Tyrosine Kinase Inhibitor PTK/ZK Enhances the Antitumor Effects of Interferon-α/5-Fluorouracil Therapy for Hepatocellular Carcinoma Cells

Purpose

There is no standardized treatment for hepatocellular carcinoma (HCC) with portal vein tumor thrombus. We previously reported the efficacy of interferon-alpha and 5-fluorouracil combination (IFN/5-FU) therapy for these patients and the potential mechanism via the regulation of vascular endothelial growth factor (VEGF). In this study, we showed the VEGF-related effects of IFN/5-FU therapy using VEGF-receptor (VEGFR) selective inhibitor, PTK787/ZK222584 (PTK/ZK), in HCC cells.

Methods

Using two VEGF secreting and VEGFR expressing human HCC cell lines, PLC/PRF/5 and HuH7, we performed growth inhibitory assays in vitro and in vivo, apoptosis assay, cell cycle analysis, and Western blot analysis for the mechanism, with or without PTK/ZK in IFN/5-FU therapy.

Results

The combination of PTK/ZK and IFN/5-FU significantly inhibited cell growth in vitro and tended to reduce tumor growth in vivo in a HuH7 xenograft model in nude mice—in both cases without affecting VEGF secretion. PTK/ZK enhanced the IFN/5-FU induced apoptosis, based on increased proteins levels of Bax and reduced Bcl-xL and Bcl-2. Cell cycle analysis showed different results between the HCC cell lines following the combination therapy, possibly due to differences in p21 protein.

Conclusions

VEGF signaling inhibition would support an antitumor effect of IFN/5-FU therapy against HCC cell lines via induction of apoptosis and cell cycle delay.     

The Influence of Prognostic Factors and Adjuvant Chemoradiation on Survival After Pancreaticoduodenectomy for Ampullary Carcinoma

Introduction  

The prognosis after pancreaticoduodenectomy (PD) for ampullary carcinoma (AC) is superior to that of pancreatic cancer. Decisions regarding adjuvant therapy are influenced by factors such as nodal status, stage, and grade, but the influence of these individual variables on survival is unclear.     

Survival after Resection of Pancreatic Adenocarcinoma: Results from a Single Institution over Three Decades

Background  

Randomized trials have demonstrated a benefit associated with adjuvant therapy for pancreatic cancer, and retrospective studies have demonstrated improvements in postoperative mortality. The purpose of this study was to evaluate whether these improvements could be identified in a cohort of patients who underwent resection for pancreatic cancer at a single institution over three decades.     

Adjuvant Therapy With Capecitabine Postpones Recurrence of Hepatocellular Carcinoma After Curative Resection: A Randomized Controlled Trial

Background  

Postoperative recurrence of hepatocellular carcinoma (HCC) is a major problem after surgical resection. To date, adjuvant chemotherapy or other adjuvant modalities have not been proven effective in preventing or delaying recurrence. The aim of this prospective randomized study was to evaluate the effectiveness of capecitabine as a postoperative adjuvant regimen in inhibiting the recurrence of HCC.     

Clinicopathological assessment of T1 soft tissue sarcomas

Introduction  

Many studies have identified factors prognostic for soft tissue sarcomas of local recurrence, and distant metastasis. Several studies demonstrated that some subsets of patients could be safely treated by surgery alone, with acceptable rates of local recurrence. The aim of this study was to better clarify the necessity for adjuvant therapy and the width of the resected margin, by investigating the clinicopathological results of T1 (≤5 cm) soft tissue sarcomas.     

Risk Factors Influencing Recurrence, Patterns of Recurrence, and the Efficacy of Adjuvant Therapy After Radical Resection for Gallbladder Carcinoma

Backgrounds

Gallbladder carcinoma (GBC) is an aggressive neoplasm, and resection is the only curative modality. Recurrence frequently occurs after the curative resection of advanced GBC. Adjuvant treatment, particularly radiotherapy, is recommended and is used without any evidence of a beneficial effect. The aim of this study was to characterize patterns of recurrence and to identify the factors that influence recurrence and the efficacy of adjuvant therapy after the curative resection of GBC.

Methods

The records of patients that underwent surgical resection with curative intent for gallbladder carcinoma from October 1994 and August 2007 were retrospectively reviewed. Recurrence patterns, times to recurrence, and survival rates were analyzed. Sites of recurrence were identified retrospectively and categorized as locoregional or distant.

Results

One hundred sixty-six patients underwent surgical resection with curative intent for gallbladder adenocarcinoma. The 5-year recurrence rates of stages IA, IB, IIA, and IIB patients were 0%, 24.3%, 44.9%, and 58.3%, retrospectively. Positivity for lymph node metastases was found to have predictive significance for disease-free survival (p?=?0.009). Regional lymph node recurrence (27.7%) was observed most frequently. There was no significant disease-free survival rates between the no adjuvant therapy and the adjuvant therapy groups.

Conclusions

The regional lymph nodes and the liver were found to be the most common sites of recurrence after curative resection. Lymph node metastases were identified as an independent predictor of tumor recurrence by multivariate analysis. Based on the disease-free survivals observed in this study, the authors find it would be difficult to advocate the routine use of adjuvant radiotherapy and/or chemotherapy     

Cost-effectiveness of Treatment Strategies for Pancreatic Head Adenocarcinoma and Potential Opportunities for Improvement

Background

Generally dismal outcomes have led to a nihilistic attitude toward treating pancreatic cancer, while fiscal constraints have increased scrutiny of treatments costs. Our objective was to compare the cost-effectiveness of various treatment strategies for resectable pancreatic head adenocarcinoma, and to identify opportunities for improved cost effectiveness.

Methods

A decision model compared 6 strategies: no treatment, radiotherapy only, chemotherapy only, chemotherapy plus radiotherapy, surgery alone, and surgery plus adjuvant therapy. Outcomes and probabilities were identified using the National Cancer Data Base, the American Cancer Society National Surgical Quality Improvement Program, and the literature. Costs were estimated using Medicare payment. Incremental cost-effectiveness ratios (ICERs) were calculated, and sensitivity analyses were performed by varying potentially modifiable parameters of the model. Survival was reported in quality-adjusted life-months (QALMs).

Results

Surgery plus adjuvant therapy, chemotherapy alone, and no treatment were the only viable strategies in terms of cost effectiveness. Surgery plus adjuvant therapy versus no treatment demonstrated an incremental cost-effectiveness ratio (ICER) of $7,663/QALM. Theoretically increasing survival in node-negative, margin-negative patients from 14 to 22 QALMs produced the largest reduction in the ICER for surgery plus adjuvant therapy compared to no treatment ($6,386/QALM), whereas reducing the perioperative mortality from 3 to 1?% had only a marginal effect. The ICER was significantly lower for high-performing centers ($5,991/QALM) than for low-performing centers ($9,144/QALM).

Conclusions

Surgery plus adjuvant therapy for resectable pancreatic head adenocarcinoma extends survival, but at considerable expense. Significant cost reductions could be realized by improving treatment outcomes to levels of high-performing centers and development of increasingly effective adjuvant therapies.     

Risk Factors for Peritoneal Recurrence in Stage II/III Gastric Cancer Patients Who Received S-1 Adjuvant Chemotherapy After D2 Gastrectomy

Background  

The peritoneum is still the most frequent site of recurrence in stage II/III gastric cancer patients, although the survival rate was improved by the introduction of S-1 adjuvant chemotherapy. The objective of this retrospective study was to clarify the risk factors for peritoneal recurrence in patients who received S-1 adjuvant chemotherapy.     

TSU68, an antiangiogenic receptor tyrosine kinase inhibitor,induces tumor vascular normalization in a human cancer xenograft nude mouse model

Purpose  

Combination therapy using antiangiogenic and cytotoxic agents is a useful strategy for advanced cancer, but the mechanism has not yet been elucidated. Moreover, there is a persistent paradox that destroying tumor vasculature with antiangiogenic agents disturbs the delivery of cytotoxic agents. It has been hypothesized that antiangiogenic agents can lead to normalization of tumor vessels that are structurally and functionally abnormal. The normalization means enhancing the deliver of cytotoxic agents. Our purpose was to investigate whether TSU68, a multiple receptor tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), would induce the normalization of tumor vessels.     

The consequence of undertreatment of patients treated with breast conserving therapy for ductal carcinoma in-situ

Background

The use of clinical features to allocate adjuvant therapy in the treatment of ductal carcinoma in situ with breast-conserving therapy remains controversial.

Methods

A review of patients with ductal carcinoma in situ treated with breast-conserving therapy was performed. The recurrence rate was examined in relation to patient age, tumor characteristics, Van Nuys Prognostic Index, and the receipt of prescribed adjuvant therapies.

Results

Six percent of patients (17 of 294) had developed local recurrences after a median follow-up period of 63 months. Fifty-nine percent of patients (91 of 154) with estrogen receptor–positive tumors did not receive prescribed tamoxifen. Thirty-one percent of patients (45 of 147) with Van Nuys Prognostic Index scores ≥7 did not receive recommended radiation therapy. Receipt of prescribed adjuvant therapy did not result in a decrease in the rate of local recurrence. Patient age was the only factor associated with local recurrence on univariate but not on multivariate analysis (P = .374).

Conclusions

A low rate of local recurrence was achieved despite a large number of patients' not receiving prescribed adjuvant therapies.     

Adjuvant Chemolipiodolization Reduces Early Recurrence Derived from Intrahepatic Metastasis of Hepatocellular Carcinoma After Hepatectomy

Background  

The recurrence of hepatocellular carcinoma is still high even after surgery. Two general recurrence patterns occur: intrahepatic metastasis (IM) and multicentric carcinogenesis (MC). The aim of this study was to investigate the effectiveness of adjuvant chemolipiodolization for reducing IM or MC recurrences after surgery.     

Survival and Quality of Life of Patients with Resected Pancreatic Adenocarcinoma Treated with Adjuvant Interferon-Based Chemoradiation: A Phase II Trial

Purpose  

We conducted a phase II trial to assess the survival duration and quality of life of patients who received adjuvant interferon-based chemoradiation for pancreatic adenocarcinoma after pancreaticoduodenectomy.     

Recurrence of Adrenal Cortical Carcinoma Following Resection: Surgery Alone Can Achieve Results Equal to Surgery Plus Mitotane

Background  

A recent nonrandomized interinstitutional study reported that adjuvant mitotane following surgery for adrenocortical carcinoma (ACC) was associated with decreased recurrence. Because of the limitations of this study, we investigated the influences of surgery and adjuvant mitotane in a large series of ACC patients evaluated and treated at a single referral center.     

S-1 vs. Gemcitabine as an Adjuvant Therapy after Surgical Resection for Ductal Adenocarcinoma of the Pancreas

Background

Pancreatectomy with regional lymphadenectomy remains the only curative treatment option for pancreatic cancer. There is no clear consensus on what type of adjuvant therapy should be used for patients with pancreatic cancer.

Objective

Our objective was to retrospectively evaluate whether postoperative adjuvant chemotherapy using S-1 is clinically beneficial in managing resectable pancreatic cancer.

Methods

Patients were divided into three groups: those undergoing surgery alone, those receiving gemcitabine infusion, and those receiving S-1 orally.

Results

Of 189 studied patients, the median overall survival was 15.0 months after surgery alone, 33.0 months in the gemcitabine group, and 45.0 months in patients receiving S-1. A multivariate analysis identified regional lymph node metastasis, positive surgical margins, and absence of adjuvant chemotherapy as independent negative prognostic factors. S-1 was not inferior to gemcitabine in terms of survival outcomes and showed a favorable hazard ratio compared with gemcitabine in the subsets of patients with positive vascular invasion.

Conclusions

There was no difference between adjuvant chemotherapy with S-1 and gemcitabine in overall survival for patients with curative pancreatic cancer. Our results suggested that S-1 can be used as a second agent to gemcitabine after surgical resection for ordinary adenocarcinoma of the pancreas.     

VEGF-A/VEGFR-2 Signaling Plays an Important Role for the Motility of Pancreas Cancer Cells

Background

Pancreatic cancer is one of the most lethal solid tumors. Vascular endothelial growth factor receptors (VEGFRs) are expressed not only by endothelial cells but also by pancreatic cancer cells. VEGFRs might play an important role for the development of pancreatic cancer cells. The purpose of this study was to evaluate the efficacy of VEGF/VEGFR-2??targeted therapy in pancreatic carcinoma.

Methods

Five pancreatic carcinoma cell lines were used. The expression level of VEGFR-2 of cancer cells was examined by RT-PCR and Western blot. The effects of VEGFs, bevacizumab as an anti-VEGF antibody, sunitinib as a tyrosine kinase inhibitor against VEGFRs, and VEGF-R2 siRNA on the motility activity of pancreatic cancer cells were examined by invasion assay and wound healing assay. The effect of VEGF, bevacizumab, and sunitinib on the phosphorylation of VEGFR-2 and downstream effecter molecules, MAPK and PI3K, was examined by western blot.

Results

Pancreatic cancer cell lines expressed VEGFR-2. VEGF-A significantly increased the motility of pancreas cancer cells, which was inhibited by VEGFR-2 siRNA. Conditioned medium from pancreas cancer cells significantly stimulated the motility of pancreas cancer cells. VEGF/VEGFR inhibitors, bevacizumab and sunitinib, significantly decreased the motility of pancreas cancer cells. VEGFR-2 phosphorylation level of pancreas cancer cells was increased by VEGF-A. Bevacizumab and sunitinib decreased the level of VEGFR-2 phosphorylation, p-ERK, and p-Akt expression. VEGF-A decreased zonula occludens (ZO-1) or ZO-2 expression in pancreas cancer cells.

Conclusions

VEGF-A/VEGFR-2 signaling plays an important role in inducing invasion and migration of pancreatic cancer cells.     

Addition of Algenpantucel-L Immunotherapy to Standard Adjuvant Therapy for Pancreatic Cancer: a Phase 2 Study

Background

Despite continued investigation, limited progress has been made in the adjuvant treatment of resected pancreatic cancer. Novel or targeted therapies are needed.

Methods

Multi-institutional, open-label, dose-finding, phase 2 trial evaluating the use of algenpantucel-L (NewLink Genetics Corporation, Ames, IA) immunotherapy in addition to chemotherapy and chemoradiotherapy in the adjuvant setting for resected pancreatic cancer (ClinicalTrials.gov identifier, NCT00569387). The primary outcome was 12-month disease-free survival. Secondary outcomes included overall survival and toxicity.

Results

Seventy patients were treated with gemcitabine and 5-fluorouracil-based chemoradiotherapy as well as algenpantucel-L (mean 12 doses, range 1–14). After a median follow-up of 21 months, the 12-month disease-free survival was 62 %, and the 12-month overall survival was 86 %. The most common adverse events were injection site pain and induration.

Conclusions

The addition of algenpantucel-L to standard adjuvant therapy for resected pancreatic cancer may improve survival. A multi-institutional, phase 3 study is ongoing (ClinicalTrials.gov identifier, NCT01072981).     

Curettage and Cryosurgery for Low-grade Cartilage Tumors Is Associated with Low Recurrence and High Function

Background  

Chondrosarcomas of bone traditionally have been treated by wide or radical excision, procedures that may result in considerable lifelong disability. Grade 1 chondrosarcomas have little or no metastatic potential and are often difficult to distinguish from painful benign enchondromas. Curettage with adjuvant cryosurgery has been proposed as an alternative therapy for Grade 1 chondrosarcomas given the generally better function after the procedure. However, because it is an intralesional procedure, curettage and cryosurgery may be associated with higher rates of recurrence.     

Case report: Successful treatment of recurrent chordoma and bilateral pulmonary metastases following an 11-year disease-free period

INTRODUCTION

Chordomas are rare but aggressive tumors due to local recurrence and distant metastases. They originate commonly in the sphenooccipital and sacrococcygeal regions, and metastasize to the lungs, bone, skin, liver, and lymph nodes. They occur more frequently in men and people over the age of 40.

PRESENTATION OF CASE

A 28 year-old female presented with sacrococcygeal chordoma for which she received wide local excision and adjuvant radiation therapy. She enjoyed an unusual disease-free survival for 11 years until a routine surveillance scan of the pelvis identified local recurrence. Further work up revealed bilateral pulmonary metastases. She underwent local excision of the recurrent tumor and video-assisted thoracoscopic (VATS) wedge resection of pulmonary metastases. She also received adjuvant radiation therapy to the recurrent resection bed. Two years later, she remains free of disease and symptoms.

DISCUSSION

Chordomas are commonly insensitive to chemotherapy and radiation, making surgery the most successful therapeutic modality. However, there are few guidelines on the surveillance and treatment of recurrent chordoma. We report success with aggressive surgical resection of recurrence and metastasis as well as adjuvant radiation therapy.

CONCLUSION

The prolonged survival of our patient underscores the importance of (1) aggressive surgical resection of chordoma, whether primary, recurrent, or metastatic, with adjuvant radiation therapy, (2) minimization of surgical seeding of tumor, and (3) diligent cancer surveillance.     

Lower recurrence rate in chondroblastoma using extended curettage and cryosurgery

Purpose

Various methods for the treatment of chondroblastoma of bone have been used including simple curettage, or combined with bone grafting, in addition to the use of adjuvant therapy. However, local recurrence still represents a challenge in the management of this aggressive tumour. This study focuses on evaluating the role of intraregional extended curettage together with the use of adjuvant cryotherapy and autogenous bone grafting in the treatment of benign chondroblastoma of bone aiming to decrease the recurrence rate.

Methods

All patients with chondroblastoma included in this study underwent intralesional extended curettage, adjuvant cryotherapy using liquid nitrogen, and autogenous iliac crest bone grafting. Follow up for healing of chondroblastoma lesions and detection of any local recurrence was assessed on clinical and radiological bases. The functional outcome was assessed by the Musculoskeletal Tumour Society scoring system.

Results

The mean follow-up period was 49 months. The average time for bone healing was 7.4 months. Our rate of local recurrence is 7.1 %. Two patients (14.3 %) developed physeal growth arrest. One patient had superficial skin sloughing (7.1 %). None of the cases had pathological fracture. The mean Musculoskeletal Tumour Society functional score was 92.7 %.

Conclusion

Chondroblastoma is an aggressive benign bone tumour with a high rate of recurrence. The use of high-speed burr combined with adjuvant intralesional cryotherapy and iliac crest autogenous bone grafting is a reliable method of treatment with a low rate of recurrence.     

A Single Institution Review of Adjuvant Therapy Outcomes for Resectable Pancreatic Adenocarcinoma: Outcome and Prognostic Indicators

Introduction  

A large single-institution series of patients who recently underwent pancreaticoduodenectomy for resectable pancreatic cancer was analyzed to determine prognostic factors for overall survival, including the impact of adjuvant radiation and chemotherapy.