Prognostic relevance of serial endoscopic ultrasound after chemoradiation in esophageal cancer.

The objective of this study is the feasibility of sequential endoscopic and endosonographic measurement of locoregional tumor load for the prediction of tumor recurrence in patients after neoadjuvant or definitive chemoradiotherapy, treated in curative intent for locally advanced esophageal carcinoma. In 67 patients with esophageal cancer, serial endoscopic ultrasound was performed before and after neoadjuvant (25) or definitive (42) chemoradiotherapy. Rate of complete endoscopic and endosonographic tumor response, reduction in tumor length or circumferential tumorous extension, maximal tumor thickness, lymph node size, and endosonographic uT- and uN-stage shift was measured. Results were correlated with tumor recurrence rate. After chemoradiotherapy, endosonography revealed a complete response of the primary tumor in 27 patients, and complete resolution of suspicious lymph nodes in 24 patients. According to uTN-stage, 43 patients showed a therapeutic response, with stage shift to a lower tumor stage. In patients with macroscopic residual disease, mean tumor thickness decreased from 13 to 9 mm, with nine patients presenting with a decrease of >50%. Mean tumor length decreased from 5.6 to 4.6 cm, with 10 patients showing a decrease of >50%. Mean lymph node size decreased from 14.5 to 12 mm, with four patients having a reduction in size of >50%. Tumor response was generally more pronounced after definitive than after neoadjuvant chemoradiotherapy. During follow-up, 33 patients developed a tumor recurrence. None of the endoscopic and endosonographic parameter analyzed was predictive for patient's prognosis, irrespective of the kind of chemoradiotherapy (neoadjuvant or definitive). Sequential measurement of locoregional tumor load with endoscopic ultrasound before and after chemoradiotherapy is not suitable for the prediction of tumor recurrence risk.

Improvement in advanced pancreatic cancer survival with novel chemotherapeutic strategies - experience of a community based hospital.

Background: New chemotherapeutic strategies for locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) have been shown to improve survival in randomized clinical trials. Little is known about the use of such chemotherapies and their benefit in community-based hospitals. This retrospective study analyzes the overall survival of these patients under "real life conditions" before and after the introduction of FOLFIRINOX in 2011. Methods: We retrospectively identified consecutive patients with PDAC who were treated at our hospital from 2011 to June 2014 (2011+ cohort) and 2004 to 2010 (historical cohort). Patients were included if PDAC was diagnosed in a locally advanced or metastatic state and at least 1 cycle of chemotherapy was given. Survival was assessed until April 2016. Patients with FOLFIRINOX were further analyzed regarding drug administration and side effects. Results: 128 patients met the inclusion criteria. Of the 74 patients in the historical cohort, 62 patients received Gemcitabine. Of the 54 patients diagnosed between 2011 and June 2014, 28 patients received FOLFIRINOX and 22 Gemcitabine as the first-line chemotherapy. Only 34 % of the patients in the historical cohort received a second-line chemotherapy in comparison to 69 % in the 2011+ cohort. Median overall survival (OS) showed a survival of 13.1 months (95 % CI; 11.6 - 14.5) for the 2011+ cohort compared to 9.6 months (95 % CI; 6.1 - 13.1) in the historical group. Conclusion: This study shows a marked improvement in survival of patients diagnosed with locally advanced or metastatic PDAC in a community-based hospital during the past 4 years. The most likely reasons are the use of new polychemotherapies like FOLFIRINOX and the use of second-line chemotherapy.

Ultrasound in radioembolization induced liver disease (REILD).

BACKGROUND: REILD (radioembolization-induced liver disease) is a rare complication after SIRT (selective internal radiotherapy) of the liver. The diagnosis is based on a combination of clinical signs and symptoms, laboratory values, and MRT findings. Data about sonographic signs associated with REILD are lacking. In this report, we describe sonographic changes in two female patients with REILD. CASE REPORTS: Patient 1: a 34-year-old woman with colorectal carcinoma liver metastasis. Two weeks after SIRT, the patient developed histology-proven REILD. Abdominal ultrasound revealed pronounced hepatomegaly, with inhomogeneous, slightly hyperechoic parenchyma without attenuation. The well-known metastasis could not be delineated easily. Liver veins were compressed, with ill defined borders, and flattened biphasic blood flow in duplex sonography. Signs of portal hypertension with ascites, and splenomegaly were present. A therapy with diuretics, heparin, steroids, and ursodesoxycholic acid was introduced, and the patient recovered. After seven weeks, the ascites had resolved, and the liver parenchyma returned to normal echogenicity. Furthermore, the metastases in both lobes were clearly visible again. The liver veins were well delineated, normal sized, with regular triphasic blood flow in duplex sonography, but splenomegaly persisted. Patient 2: a 58-year-old women with recurrent multifocal peripheral cholangiocarcioma. Abdominal ultrasound 5 weeks after SIRT revealed a slightly increased echogenicity of the liver. Liver veins showed slightly irregular borders with biphasic flow pattern. In contrast to patient no.1, liver metastases could still be delineated easily. Ascites or splenomegaly were not present. Laboratory parameters and MRT findings were consistent with a diagnosis of mild REILD. Liver biopsy was not performed. No specific therapy was introduced. Five weeks later, the liver parenchyma became more homogeneous again, and the liver veins normalized with smooth vessel borders, but still flattened biphasic flow pattern. CONCLUSION: Transient hepatomegaly, with inhomogeneous hyperechoic parenchyma without attenuation, and compressed, ill delineated liver veins, with monophasic or flattened biphasic blood flow, are typical sonographic findings in REILD. In addition, common signs of portal hypertension can be present. Liver alterations and ascites resolve parallel with clinical improvement. Splenomegaly can persist.

Mediastinitis after EUS-FNA in a patient with sarcoidosis - case report with endosonographic features and review of the literature.

BACKGROUND: EUS-FNA of lymph nodes is believed to harbour no risk of serious complications. However, recently, a case series of mediastinal abscess formation after EUS-FNA in patients with sarcoidosis has been published. Here, we describe a patient with sarcoidosis and mediastinitis after EUS-FNA. CASE REPORT: Two years before EUS-FNA, the patient with a history of sarcoidosis, was operated because of esophageal adenocarcinoma. Due to progredient mediastinal lymphoma, we performed EUS-FNA to exclude tumor recurrence. 30 hours later, the patient developed general weakness, musculoskeletal pain, non-productive cough, and mild dysphagia. Ten days later, the patient was admitted with fever and thrombocytopenia. A CT scan showed a mediastinal mass without liquid areas, but small deposits of air. Meropenem, steroid, and low-dose heparin were started. The fever resolved after 24 hours, CRP, as well as coagulatory parameters returned to normal levels after 5 days. Endoscopic ultrasound revealed an inhomogeneous, slightly hyperechoic, mediastinal mass. The lymph nodes were partly dislodged, and partly embedded into this mass with a rounded shape and large hyperechoic center. Vascularization was not increased, liquid areas, or inclusions of gas were not present. A follow-up examination 6 weeks later revealed complete resolution of the mass. CONCLUSION: EUS-FNA, but not EBUS-FNA, seems to be associated with an increased infectious risk in patients with sarcoidosis. Endosonographic features include inhomogeneous, mass-forming mediastinal infiltration, and swelling of lymph nodes with hyperechoic central parts. In cases of suspected sarcoidosis, EBUS-FNA should be preferred. EUS-FNA, probably with antibiotic prophylaxis, should only be done after a non-diagnostic bronchoscopic work-up.

Contrast-enhanced ultrasound (CEUS) for differentiating between hepatocellular and cholangiocellular carcinoma.

PURPOSE: HCC and CC are the most common primary malignancies of the liver. There is only minimal evidence as to whether these two entities can be reliably differentiated by contrast-enhanced ultrasound. MATERIALS AND METHODS: We retrospectively analyzed the CEUS pattern of 39 patients with HCC, 11 patients with intrahepatic cholangiocarcinoma (ICC), 3 patients with Klatskin tumor, and 4 patients with gallbladder carcinoma. CEUS was performed using a standardized protocol (low MI, SonoVue®) with documentation of the arterial, portal-venous, and late phase. Besides the contrast enhancement compared to the adjacent normal liver tissue in every phase, the specific contrast pattern during the arterial phase (complete filling, incomplete filling of different grade, rim sign) was analyzed. RESULTS: Most HCC and ICC showed hyperenhancement during the arterial phase, with hypoenhancement or isoenhancement in the portal-venous and late phase. Hyperenhancement during the portal-venous phase was only observed in some cases of HCC, but not in ICC. In the case of arterial hyperenhancement, HCC showed complete filling more often than ICC. In the case of incomplete filling, the area of contrast-enhanced tumor in most HCCs was larger than in ICCs. A rim sign was present in only less than half ICCs, but in no HCCs. CONCLUSION: HCC and ICC differ to some extent in their CEUS enhancement pattern. Incomplete arterial hyperenhancement is more often seen in ICC than in HCC. A rim sign seems to be specific for ICC, but is only rarely present. However, in a case-to-case decision, due to overlapping characteristics, a reliable differentiation between the two tumor types by CEUS alone is very often not possible.

Role of ultrasonography for monitoring tumor necrosis after chemotherapy.

Ultrasonography for monitoring the response of malignant liver lesions to regional therapy offers several advantages. The instrument is easy to transport and can be used in intensive care units, so it is the procedure of choice within the first few days after invasive techniques, such as isolated liver perfusion, to demonstrate tumor response. Changes in size or in the sonomorphological pattern of liver lesions early after therapy indicate a therapeutic response. There are no data available on the sensitivity of ultrasonography for differentiating the necrotic and viable parts of the tumor. If information on the extent of tumor necrosis is crucial for decisions on further treatment of a patient, ultrasonography should be complemented with other techniques, such as fine-needle puncture or imaging techniques such as computed tomography, nuclear magnetic resonance, and single photon emission computed tomography. The contribution of more recent developments in ultrasonography, such as color Doppler analysis of intratumoral blood flow or three-dimensional ultrasonography, for monitoring tumor necrosis remains to be evaluated.

Carotenoids are decreased in biopsies from colorectal adenomas.

UNLABELLED: A lower intake of carotenoids is associated with an increased risk of colorectal cancer. In order to take advantage of the chemopreventive properties of carotenoids, it is necessary to determine carotenoid concentration at the target tissue. As early stages in the adenoma-carcinoma sequence of colorectal cancer might be susceptible to chemoprevention, we sought to determine carotenoid concentrations in biopsies from colorectal adenomas. METHODS: Biopsies from colorectal adenomas and non-involved mucosa were taken from seven patients. For controls, biopsies were obtained from the ascending and descending colon of patients without polyps (n = 5). Concentration of carotenoids (alpha-, beta-carotene, lutein, lycopene, zeaxanthin, beta-cryptoxanthin) were determined by optimizing gradient HPLC-analysis. Results are expressed as pmol/microg DNA. RESULTS: Except for alpha-carotene, all carotenoids could reliably be detected in all specimens. In control patients carotenoid concentrations were highest in the ascending colon, being followed by the descending colon and non-involved mucosa from polyp-carriers. In colorectal adenomas all carotenoids were significantly reduced as compared to-non-involved mucosa (beta-carotene: 0.37 vs 0.19, P<0.03; lycopene: 0.34 vs 0.21, P<0.06, beta-cryptoxanthin: 0.14 vs 0.09, P<0.03, zeaxanthin: 0.18 vs 0.09, P<0.02; lutein: 0.18 vs 0.13,P <0.02). CONCLUSION: All carotenoids investigated are reduced in colorectal adenomas, suggesting that mucosal carotenoids could serve as biomarkers for predisposition to colorectal cancer. Moreover, anti-tumor activity exerted by carotenoids is limited due to mucosal depletion. We speculate that supplementation of a larger array of carotenoids might be beneficial for patients with colorectal adenoma.

Medical prophylaxis of haemorrhage from oesophageal varices in patients with liver cirrhosis.

Haemorrhage from oesophageal varices is a life-threatening event in patients with liver cirrhosis. About 40-80% of patients surviving the first bleeding suffer a recurrence within 1 year. This high recurrence rate substantially contributes to the mortality in patients with liver cirrhosis. Therefore, various treatment regimens in both primary and secondary prophylaxis were studied. Most experience in medical primary prophylaxis was collected with beta-blockers, mainly propranolol. Treating patients with oesophageal varices with propranolol significantly reduces the incidence of first variceal bleeding. However, the effect on mortality is marginal, and primary prophylaxis is generally not recommended in these patients. Several studies support the hypothesis that medical prophylaxis with beta-blockers is more effective in reducing the rate of first oesophageal bleeding in patients with a high risk of haemorrhage, such as those with very large varices with red spots. A score to assess an individual patient's risk of variceal bleeding would be helpful, but until such a score has been validated, no general rule for this treatment decision can be given. In secondary prophylaxis, both beta-blockers and endoscopic therapy (sclerotherapy or ligation of the varices) are effective in lowering the rate of rebleeding. However, the effect on mortality was not significant in most studies. Several studies comparing the efficacy of medical prophylaxis and endoscopic treatment showed advantages of the endoscopic therapy with a greater reduction in recurrent bleeding episodes. However, medical prophylaxis with beta-blockers has the important advantage of being immediately effective, whereas endoscopic procedures provide the best protection against recurrent bleeding after complete obliteration of the varices. Therefore, in the first weeks and months of endoscopic therapy, additional treatment with beta-blockers may further reduce the risk of rebleeding. Only half of all studies on this topic reported a significant advantage with this combined therapy. Therefore, it seems reasonable to restrict this approach to patients with a high risk of rebleeding, such as patients with large sclerotherapy-derived oesophageal ulcers.

High-dose intravenous vitamin C is not associated with an increase of pro-oxidative biomarkers.

OBJECTIVE: High-dose vitamin C therapy might mediate beneficial clinical effects by counteracting reactive oxygen species. However, concerns are raised whether this approach might provoke diametrical (ie pro-oxidative) effects. The objective was to determine ascorbyl free radical (AFR) concentrations and potential variables of pro-oxidative damage. DESIGN: Crossover study; six healthy males received daily infusions of 750 or 7500 mg vitamin C for six consecutive days. Fasting concentrations of vitamin C and AFR were determined daily. On day 1, concentrations of vitamin C and AFR were measured at 0.25, 0.5, 1, 2, 4 and 8 h post infusion. Plasma concentrations of thiobarbituric acid-reactive substances (TBARS), tocopherol and urine concentrations of 8-oxoguanosine were determined on days 1 and 6. RESULTS: Kinetic studies on day 1 showed that concentrations of vitamin C and AFR displayed parallel dose- and time-dependent kinetics and elimination was highly efficient. Vitamin C and AFR fasting concentrations on days 2-6 were slightly above the baseline, suggesting new, stable steady states. TBARS decreased in both groups, whereas tocopherol and 8-oxoguanosine concentrations remained unchanged. CONCLUSION: Kinetics of AFR largely depend on plasma vitamin C concentrations and AFR is eliminated efficiently. Our data do not support induction of pro-oxidative effects in healthy volunteers given intravenous high-dose vitamin C. SPONSORSHIP: Pascoe Pharmazeutische Präparate GmbH, Giessen, Germany.

Beta-blockers for prophylaxis of bleeding from esophageal varices in cirrhotic portal hypertension. Review of the literature.

Hemorrhage from esophageal varices is a life-threatening event in patients with liver cirrhosis. About 40% to 80% of the patients surviving the first bleeding suffer from a recurrence of variceal bleeding within one year. This high recurrence rate substantially contributes to the mortality in patients with liver cirrhosis. Therefore, various treatment regimens both in primary and secondary prophylaxis were studied. Most experience in medical primary prophylaxis was collected with beta-blockers, mainly propranolol. Treating patients with esophageal varices with propranolol significantly reduces the incidence of first variceal bleeding. However, the effect on mortality is marginal, and primary prophylaxis is generally not recommended in these patients. Several studies support the hypothesis, that medical prophylaxis with beta-blockers is more effective in reducing the rate of first esophageal bleeding in patients with a high risk of hemorrhage, such as the presence of very large varices with red spots. A score to assess the individual risk of a given patient to suffer a variceal bleeding would be helpful. As long as such a score is not validated, no general rule for this treatment decision can be given. In secondary prophylaxis, both administration of beta-blockers and endoscopic therapy (sclerotherapy or ligation of the varices) are effective in significantly lowering the rate of re-bleeding. However, the effect on mortality was not significant in most studies. Several studies comparing the efficacy of medical prophylaxis and endoscopic treatment showed advantages of the endoscopic therapy with a greater reduction in recurrent bleeding episodes. However, medical prophylaxis with beta-blockers has the important advantage of being immediately effective whereas endoscopic procedures provide the best protection against recurrent bleeding after complete obliteration of the varices. Therefore, in the first weeks and months of endoscopic therapy, the additional treatment with beta-blockers may further reduce the risk of re-bleeding. Only half of all studies on this topic reported a significant advantage of such a combined therapy. Therefore, it seems reasonable to restrict this approach to patients with a high risk of re-bleeding such as patients with large sclerotherapy-derived esophageal ulcers.

The influence of the spatial structure of focal hepatic lesions on volume measurements performed with two and three-dimensional sonography using the ellipsoid formula.

A total of 63 patients with localized hepatic lesions were examined using two and three-dimensional sonography. The tumor volumes were calculated by means of the ellipsoid formula, compared with an experimentally determined reference volume and subsequently differentiated into correct and erroneous measurements according to the WHO criteria for tumor volumes. In a second test series, an analysis of the tumor shapes was carried out using parallel projections. It could be seen that 65% of the erroneous measurements resulted from the use of the ellipsoid formula, a procedure which is used to determine the volume of hepatic lesions. In the third part of this study, it was found that findings which are difficult to measure are frequently not recognized as such by the investigator making use of two-dimensional sonography. As a consequence, the volume measurements of focal hepatic lesions in oncology patients being considered for particular therapies should preferably be carried out with the aid of planimetric measurements rather than with the use of the ellipsoid formula.

Colorectal cancer: A rational follow-up program adapted to patient's individual risk of recurrence and review of the literature.

Follow-up programs in patients with colorectal cancer have been criticized concerning their efficacy. Uniform programs for all patients as practised during the last decade did neither influence survival nor did they improve the number of secondary tumor resection for cure. Therefore we developed a follow-up program that stratifies according to patient s healthiness, residual tumor and the expected risk of tumor recurrence. Patients were divided into three categories: patients with low or high risk of tumor recurrence and patients treated for palliation. By such an approach the number of apparative examinations and the cost of a follow-up program could be theoretically reduced by more than 50%.

[3-dimensional sonography for volume determination of liver tumors--report of initial experiences]. / Dreidimensionale Sonographie zur Volumenbestimmung von Lebertumoren--ein erster Erfahrungsbericht.

In a clinical trial the accuracy of volumetry by use of three-dimensional ultrasound (3-D-US) in comparison to three-dimensional computer tomography (3-D-CT) was evaluated. Overall, 42 patients with focal hepatic lesions were investigated with 2-D- and 3-D ultrasound. In 11 patients additional computerized tomographic arterial portography using spiral technique was performed. The volumes of the lesions were calculated using the ellipsoid formula (for 2-D- and 3-D-US) as well as with a planimetric reconstruction for 3-D-US and 3-D-CT. In addition the intra- and inter-investigator variability of 3-D ultrasound was determined. The volume of the investigated liver lesions (planimetric reconstruction with 3-D ultrasound) ranged between 1.5 cm3 and 1231 cm3 with a mean volume of 155 cm3 and a median volume of 68 cm3. The deviation of 2-D-US vs 3-D-CT was -62% to +68%, in the case of 3-D-US (ellipsoid) vs 3-D-CT it was -28% to +9%, and for 3-D-US (planimetry) vs 3-D-CT it was -21% to +9%. The concordance index kappa was 0.886, showing very good agreement between the two investigators. The intra-investigator variability was 5%. Our data show that volume measurement by use of 3-D-US in independent of the investigator. With regard to accuracy of volume measurements 3-D-US is comparable to 3-D-CT but more precise than 2-D-US. These results indicate that 3-D-US may be applied in the follow-up of tumor patients as an alternative diagnostic procedure to computer tomography. In addition 3-D-US might be useful in planning liver resections by virtue of better evaluation of the volume of the liver tissue remaining after resection and better visualization of the topography of liver tumors and major hepatic vessels.

[Validity of endoscopic ultrasonography-guided fine needle aspiration of mediastinal and abdominal lymph nodes in daily clinical practice]. / Endosonographisch gesteuerte Feinnadelpunktion bei mediastinalen und abdominellen Lymphknotenvergrößerungen.

BACKGROUND: According to recent clinical trials, EUS-FNA has a high diagnostic yield in case of mediastinal and abdominal lymphadenopathy. However, it is questionable, if the results of centers of excellence can be maintained in daily clinical practice. METHODS: We retrospectively analyzed the results of 141 EUS-FNP in 121 patients (female 25, male 86; mean age 61,5 years, range 22-87) of 119 mediastinal and 22 abdominal lymph nodes, performed under routine conditions in daily clinical practice in a community hospital. Histopathological examination of operative specimens or clinical follow-up served as gold standard. RESULTS: In 124/141 (80 %) of cases, adequate specimens could be obtained, irrespective of lymph node size. During follow-up, the rate of adequate specimens obtained increased from 77 % (2002-2006) to 98 % (2007-2010). Sensitivity and specifity for the diagnosis of malignancy was 77 and 100 % (diagnostic accuracy 92 %). During follow-up, a relevant learning curve could be observed with a significant increase in sensitivity (72 to 80 %). CONCLUSION: In comparison to the results of centers of excellence, our diagnostic accuracy is slightly inferior. However, even in daily routine praxis, EUS-FNP is a safe and accurate method of sampling mediastinal and abdominal lymph nodes.

[The change of pathology in the era of personalized medicine using the example of discordant KRAS mutational status in metastasized colorectal carcinoma]. / Der Wandel der Pathologie in der Ära der personalisierten Medizin. Eine Übersicht am Beispiel des diskordanten KRAS-Mutationsstatusbeim metastasierten kolorektalen Karzinom.

Modern pathology has developed from "omega" to "alpha" and is vital for therapy and follow-up of tumor treatment today. Pathology has a key role as part of personalized medicine. It is possible to intervene therapeutically into the molecular genetic intricacy of tumors by establishing predictive biomarkers with corresponding tumor therapeutic agents.By identifying the KRAS mutational status at the metastasized colorectal carcinoma, a statement about the benefit of an anti-EGFR-therapy can be given, which is nowadays the basis of diagnostic and therapy of this cancer.For a long period of time a high concordance between primary and metastases inside the KRAS status was taken for granted. Meanwhile, there are many studies demonstrating a possibly underestimated high degree of discordance. The identification of discordances might gather a subcollective, which partially holds a KRAS wild type tissue and thereby might respond with a partial remission. Thus, the survival time of these patients and their quality of living could be successfully improved.