Dietmar Tamandl

Bevacizumab, Capecitabine, and Oxaliplatin As Neoadjuvant Therapy for Patients With Potentially Curable Metastatic Colorectal Cancer

PURPOSE Patients with colorectal cancer (CRC) and liver metastases have a poor prognosis, but can benefit from perioperative chemotherapy and disease resection. Bevacizumab improves outcomes in patients with metastatic CRC; however, its impact on surgical complications and hepatic regeneration after liver resection remains to be determined. PATIENTS AND METHODS Fifty-six patients with metastatic CRC with liver metastases potentially curable by resection were eligible for this single-center, nonrandomized phase II trial. Eligibility criteria defined patients at high risk of early recurrence. Patients received biweekly bevacizumab plus capecitabine and oxaliplatin for six cycles. The sixth cycle of therapy did not include bevacizumab, resulting in 5 weeks between the last administration of bevacizumab and surgery. RESULTS Objective response to neoadjuvant chemotherapy was achieved in 41 patients (73%). Fifty-two patients underwent liver resection including 11 with synchronous primary tumor resection. No increased intraoperative bleeding events or wound-healing complications were observed and only three patients (6%) required perioperative blood transfusions. Further surgery was necessary in a single patient. Postoperative liver function and regeneration were normal in all but one patient. No postoperative mortality occurred and morbidity was encountered in 11 patients (20%). The mean length of postoperative hospitalization was 9 days (+/- 4.0). CONCLUSION These data suggest that bevacizumab can be safely administered until 5 weeks before liver resection in patients with metastatic CRC without increasing the rate of surgical or wound healing complications or severity of bleeding. To our knowledge, they are also the first to show that neoadjuvant bevacizumab does not affect liver regeneration after resection.

Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns.

Toll‐like receptors (TLR) represent an ancient front‐line defence system that enables the host organism to sense the presence of microbial components within minutes. As inducers of inflammation, TLR act as important triggers of distinct entities such as sepsis or autoimmune disease exacerbation. We report here that vitamin D3 [1α,25‐dihydroxycholecalciferol, 1,25(OH)2D3] suppresses the expression of TLR2 and TLR4 protein and mRNA in human monocytes in a time‐ and dose‐dependent fashion. Despite 1,25(OH)2D3‐induced up‐regulation of CD14, challenge of human monocytes with either LPS or lipoteichoic acid resulted in impaired TNF‐α and procoagulatory tissue factor (CD142) production, emphasizing the critical role of TLR in the induction of inflammation. Moreover, reduced TLR levels in 1,25(OH)2D3‐treated phagocytes were accompanied by impaired NF‐κB/RelA translocation to the nucleus and by reduced p38 and p42/44 (extracellular signal‐regulated kinase 1/2) phosphorylation upon TLR‐ligand engagement. Both TLR down‐regulation and CD14 up‐regulation were substantially inhibited by the vitamin D receptor (VDR) antagonist ZK 159222, indicating that the immunomodulatory effect of 1,25(OH)2D3 on innate immunity receptors requires VDR transcription factor activation. Our data provide strong evidence that 1,25(OH)2D3 primes monocytes to respond less effectively to bacterial cell wall components in a VDR‐dependent mechanism, most likely due to decreased levels of TLR2 and TLR4.

Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study

BACKGROUND Patients with biliary tract cancer have a poor prognosis, and, until recently, no standard palliative chemotherapy has been defined. We aimed to investigate the efficacy and safety of cetuximab in combination with gemcitabine and oxaliplatin (GEMOX) for first-line treatment of biliary tract cancer. METHODS From Oct 1, 2006, to July 26, 2008, patients with unresectable locally advanced or metastatic biliary tract cancer were sequentially enrolled and treated at one centre in Austria. All patients received intravenous infusions of 500 mg/m(2) cetuximab on day 1, 1000 mg/m(2) gemcitabine on day 1, and 100 mg/m(2) oxaliplatin on day 2, every 2 weeks for 12 cycles. The primary outcome was overall response rate. Analysis was by intention to treat. Adverse reactions were assessed according to National Cancer Institute Common Toxicity Criteria. The study is completed and registered with ClinicalTrials.gov, number NCT01216345. FINDINGS 30 patients with median age of 68 years (IQR 62-73) were enrolled and included in the analysis. Objective response occurred in 19 patients (63%; 95% CI 56·2-69·8), of whom three (10%; 3·2-16·8) achieved complete response, and 16 (53%; 46·2-59·8) achieved partial response. Nine patients underwent potentially curative secondary resection after major response to therapy. Grade 3 adverse events were recorded in 13 patients: skin rash (n=4), peripheral neuropathy (n=4), thrombocytopenia (n=3), nausea (n=1), diarrhoea (n=1), and neutropenia (n=1); no grade 4 adverse events were recorded. INTERPRETATION Cetuximab plus GEMOX was well tolerated and had encouraging antitumour activity, leading to secondary resection in a third of patients. These findings warrant further study of cetuximab plus GEMOX in a large randomised trial.

Monocyte Toll-Like Receptor 4 Expression and LPS-Induced Cytokine Production Increase during Gestational Aging

Premature newborns are highly susceptible to severe bacterial infections. This is partially due to their immature innate immune system, characterized by decreased neutrophil and monocyte activity as well as by reduced concentrations of complement factors. However, additional mechanisms might be important for innate immunity and are still the subject of considerable debate. The importance of pattern recognition domains such as Toll-like receptors (TLR) has been fully acknowledged within the last few years. Therefore, we investigated age-related monocyte TLR4 expression and lipopolysaccharide-induced cytokine secretion from very low birth weight infants (VLBWI) and from newborns after wk 30 of gestation in comparison to healthy adults. In VLBWI, expression of TLR4 surface protein, detected by flow cytometry, and TLR4-specific mRNA, quantified by real time-PCR, were significantly reduced in comparison to mature infants and to adults. Reduced TLR4 expression was paralleled by significantly diminished ex vivo LPS stimulated IL-1β, IL-6, and tumor necrosis factor-α secretion into whole blood. We conclude that, in VLBWI, the minimized expression of TLR4 contributes to the susceptibility of VLBWI to infections with Gram-negative bacteria due to the lack of cytokines to boost initial immune response.

Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases

AIM In patients suffering from colorectal cancer liver metastases, 5-fluorouracil-based chemotherapy plus oxaliplatin ensures superior response rates at the cost of hepatic injury. Knowledge about the consequences of bevacizumab on chemotherapy-induced hepatic injury and tumor response is limited. METHODS Resected liver specimens from patients of two prospective, non-randomized trials (5-fluorouracil/oxaliplatin+/-bevacizumab) were analyzed retrospectively. Hepatotoxicity to the non-tumor bearing liver was evaluated for sinusoidal obstruction syndrome, hepatic steatosis and fibrosis. Tumor response under chemotherapy was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS Bevacizumab decreased the severity of the sinusoidal obstruction syndrome. Bevacizumab had no impact on hepatic steatosis and fibrosis. The addition of bevacizumab to chemotherapy had no effect on tumor response compared to combination chemotherapy alone. CONCLUSIONS This analysis shows that bevacizumab protects against the sinusoidal obstruction syndrome and thus provides the histological explanation of the safe use of bevacizumab prior to liver resection. Furthermore, we show that bevacizumab does not improve tumor response according to RECIST.

Importance of response to neoadjuvant chemotherapy in potentially curable colorectal cancer liver metastases

BackgroundSurgical resection of liver metastases arising from colorectal cancer is considered the only curative treatment option. However, many patients subsequently experience disease recurrence. We prospectively investigated whether neoadjuvant chemotherapy reduces the risk of recurrence following potentially curative liver resection. Special emphasis was directed to the importance of response.Methods50 patients with resectable liver metastases received neoadjuvant XELOX or FOLFOX4 for six cycles (3 months). Complete resection of liver metastases was intended thereafter. Assessments included response rate, postoperative morbidity and recurrence-free survival.ResultsAn objective response was observed in 72% of all patients, including two complete responses. Chemotherapy was well tolerated and the majority of adverse events were mild to moderate (grade 1/2). Potentially curative R0 resection was performed in all patients and postoperative complications were observed in only 12%. The median recurrence-free survival was significantly influenced by tumor response with 24.7 months (95% CI: 4.50 to 44.97) in responding patients, 8.2 months (95% CI: 3.09 to 13.31) in patients with stable disease and 3.0 months (95% CI: 0 to 8.91) in patients with progressive disease.ConclusionThese data suggest that neoadjuvant Oxaliplatin based chemotherapy provides high response rates without increased risk of perioperative morbidity. Response to chemotherapy can lead to long-term recurrence-free survival. Neoadjuvant chemotherapy may identify best candidates for a potentially curative treatment approach.

Size of surgical margin does not influence recurrence rates after curative liver resection for colorectal cancer liver metastases.

The aim of this study was to examine the relationship between surgical margin status and site of recurrence after potentially curative liver resection for colorectal metastases using an ultrasonic dissection technique.

Modulation of toll-like receptor 4 expression on human monocytes by tumor necrosis factor and interleukin-6: Tumor necrosis factor evokes lipopolysaccharide hyporesponsiveness, whereas interleukin-6 enhances lipopolysaccharide activity

Toll-like receptors (TLR) play a pivotal role in the innate immune response, and the expression levels of these receptors may reflect the sensitivity of immune cells to infections. The binding of lipopolysaccharide (LPS) to TLR-4 triggers human monocytes to produce cytokines, which play a dominant role in the inflammatory response, as can be observed during sepsis and after polytrauma. Here, we evaluated TLR-4 expression of isolated monocytes in the presence of tumor necrosis factor (TNF)-&agr;, interleukin (IL) 6, IL-8, and IL-10, and we investigated cellular activation of this treatment. TNF-&agr; significantly down-regulated TLR-4 mRNA expression after 6 h (100% vs. 38.5% ± 4%; P < 0.05). This down-regulation was followed by a dose- and time-dependent diminished expression of TLR-4 surface protein (100% vs. 8.0% ± 5%; P < 0.01). Forty-eight hours after TNF-&agr; treatment, a reduced nuclear factor (NF)-&kgr;B translocation and a diminished IL-6 secretion after LPS stimulation were found (100% vs. 42.0% ± 23%; P < 0.05). In contrast, IL-6 incubation upregulated TLR-4 cell surface protein (100% vs. 165.8% ± 24%; P < 0.05) and increased the ability to activate NF-&kgr;B and AP-1 after LPS stimulation. Stimulation with IL-8 or IL-10 had no significant effects. We conclude that not only LPS but also TNF-&agr; and IL-6 have the potency to regulate the immune response via TLR-4. Down-regulation of TLR-4 by TNF-&agr; is associated with LPS hyporeactivity for NF-&kgr;B formation, whereas upregulation of TLR-4 via IL-6 can increase the responsiveness of mononuclear phagocytes.

Preoperative detection of colorectal liver metastases in fatty liver: MDCT or MRI?

OBJECTIVE To compare the diagnostic value of multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) in the preoperative detection of colorectal liver metastases in diffuse fatty infiltration of the liver, associated with neoadjuvant chemotherapy. MATERIALS AND METHODS Twenty preoperative tri-phasic MDCT (4-64-row, Siemens) and dynamic contrast-enhanced MRI (1.5T or 3.0T, Siemens) examinations of patients with colorectal cancer and liver metastases in diffuse steatosis were retrospectively evaluated. All patients underwent surgical resection for liver metastases (time interval 1-60 days). The amount of fatty infiltration of the liver was determined histopathologically by semi-quantitative percent-wise estimation and ranged from 25 to 75%. RESULTS Overall, 51 metastases were found by histopathology of the resected liver segments/lobes. The size of the metastases ranged from 0.4 to 13 cm, with 18 (35%) being up to 1cm in diameter. In the overall rating, MDCT detected 33/51 lesions (65%), and MRI 45/51 (88%). For lesions up to 1cm, MDCT detected only 2/18 (11%) and MRI 12/18 (66%). One false positive lesion was detected by MDCT. Statistical analysis showed that MRI is markedly superior to MDCT, with a statistically significant difference (p<.001), particularly for the detection of small lesions (≤ 1 cm; p<.004). There was no significant difference between the two modalities in the detection of lesions>1cm. CONCLUSION For the detection of colorectal liver metastases after neoadjuvant chemotherapy and consecutive diffuse fatty infiltration of the liver, MRI is superior to MDCT, especially for the detection of small lesions.

Lymph node ratio after curative surgery for intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is rare but its incidence is rising worldwide. The value of lymph node dissection for ICC is under discussion; the current staging systems do not differentiate between numbers of involved nodes.