p.-PTX regimen may improve survival in patients with PDAC with peritoneal dissemination.Background: Intraperitoneal chemotherapy using paclitaxel (i.p.-PTX) is expected to be a new therapeutic strategy for patients with pancreatic ductal adenocarcinoma (PDAC) and peritoneal dissemination. We evaluated the survival benefit of i.p.-PTX compared with standard systemic chemotherapy. Methods: Clinical data of 101 consecutive PDAC patients with peritoneal dissemination between 2007 and 2018 were analyzed. All patients were determined to have no other sites of distant organ metastasis to the lung, bone, or liver on contrast-enhanced CT imaging. Patients underwent staging laparoscopy or open laparotomy to confirm pathological evidence of peritoneal dissemination, and to exclude occult liver metastasis. Survival curves were estimated using the Kaplan–Meier method, and differences were compared using the log-rank test. Results: Forty-three patients were treated with i.p.-PTX (i.p.-PTX group) and forty-nine patients received standard systemic chemotherapy (Ctrl group). Nine patients did not receive any treatment (BSC group). The median survival time (MST) in the i.p.-PTX group was significantly longer than that in the Ctrl group (17.9 months vs. 10.2 months, p = 0.006). Negative peritoneal washing cytology was observed in 24 out of 43 patients in the i.p.-PTX group. The i.p.-PTX group tended to have a higher proportion of clinical responses than the Ctrl group (30% vs. 18%, p = 0.183). Conversion surgery was performed in 10 patients in the i.p.-PTX group and 2 patients in the Ctrl group after confirming disappearance of peritoneal dissemination with staging laparoscopy or open laparotomy (p = 0.005). The MST in patients who underwent surgical resection was significantly longer than that in patients who did not (27.4 months vs. 11.3 months; p < 0.0001). Conclusion: i.p.-PTX therapy provided improved survival in PDAC patients with peritoneal dissemination, and conversion surgery enhanced it in patients with favorable responses to chemotherapy. i.p.-PTX might become one of the treatment options to PDAC patients with peritoneal dissemination.

Gankyrin as Potential Biomarker for Colorectal Cancer With Occult Liver Metastases.

The majority of occult liver metastases cannot be detected by computed tomography (CT), magnetic resonance imaging (MRI) or other traditionally morphological imaging approaches since the lesions are too small or they have not yet formed cancer nodules. Gankyrin is a small molecular protein composed of seven ankyrin domains. In this study, the expression of Gankyrin in colorectal cancer (CRC) patients with liver metastases was investigated to determine its prognosis value. Gankyrin expression in CRC patients was initially analyzed using data from The Cancer Genome Atlas (TCGA) database and bioinformatics tools. RT-qPCR, western blotting, immunohistochemistry (IHC) and transwell migration and invasion assays were then performed to verify the expression and function of Gankyrin in CRC cell line, CRC tissues and matched non-tumor tissues of clinical patients. General clinicopathological information including TNM stage as well as preoperative and postoperative imaging results were collected. The main outcome indicator was overall survival (OS), referring to the length of time from surgery to either death or the last visit. Statistical analyses included chi-squared tests, Cox analyses, progression free survival (PFS) rates and OS rates. Elevated Gankyrin expression was confirmed in CRC patients. The upregulated Gankyrin expression was positively correlated with the progression of disease and liver metastasis in CRC patients. OS analysis revealed that prognosis was worse in CRC patients with high Gankyrin expression compared to those with low expression. CRC patients with higher Gankyrin expression also had a higher risk of occult liver metastases and a lower PFS rate. Therefore, Gankyrin can be used as a potential biomarker for early diagnosis of CRC with occult liver metastasis.

Fatal case of pancreatic panniculitis caused by occult neuroendocrine tumor in the corresponding organ: A case report and review of the published work

Pancreatic panniculitis (PP) is a rare clinical variant of subcutaneous fat necrosis, developing in patients with a variety of pancreatic diseases such as acute or chronic pancreatitis, tumors and cysts. The tumor-associated PP represents a noteworthy skin manifestation of underlying internal malignancies, also known as dermadrome. Among causative pancreatic tumors, acinar cell carcinoma is the most frequent malignancy; however, little is known about how the origin of tumor cells and progression stage of pancreatic tumors potentially contribute to the establishment of panniculitis. Here, we present a 69-year-old Japanese male case of clinically aggressive PP on the bilateral legs, whose skin lesions developed prior to the diagnosis of occult pancreatic tumor and liver metastasis. Moreover, the immunopathology of the pancreatic lesion revealed neuroendocrine tumor (NET), a rare pathological variant. Skin lesions immediately spread to the upper limbs with extensive ulcerations and necrosis, accompanied by high levels of serum lipase and elastase, but not with other pancreatic enzymes. He died 2months after the initial development of the skin lesion due to rapid deterioration of general condition. We reviewed 14 cases, including ours, of PP with NET in the pancreas thus far reported, to identify the clinicopathological characteristics regarding to what extent this rare complication could reflect the clinical course of pancreatic tumors and overall prognosis. Our published work review found that the disease has a significant male predominance (male:female, 13:1) and cases with occult pancreatic tumors died within 4months after the development of their skin lesions. Our case was the poorest prognostic outcome. This report emphasizes that dermatologists should recognize PP with NET, reflecting a fatal prognosis, and to make a prompt diagnosis.

The value of contrast-enhanced laparoscopic ultrasound during robotic-assisted surgery for primary colorectal cancer.

The aim of this study was to assess the potential clinical value of contrast enhanced laparoscopic ultrasonography (CE-LUS) as a screening modality for liver metastases during robotic assisted surgery for primary colorectal cancer (CRC). A prospective, descriptive (feasibility) study including 50 consecutive patients scheduled for robotic assisted surgery for primary CRC. CE-LUS was performed by 2 experienced specialists. Only patients without metastatic disease were included. Follow-up was obtained with contrast-enhanced CT imaging at 3 and 12 months postoperatively. Fifty patients were included; 45 patients were available for final analysis. The patients were equally distributed between stage I, II, and III according to the TNM classification system. No liver metastasis was detected during LUS and CE-LUS. CE-LUS was easy to perform and there was no complication. Follow-up revealed no liver metastasis in any of the patients. CE-LUS did not increase the detection rate of occult liver metastasis during robotic assisted primary CRC surgery. The use of CE-LUS as a screening modality for detection of liver metastasis cannot be recommended based on this study, but larger controlled studies on high-risk patients seem relevant.

Abstract B21: In a patient-derived xenograft model of occult hepatic metastasis from pancreatic cancer the MEK inhibitor trametinib delays tumor outgrowth and prolongs survival

Abstract Background: Survival for patients with pancreatic ductal adenocarcinoma (PDAC) remains dismal and the majority of patients succumb to metastatic disease. Even for those with localized PDAC, most will die from metastatic disease despite margin-negative resection and adjuvant therapy. Therefore, these patients must harbor occult metastatic PDAC at presentation. There is a compelling need for the development of preclinical models that efficiently recapitulate occult metastatic liver PDAC to identify molecular and cellular pathways that drive metastatic cellular survival and growth. Towards this aim, we have developed a PDAC model of occult liver metastases using patient-derived xenografts (PDXs) to study the growth of PDAC within the metastatic environment and evaluated the effect of MEK inhibitor therapy on tumor progression. Methods and Results: Extensively characterized patient-derived KRAS-mutant (Tumors 608, 366, and 654) and wild-type (Tumors 738 and 215) PDAC cells were transduced with luciferase and injected into the spleens of athymic, nude mice, allowed to circulate for 10 minutes, after which a splenectomy was performed. To evaluate metastatic cell growth kinetics in the liver, tumor burden was monitored by sequential bioluminescent imaging. All mice exhibited defined phases of survival/dormancy and the proliferative outgrowth; however, differential kinetics were observed for each tumor cell line. To evaluate the effect of MEK inhibition of occult metastatic PDAC cells in the liver, Tumor 608 cells were injected and mice either received the MEK inhibitor trametinib (0.3 mg/kg, daily) or vehicle control beginning 48 hour post-injection. Trametinib significantly reduced metastatic tumor burden, delayed time to proliferative outgrowth, and greatly prolonged survival as compared to control (med. survival: 114 vs. 43 days, p&amp;lt;0.001). In contrast, in an orthotopic model with 250-500 mm3 tumors trametinib led to no inhibition in tumor growth for Tumor 608. To characterize metastatic PDAC cells within the liver after similar treatment conditions, we isolated cells from the liver 48 and 72 hours, 10 and 28 days after splenic injection. Tumor 608 cells were injected and metastatic PDAC cells were retrieved from the liver at the aforementioned timepoints post injection using magnetic column separation with human EpCAM (CD326)-targeted magnetically labeled microbeads. Flow cytometric analyses of retrieved cells revealed that decreased cellular markers of proliferation and increased caspase-3 cleavage correlated with decreased tumor burden observed at these timepoints in mice treated with trametinib. Conclusions: In a model of occult liver metastatic PDAC, patient-derived tumors exhibit different growth kinetics in the liver environment. Furthermore, MEK inhibition with trametinib decreased metastatic cellular proliferation, increased apoptosis, prolonged metastatic tumor outgrowth, and significantly increased survival of mice harboring occult hepatic metastases from PDAC. This efficacy of single agent trametinib is unique to occult metastatic disease and is not seen in orthotopic models of advanced, established pancreatic tumors. This finding illustrates the importance of using specific preclinical models that best recapitulate the clinical aspects of patients who will be evaluated in future clinical trials. Further investigation into the cellular and molecular factors promoting PDAC cell survival within the hepatic microenvironment utilizing this model will lead to development of rational therapeutic strategies for patients with occult metastatic disease. Citation Format: Timothy Newhook, James Lindberg, Sara Adair, J. Thomas Parsons, Todd W. Bauer. In a patient-derived xenograft model of occult hepatic metastasis from pancreatic cancer the MEK inhibitor trametinib delays tumor outgrowth and prolongs survival. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B21.

Abstract 4040: The MEK inhibitor trametinib delays tumor outgrowth and prolongs survival in a patient-derived mouse model of occult hepatic metastatic pancreatic cancer

Abstract Background: Survival for patients with pancreatic ductal adenocarcinoma (PDAC) remains dismal and the majority of patients succumb to metastatic disease. Even for those with localized PDAC, most will die from metastatic disease despite margin-negative resection and adjuvant therapy. Therefore, these patients must harbor occult metastatic PDAC at presentation. We have developed a PDAC model of occult liver metastases using patient-derived xenografts (PDXs) to study the growth of PDAC within the metastatic microenvironment of the liver and evaluated the role of KRAS-MEK-ERK signaling on tumor progression. Methods and Results: Extensively characterized low passage, patient-derived KRAS-mutant (Tumors 608, 366, and 654) and wild-type (Tumors 738 and 215) PDAC cells expressing luciferase were injected into the spleens of athymic, nude mice and allowed to circulate for 10 minutes, after which a splenectomy was performed. To evaluate metastatic cell growth kinetics in the liver, tumor burden was monitored by sequential bioluminescent imaging. Each of the PDX tumors exhibited a characteristic and reproducible time to proliferative outgrowth ranging from 20 days (Tumor 608) to greater than 100 days (Tumor 654). To evaluate the role of KRAS signaling in maintaining dormant cell survival and proliferative outgrowth, tumor 608 cells were injected and mice were treated with the MEK inhibitor trametinib (0.3 mg/kg, daily) or control beginning 48 hours post-injection. Trametinib significantly reduced metastatic tumor burden, delayed time to proliferative outgrowth, and greatly prolonged survival as compared to control (med. survival: 114 vs. 43 days, p&amp;lt;0.001). In contrast, in an orthotopic model with 250-500 mm3 tumors trametinib led to limited inhibition in tumor growth for Tumor 608. To characterize these PDAC cells, we isolated Tumor 608 cells from the liver 48 and 72 hours, 10 and 28 days after splenic injection using magnetic column separation with human EpCAM (CD326)-targeted magnetically labeled microbeads. Flow cytometric analyses of retrieved cells revealed that decreased cellular markers of proliferation and increased PARP cleavage correlated with decreased tumor burden observed at these timepoints in mice treated with trametinib. Conclusions: Using a model of occult liver metastatic PDAC, patient-derived tumors exhibited characteristic, albeit different growth kinetics in the liver microenvironment. Further, inhibition of KRAS-MEK-ERK signaling with the MEK inhibitor trametinib decreased metastatic cellular proliferation, increased apoptosis, prolonged metastatic tumor outgrowth, and significantly increased survival. Further investigation into factors promoting PDAC cell survival within the hepatic microenvironment will lead to development of rational therapeutic strategies for patients with occult metastatic PDAC. Citation Format: Timothy Eric Newhook, James M. Lindberg, Sara J. Adair, J. Thomas Parsons, Todd W. Bauer. The MEK inhibitor trametinib delays tumor outgrowth and prolongs survival in a patient-derived mouse model of occult hepatic metastatic pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4040. doi:10.1158/1538-7445.AM2014-4040

Doppler perfusion index and contrast-enhanced ultrasound in patients with colorectal cancer liver metastases.

To assess the value of the Doppler perfusion index (DPI) and contrast agent for the detection of liver metastases in patients with colorectal cancer. DPI was measured in 18 patients with colorectal cancer liver metastases and 18 control subjects. Sixteen patients were underwent contrast-enhanced ultrasonography (CEUS). patients with liver metastases had significantly greater DPI than control group (0.39 +/- 0.10 vs. 0.19 +/- 0.07, p < 0.05). Sixteen liver metastasis lesions underwent a rapid wash-out of contrast agent during the portal venous phase followed by a complete wash-out of SonoVue during the sinusoidal phase and were differentiated as "fast-in and fast-out" contrast enhancement patter. Another 3 lesions which were not found by baseline ultrasonography were detected to be enhancement defects at sinusoidal phases by CEUS. DPI is a sensitive index in detection of colorectal liver metastases; if used combined with contrast agent, much more occult liver metastasis would be detected by ultrasonography.

Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Targeting occult metastatic disease: A hematogenously derived xenograft model of human pancreatic tumor growth in the murine liver.

198 Background: Most pancreatic cancer patients will die following surgery due to recurrent metastatic disease. Thus, better systemic therapies are needed to treat occult metastases to improve survival. We have developed a model of occult liver metastasis from pancreatic cancer in order to evaluate novel treatment strategies. Methods: Pancreatic cancer cells (MAD 09-366, 08-608, MPanc96) transduced with green fluorescent protein (GFP) and luciferase were injected into the spleens of athymic, nude mice to generate hepatic metastases. Ninety-six hours after injection, tumor-bearing mice were treated with MEK1/2 inhibitor (trametinib, 0.3mg/kg, daily), gemcitabine (100mg/kg, twice weekly), or vehicle control. Sequential bioluminescence imaging, flow cytometry, and histologic evaluation were used to assess hepatic tumor growth and behavior. Results: All injected cell lines generated hepatic metastases. Different cell lines exhibited different growth kinetics. MPanc96 injected mice demonstrated a 64% decrease in average luminescence from 6 to 72 hrs after injection followed by a 146-fold increase from 72hrs until sacrifice at 21 days. Extensive liver metastases were noted at necropsy. Flow cytometry analysis of digested mouse livers following MPanc96 injection revealed rapid clearance followed by sharp outgrowth of tumor cells that mirror the bioluminescent imaging data. MPanc96 injected mice treated with trametinib exhibited significant hepatic tumor growth inhibition relative to gemcitabine and control treated mice. At 21 days, trametinib treated mice demonstrated a 14.9-fold increase in average luminescence while on treatment compared to an 82.5-fold increased for gemcitabine treated mice (p = 0.028) and a 195.5-fold increase for control mice (p = 0.027). Conclusions: This in vivo model of pancreatic liver metastases has proven effective in assessing treatment effects on pancreatic metastatic growth. Trametinib appears to be a superior agent to gemcitabine at inhibiting metastatic pancreatic tumor growth and its effectiveness will be evaluated using this model with additional patient-derived tumor cell lines.

Impact of F18‐fluorodeoxyglycose positron emission tomography/computed tomography on the management of resectable pancreatic tumours

Positron emission tomography/computed tomography (PET/CT) using F18-fluorodeoxyglucose has been shown to be valuable in the management of malignant disease. The aim of this study is to investigate the impact of this technique on the management of patients with resectable pancreatic tumours. Thirty-six patients with 37 potentially resectable pancreatic tumours on diagnostic CT imaging underwent PET/CT scans. Operative findings, histological reports and/or clinical follow-up served as standard of reference. The impact of PET/CT on patient management was estimated by calculating the percentage of patients whose treatment plan was altered due to PET/CT. Pancreatic adenocarcinoma was diagnosed in 30 patients, neuroendocrine tumours in 3, mass-forming pancreatitis in 3 and serous cystadenoma in 1. The median standard uptake (max) value was 5.0 (range 2.2-12.0). Sensitivity and specificity of detecting extrapancreatic metastatic disease were 73% and 100%, respectively. Three occult liver metastases were detected at laparotomy following negative PET/CT. PET/CT findings influenced the management of 8 (22%) patients - 3 with liver metastases, 3 with bone metastases, 1 with lymph node metastases and 1 by identifying the benign appearance of the pancreatic tumour. PET/CT achieves a significant diagnostic impact in detecting extrapancreatic metastatic disease. F18-fluorodeoxyglucose PET/CT appears to be useful in assessing suspicious pancreatic masses.

Doppler hemodynamic study in evaluation of liver metastases

The color Doppler spectral analyses can be usefully in description of the liver circulation as one from non-invasive methods. Using color Doppler B mod ultrasound (Toshiba Core Vision) with duplex ultrasound we founded difference in liver circulation between patients with colon cancer and liver metastasis in comparison with those without metastases. We suggested this non invasive method for early detection of occult liver metastasis presence.

The routine use of intra‐operative ultrasound in patients with colorectal cancer improves the detection of hepatic metastases

Up to one fifth of patients with carcinoma of the colon have occult liver metastases at the time of presentation. Intra-operative hepatic ultrasonography might improve disease staging. We report the use of intra-operative ultrasonography (IOUS) in routine clinical practice over a five-year period. Seventy-six patients with colorectal carcinoma (F 21, M 55) of median age 67 years (range 43-89 years) for whom full data were available had IOUS at the time of colonic resection. All patients had had a computerized tomography (CT), magnetic resonance imaging (MRI) or ultrasonography (USS). Of 76 patients, 10 had a Dukes A, 32 had a Dukes B and 34 a Dukes C carcinoma. In 20 patients IOUS detected lesions not seen on pre-operative scanning including 11 metastases (one suitable for resection), seven benign hepatic cysts and two were benign hepatic nodules. Forty-nine patients have remained free of disease and 25 have died with systemic disease (mean survival 10 months, range 2-24 months). In the seven patients diagnosed as having hepatic cysts at IOUS two have died of systemic disease. The remaining patients (n=12) who died with systemic disease had a negative IOUS. IOUS increases diagnostic yield but a significant proportion of patients with occult hepatic metastases are not detected. IOUS improves disease staging in some patients refining the indications for adjuvant therapy and enhancing the estimate of prognosis and improving decision-making.

Tuech et al.: Detection of occult liver metastases in colorectal cancer by measurement of biliary carcinoembryonic antigen concentration: a prospective study

Tuech et al.: Detection of occult liver metastases in colorectal cancer by measurement of biliary carcinoembryonic antigen concentration: a prospective study

Regression of primary murine colon cancer and occult liver metastasis by intralesional injection of lyophilized preparation of insect cells producing murine interferon-β

We investigated the efficacy of interferon (IFN)-beta therapy against colon cancer using a novel approach mediated by a lyophilized preparation of High 5 (H5) insect cells transduced with a recombinant baculovirus encoding murine IFN-beta (H5BVIFN-beta). The orthotopic model of CT-26 murine colon cancer in syngeneic BALB/c mice was used in the study, and H5BVIFN-beta was intratumorally delivered. Two injections of H5BVIFN-beta (on days 14 and 21 after tumor cell implantation), but not lyophilized H5 cells (control), significantly reduced the size of cecal tumors and the number of liver metastases. Immunohistochemical analysis revealed that cecal tumors injected with saline or H5 contained many proliferating cells (PCNA+) and few apoptotic cells (TUNEL+). In sharp contrast, H5BVIFN-beta-treated tumors contained fewer PCNA+ cells and significantly more TUNEL+ cells. The H5BVIFN-beta-treated tumors were infiltrated by a large number of CD8+ and F4/80+ cells and expressed a high level of inducible nitric oxide synthase (iNOS). Immunofluorescent double staining technique demonstrated a significant increase of apoptotic endothelial cells (CD-31+/TUNEL+) in tumors treated with H5BVIFN-beta. In conclusion, the data show that intralesional injections of H5BVIFN-beta can suppress the progressive growth of established orthotopic tumors of colon cancer cells and occult liver metastasis. The therapeutic effects directly correlate with destruction of tumor vasculature.

Interleukin-12 administration is more effective for preventing metastasis than for inhibiting primary established tumors in a murine model of spontaneous hepatic metastasis.

The effect of interleukin-12 (IL-12) on tumor growth at the primary site and its therapeutic efficacy against metastasis were examined using a model of spontaneous hepatic metastasis. IL-12 was peritumorally injected into RL male1 tumor-bearing BALB/c male mice at the different tumor stage. Striking inhibition of hepatic metastasis in both athymic and euthymic mice was induced by the administration of IL-12 irrespective of the stage of tumor progression. In contrast, IL-12 failed to produce any antitumor effect in athymic mice which lack conventional T cells. These results suggest that the antitumor effect of IL-12 is mediated mainly by T cells, and that the antimetastatic effect is mediated mainly by natural killer (NK) and/or NKT cells. Next we examined the direct effect of IL-12 on these cells. IL-12-induced T-cell proliferation was remarkably augmented in the early stage, then decreased dramatically in the advanced stage, while IL-12-induced cytotoxic activity, mediated by NK and NKT cells, was not attenuated even in the advanced stage. This dissociation in IL-12 responsiveness appeared to be the reason for the remarkable antimetastatic effect but insufficient antitumor effect of IL-12 in the advanced stage. The findings of this study support the clinical use of IL-12 for immunotherapy against either occult or evident liver metastasis.

Oncological problems in pancreatic cancer surgery.

Despite the development of more sophisticated diagnostic techniques, it remains difficult to detect pancreatic carcinoma in the early stage. The resection rate has been increasing due to recent advances in surgical techniques and the application of extensive surgery. However, the postoperative prognosis has been poor due to commonly occurring liver metastasis. Recent molecular-biological studies have been clarifying occult liver metastasis and systemic disease in pancreatic cancer. This paper will review our experience and several problems in pancreatic cancer surgery.