Taxanes, such as docetaxel, are microtubule-targeting chemotherapeutics that have been successfully used in the treatment of cancer. Based on data obtained from cell cultures, it is believed that taxanes induce tumor cell death by specifically perturbing mitotic progression. Here, we report on data that suggest that this generally accepted view may be too simplified. We describe a high-resolution intravital imaging method to simultaneously visualize mitotic progression and the onset of apoptosis. To directly compare in vitro and in vivo data, we have visualized the effect of docetaxel on mitotic progression in mouse and human colorectal tumor cell lines both in vitro and in isogenic tumors in mice. We show that docetaxel-induced apoptosis in vitro occurs via mitotic cell death, whereas the vast majority of tumor cells in their natural environment die independent of mitotic defects. This demonstrates that docetaxel exerts its anti-tumor effects in vivo through means other than mitotic perturbation. The differences between in vitro and in vivo mechanisms of action of chemotherapeutics may explain the limited response to many of the anti-mitotic agents that are currently validated in clinical trials. Our data illustrate the requirement and power of our intravital imaging technique to study and validate the mode of action of chemotherapeutic agents in vivo, which will be essential to understand and improve their clinical efficacy.

Pancreatic ductal adenocarcinoma (PDAC) stands as the poorest prognostic tumor of the digestive tract, with a 5-year survival rate of less than 5 %. Therapeutic options for unresectable PDAC are extremely limited and there is a pressing need for expanded therapeutic approaches to improve current options available with gemcitabine-based regimens. With PDAC displaying one of the most prominent desmoplastic stromal reactions of all carcinomas, recent research has focused on the microenvironment surrounding PDAC cells. Secreted protein acid and rich in cysteine (SPARC), which is overexpressed in PDAC, may display tumor suppressor functions in several cancers (e.g., in colorectal, ovarian, prostate cancers, and acute myelogenous leukemia) but also appears to be overexpressed in other tumor types (e.g., breast cancer, melanoma, and glioblastoma). The apparent contradictory functions of SPARC may yield inhibition of angiogenesis via inhibition of vascular endothelial growth factor, while promoting epithelial-to-mesenchymal transition and invasion through matrix metalloprotease expression. This feature is of particular interest in PDAC where SPARC overexpression in the stroma stands along with inhibition of angiogenesis and promotion of cancer cell invasion and metastasis. Several therapeutic strategies to deplete stromal tissue have been developed. In this review, we focused on key preclinical and clinical data describing the role of SPARC in PDAC biology, the properties, and mechanisms of delivery of drugs that interact with SPARC and discuss the proof-of-concept clinical trials using nab-paclitaxel.

Gastrointestinal (GI) cancers are a significant source of morbidity and mortality in Iran, with stomach adenocarcinoma as the most common cancer in men and the second common cancer in women. Also, some parts of Northern Iran have one of the highest incidences of esophageal cancer in the world. Multi-disciplinary organ-based joint clinics and tumor boards are a well-recognized necessity for modern treatment of cancer and are routinely utilized in developed countries, especially in major academic centres. But this concept is relatively new in developing countries, where cancer treatment centres are burdened by huge loads of patients and have to cope with a suboptimum availability of resources and facilities. Cancer Institute of Tehran University of Medical Sciences is the oldest and the only comprehensive cancer treatment centre in Iran, with a long tradition of a general tumor board for all cancers. But with the requirements of modern oncology, there has been a very welcome attention to sub-specialized organ-based tumor boards and joint clinics here in the past few years. Considering this, we started a multi-disciplinary tumor board for GI cancers in our institute in early 2010 as the first such endeavor here. We hereby review this 2-year evolving experience. The process of establishment of a GI tumor board, participations from different oncology disciplines and related specialties, the cancers presented and discussed in the 2 years of this tumor board, the general intents of treatment for the decisions made and the development of interest in this tumor board among the Tehran oncology community will be reviewed. The GI tumor board of Tehran Cancer Institute started its work in January 2010, with routine weekly sessions. A core group of 2 physicians from each surgical, radiation and medical oncology departments plus one gastroenterologist, GI pathologist and radiologist was formed, but participation from all interested physicians was encouraged. An electronic database was kept from the beginning. The number of patients presented in the tumor board increased from 4 in January 2010 to 16 in December 2011. Most patients were presented by radiation oncology department (38%) and then surgical (36%) and medical oncology (20%) departments. Physicians' participation also grew from an average of 8 each session to 12 in the same months, with a number of cancer specialists taking part from other university hospitals in Tehran. A total number of 225 patients were presented with a treatment decision made in this 2-year period. The majority of cases were colorectal (32%), stomach (23%), and esophageal (17%) cancers. The number of pancreatic (7%) and hepatobiliary (6%) cancers were much smaller. Most decisions were for a primary treatment (surgery or radiochemotherapy) and then a neoadjuvant approach.  Tehran Cancer Institute's GI tumor board is one of the first multi-disciplinary organ-based tumor boards in Iran, and as such has made a successful start, establishing itself as a recognized body for clinical decisions and consultations in GI oncology. This experience is growing and evolving, with newer presentation and discussion formats and adapted guidelines for treatment of GI cancers in Iran sought.

PURPOSE:

Liver resection may offer the only chance of cure in patients with colorectal cancer with liver metastases. In the unresectable cases, neoadjuvant chemotherapy could render curability if resectability could be achieved.

METHODS:

Newly diagnosed K-RAS wild-type colorectal cancer patients with unresectable liver-only metastases were treated with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX6) plus cetuximab every 2 weeks for a maximum of 12 cycles. Clinical response was evaluated every 6 weeks, and surgery was performed at the physician's discretion in patients with sufficient tumor shrinkage, followed by chemotherapy with the same regimen, to complete a total of 12 cycles. The primary endpoint was an overall R0 resection rate.

RESULTS:

Between July 2008 and December 2009, 73 patients were registered from 11 Korean centers. Among 53 (73 %) patients who showed at least partial response, surgery with curative intent was attempted in 36 (49 %) patients. Intention-to-treat analysis revealed a R0 resection rate of 27 % (20/73) including 8 patients whose unresectable liver metastases were successfully treated with radiofrequency ablation (RFA). The most common grade 3 and 4 toxicity was neutropenia (50/462 cycles, 10.7 %). Median time to progression (TTP) was 9.8 months (range 0.5-31.8) in all patients, but we observed TTP of 14.1 months (range 1.3 to -30.8) in patients who received R0 resection and RFA + R0 resection.

CONCLUSIONS:

Neoadjuvant chemotherapy with FOLFOX6 plus cetuximab showed high response rates and increased the resectability in colorectal patients with non-resectable liver-only metastases.

We evaluated a consecutive series of signet ring cell colorectal carcinomas in an attempt to correlate the histopathologic pattern of infiltration with molecular alterations and prognosis. Of the 4760 primary colorectal carcinomas surgically resected between the years 2002 and 2012, 53 (1%) were composed of >50% signet ring cells. Of the 53 signet ring cell carcinomas, 40 (75%) were composed of >50% extracellular mucin with signet ring cells floating within pools of mucin and were subclassified as mucin-rich signet ring cell carcinomas. Thirteen (25%) carcinomas were characterized by diffusely infiltrating carcinomas with minimal to no extracellular mucin and were subclassified as mucin-poor signet ring cell carcinomas. All 13 mucin-poor signet ring cell carcinomas were either stage III or IV, whereas many cases of mucin-rich signet ring cell carcinoma were stage I or II (17 cases) (P=0.005). Compared with mucin-rich tumors, mucin-poor signet ring cell carcinomas more frequently demonstrated adverse histologic features such as lymphatic invasion (13/13, 100% vs. 22/40, 55%; P=0.002), venous invasion (6/13, 46% vs. 3/40, 8%; P=0.004), and perineural invasion (11/13, 85% vs. 9/40, 23%; P=0.0001). Twenty-three of 53 (43%) signet ring cell carcinomas demonstrated high levels of microsatellite instability (MSI-H). Twenty-two of 23 (96%) MSI-H signet ring cell carcinomas were mucin rich; only 1 MSI-H signet ring carcinoma was mucin poor (P=0.0033). Mucin-poor signet ring cell carcinoma had significantly reduced overall and recurrence-free survival compared with mucin-rich signet ring cell carcinomas (P=0.0035 and 0.0001, respectively), even when adjusting for tumor stage. Mucin-poor signet ring cell carcinoma had a higher propensity for peritoneal dissemination (5/13, 38%) compared with mucin-rich signet ring cell carcinoma (5/40, 12.5%), although this was not statistically significant (P=0.052). Finally, MSI-H and microsatellite-stable signet ring cell carcinomas had similar overall and recurrence-free survival (P=0.2266 and 0.1055, respectively), even when adjusting for tumor stage. In conclusion, we identified a unique subset of signet ring cell colorectal carcinoma with diffuse infiltration and minimal to no extracellular mucin (mucin-poor signet ring cell carcinoma), which lacks MSI-H and has a dismal prognosis with an aggressive clinical course often with peritoneal dissemination. Further, our results confirm that MSI does not affect survival in colorectal signet ring cell carcinomas.

To develop a prognostic model to predict survival of patients with colorectal cancer (CRC).Survival data of 837 CRC patients undergoing surgery between 1996 and 2006 were collected and analyzed by univariate analysis and Cox proportional hazard regression model to reveal the prognostic factors for CRC. All data were recorded using a standard data form and analyzed using SPSS version 18.0 (SPSS, Chicago, IL, United States). Survival curves were calculated by the Kaplan-Meier method. The log rank test was used to assess differences in survival. Univariate hazard ratios and significant and independent predictors of disease-specific survival and were identified by Cox proportional hazard analysis. The stepwise procedure was set to a threshold of 0.05. Statistical significance was defined as P < 0.05.The survival rate was 74% at 3 years and 68% at 5 years. The results of univariate analysis suggested age, preoperative obstruction, serum carcinoembryonic antigen level at diagnosis, status of resection, tumor size, histological grade, pathological type, lymphovascular invasion, invasion of adjacent organs, and tumor node metastasis (TNM) staging were positive prognostic factors (P < 0.05). Lymph node ratio (LNR) was also a strong prognostic factor in stage III CRC (P < 0.0001). We divided 341 stage III patients into three groups according to LNR values (LNR1, LNR ≤ 0.33, n = 211; LNR2, LNR 0.34-0.66, n = 76; and LNR3, LNR ≥ 0.67, n = 54). Univariate analysis showed a significant statistical difference in 3-year survival among these groups: LNR1, 73%; LNR2, 55%; and LNR3, 42% (P < 0.0001). The multivariate analysis results showed that histological grade, depth of bowel wall invasion, and number of metastatic lymph nodes were the most important prognostic factors for CRC if we did not consider the interaction of the TNM staging system (P < 0.05). When the TNM staging was taken into account, histological grade lost its statistical significance, while the specific TNM staging system showed a statistically significant difference (P < 0.0001).The overall survival of CRC patients has improved between 1996 and 2006. LNR is a powerful factor for estimating the survival of stage III CRC patients.

Biomarkers that can facilitate disease detection, staging and prediction of outcome are highly desirable to improve survival and to help determine optimized treatment for colorectal cancer patients. microRNAs (miRNAs) are small non-coding RNAs that play a crucial role in gene regulatory networks. The deregulation of miRNA expression has been found in several types of cancer and may represent a novel class of cancer biomarkers. Our aim was to determine the miRNA signature of stage III colorectal cancer (CRC) tumors and to identify potential circulating miRNAs that may represent non-invasive biomarkers in CRC patients. Genome-wide microarray analysis of miRNA expression was performed on 12 paired tumor and non-tumor formalin-fixed paraffin-embedded tissues from stage III CRC patients. A selection of differentially overexpressed miRNAs was validated by quantitative real-time polymerase chain reaction (qRT-PCR) and determined in the serum of a set of 56 individuals (30 stage III CRC patients and 26 healthy individuals). Using 1.5-fold expression difference as a cut-off level, 43 miRNAs were identified as differentially expressed in tumor versus normal tissue. Using reverse transcription and qRT-PCR, 11 miRNAs (miR-135b, miR-141, miR-18a, miR-20a, miR-21, miR-224, miR-29a, miR-31, miR-34a, miR-92a and miR-96) were confirmed as significantly overexpressed in tumor samples when compared with normal samples. We were able to detect 9 of these 11 miRNAs in serum samples from CRC patients and healthy individuals. Serum levels of miR-18a and miR-29a were significantly higher in CRC patients when compared to levels in the controls (p<0.05). In conclusion, this study identified a substantial number of miRNAs which were differentially expressed in stage III colorectal tumors. Moreover, the findings provide relevant information concerning overexpressed tumoral miRNAs as potential circulating biomarkers and highlight serum miR-18a and miR-29a as promising biomarkers for the screening and monitoring of CRC patients.

The clinical practice of hyperthermic intraperitoneal chemoperfusion (HIPEC) for carcinomatosis has lacked preclinical justification. A standardized mouse model was created to evaluate the independent effects of intraperitoneal chemotherapy. Diffuse colorectal carcinomatosis was generated in mice prior to intraperitoneal lavage with mitomycin C (MMC) at clinically comparable dosing for variable lengths of time. Tumor volumes, MMC tissue concentrations and survival were measured in comparison to saline lavage and intravenous MMC. Magnetic resonance imaging revealed a direct correlation between tumor volume, MMC dose and exposure time and survival. Intravenous MMC demonstrated a rapid clearance from the blood, lower peritoneal tissue concentrations, less tumor growth inhibition and decreased survival compared to intraperitoneal administration. Intraperitoneal chemotherapy inhibited tumor growth independent of cytoreduction or hyperthermia, demonstrated improved peritoneal tissue concentration and was associated with increased survival. These data support the clinical utility of the intraperitoneal chemotherapy component of HIPEC.

Radiofrequency ablation (RFA) uses high frequency alternating current to heat a volume of tissue around a needle electrode to induce focal coagulative necrosis with minimal injury to surrounding tissues. RFA can be performed via an open, laparoscopic, or image guided percutaneous approach and be performed under general or local anesthesia. Advances in delivery mechanisms, electrode designs, and higher power generators have increased the maximum volume that can be ablated, while maximizing oncological outcomes. In general, RFA is used to control local tumor growth, prevent recurrence, palliate symptoms, and improve survival in a subset of patients that are not candidates for surgical resection. It's equivalence to surgical resection has yet to be proven in large randomized control trials. Currently, the use of RFA has been well described as a primary or adjuvant treatment modality of limited but unresectable hepatocellular carcinoma, liver metastasis, especially colorectal cancer metastases, primary lung tumors, renal cell carcinoma, boney metastasis and osteoid osteomas. The role of RFA in the primary treatment of early stage breast cancer is still evolving. This review will discuss the general features of RFA and outline its role in commonly encountered solid tumors.

To review the clinical data and treatment efficacy of bevacizumab in Chinese patients with metastatic colorectal cancer (mCRC).A total of 96 patients with mCRC treated by chemotherapy plus bevacizumab in the PLA General Hospital between December 2005 and August 2012 were analyzed retrospectively by overall response rate, disease-control rate, progression-free survival (PFS), and overall survival (OS). The tumor responses were assessed by the Response Evaluation Criteria in Solid Tumors guidelines.A total of 96 patients with mCRC were identified. Median age was 53.6 years. Eastern Cooperative Oncology Group performance status was 0-2. By the end of follow-up (August 20, 2012), 54 patients exhibited progression (56.3%), and 39 (40.6%) patients had died. A total of 27 (28.1%) achieved partial response, and 48 patients (50.0%) had stable disease, exhibiting an overall response rate of 28.1% and a disease-control rate of 78.1%. The response rates of the first-line, second-line, and third-line (or later) therapy were 41.7%, 21.9%, and 15.8%, respectively. The median durations of the PFS and OS were 8.13 months and 14.80 months, respectively. The median durations of the PFS were 12.70 months, 8.30 months, and 6.40 months for first-line, second-line, and third-line (or later) therapy, respectively, and the median durations of the OS were 24.03 months, 14.90 months, and 11.03 months for first-line, second-line, and third-line (or later) therapy, respectively.A bevacizumab-containing chemotherapy regimen was well tolerated and effective in Chinese patients with mCRC.