The efficacy of anti-EGFR therapy in treating metastatic colorectal cancer differs between the middle/low rectum and the left-sided colon.

BACKGROUND: Clinically, metastatic rectal cancer has been considered a subset of left-sided colon cancer. However, heterogeneity has been proposed to exist between high and middle/low rectal cancers. We aimed to examine the efficacy of anti-epidermal growth factor receptor (EGFR) treatment for middle/low rectal and left-sided colon cancers. METHODS: This study enrolled 609 patients with metastatic colorectal cancer who were treated with anti-EGFR therapy. They were divided into groups based on primary tumour locations: the right-sided colon, the left-sided colon or the middle/low rectum. The efficacy of first-line and non-first-line anti-EGFR treatment was analysed. Genomic differences in colorectal cancer data from The Cancer Genome Atlas (TCGA) were investigated and visualised with OncoPrint and a clustered heatmap. RESULTS: On first-line anti-EGFR treatment, patients with middle/low rectal tumours had significantly lower progression-free survival, overall survival, and overall response rates (6.8 months, 27.8 months and 43%, respectively) than those with left-sided colon cancer (10.1 months, 38.3 months and 66%, respectively). Similar outcomes were also identified on non-first-line anti-EGFR treatment. In TCGA analysis, rectal tumours displayed genetic heterogeneity and shared features with both left- and right-sided colon cancer. CONCLUSIONS: Anti-EGFR treatment has lower efficacy in metastatic middle/low rectal cancer than in left-sided colon cancer.

Real-world evidence of the safety and effectiveness of regorafenib in Taiwanese patients with metastatic colorectal cancer: CORRELATE Taiwan.

BACKGROUND/PURPOSE: This analysis reports safety and effectiveness data from the Taiwanese cohort of the CORRELATE study. METHODS: CORRELATE was a prospective, observational study to assess the safety and effectiveness of regorafenib for the treatment of metastatic colorectal cancer (CRC) in real-world clinical practice that was conducted in 13 different countries in Asia, Europe and Latin America. The primary endpoint of the study was incidence of all treatment-emergent AEs (TEAEs), and secondary endpoints included overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). RESULTS: The global study population (N = 1037) included 128 Taiwanese patients with a median age of 64 years, median weight of 62.02 kg and 66.41% were male. Reduced initiating doses of regorafenib and dose interruptions were common in Taiwanese patients (71.87% and 50.00%, respectively). The safety profile of regorafenib was consistent with that seen in Asian patients in the clinical development trials, including the CORRECT and CONCUR studies, with hand-foot-skin reactions (HFSR) of any grade occurring in 33.59% of patients. Median OS was 11.64 months in the Taiwanese patients (95% confidence interval [CI], 8.36-13.82) and median PFS was 2.17 months (95% CI, 1.97-2.89). CONCLUSION: The safety and effectiveness of regorafenib in this real-world study was generally consistent with the known efficacy and safety profile in Asian patients in clinical trials. TRIAL REGISTRATION: NCT02042144.

Insulin-Like Growth Factor 2 mRNA-Binding Protein 1 (IGF2BP1) Is a Prognostic Biomarker and Associated with Chemotherapy Responsiveness in Colorectal Cancer.

Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an RNA-binding protein and serves as a post-transcriptional fine-tuner regulating the expression of mRNA targets. However, the clinicopathological roles of IGF2BP1 in colorectal cancer (CRC) remains limited. Thus, we aimed to elucidate the clinical significance and biomarker potentials of IGF2BP1 in CRC. A total of 266 specimens from two sets of CRC patients were collected. IGF2BP1 expression was studied by immunohistochemical (IHC) staining. The Kaplan-Meier survival plot and a log-rank test were used for survival analysis. The Cox proportional hazards model was applied to determine the survival impact of IGF2BP1. Public datasets sets from The Cancer Genome Atlas (TCGA) and Human Cancer Metastasis Database (HCMDB), receiver operating characteristic (ROC) plotter, and two CRC cell lines, HCT-116 and DLD-1, were used for validating our findings. We showed that IGF2BP1 was overexpressed in tumor specimens compared to 13 paired normal parts by examining the immunoreactivity of IGF2BP1 (p = 0.045). The increased expression of IGF2BP1 in primary tumor parts was observed regardless of metastatic status (p < 0.001) in HCMDB analysis. IGF2BP1 expression was significantly associated with young age (59.6% vs. 46.7%, p-value = 0.043) and advanced stage (61.3% vs. 40.0%, p-value = 0.001). After controlling for confounding factors, IGF2BP1 remained an independent prognostic factor (HR = 1.705, p-value = 0.005). TCGA datasets analysis indicated that high IGF2BP1 expression showed a lower 5-year survival rate (58% vs. 65%) in CRC patients. The increased expression of IGF2BP1 in chemotherapy non-responder rectal cancer patients was observed using a ROC plotter. Overexpression of IGF2BP1 promoted the colony-forming capacity and 5-fluorouracil and etoposide resistance in CRC cells. Here, IGF2BP1 was an independent poor prognostic marker in CRC patients and contributed to aggressive phenotypes in CRC cell lines.

RAB27B-activated secretion of stem-like tumor exosomes delivers the biomarker microRNA-146a-5p, which promotes tumorigenesis and associates with an immunosuppressive tumor microenvironment in colorectal cancer.

The dynamic cell-cell communication is essential for tissue homeostasis in normal physiological circumstances and contributes to a diversified tumor microenvironment. Although exosomes are extracellular vesicles that actively participate in cell-cell interaction by shutting cellular components, impacts of tumor exosomes in the context of cancer stemness remain elusive. Here, we expand colorectal cancer stem cells (CRCSCs) as cancer spheroids and demonstrate that the ß-catenin/Tcf-4-activated RAB27B expression is required for the secretion of CRCSC exosomes. In an exosomal RNA sequencing analysis, a switch of exosomal RNA species from retrotransposons to microRNAs (miRNAs) is identified upon expanding CRCSCs. miRNA-146a-5p (miR-146a) is the major miRNA in CRCSC exosomes and exosomal miR-146a promotes stem-like properties and tumorigenicity by targeting Numb in recipient CRC cells. Among 53 CRC patients, those with abundant exosomal miR-146a expression in serum exhibits higher miR-146aHigh /NumbLow CRCSC traits, an increased number of tumor-filtrating CD66(+) neutrophils and a decreased number of tumor-infiltrating CD8(+) T cells. Our study elucidates a unique mechanism of tumor exosome-mediated stemness expansion.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an independent prognostic marker in wild-type KRAS metastatic colorectal cancer after colorectal liver metastasectomy.

BACKGROUND: The impact of KRAS signaling on cancerous inhibitor of protein phosphatase 2A (CIP2A) expression has not yet been explored. We investigated the impact of KRAS on CIP2A expression in colorectal cancer patients after colorectal liver metastasectomy. METHODS: We examined CIP2A expression by immunohistochemistry (IHC) and used direct sequencing to identify the mutational status of KRAS exon 2 (codon 12 and 13). The association between CIP2A expression, KRAS genotype, clinicopathological parameters and survival were examined by the Kaplan-Meier method and the Cox proportional hazards model. A combination of immunoblotting and proliferation assays were employed to elucidate the role of CIP2A in signal transduction pathways in wild-type KRAS Caco-2 cells. RESULTS: A total of 220 colorectal cancer patients who had undergone colorectal liver metastasectomy were included in the study. The mutant KRAS genotype was associated with CIP2A overexpression. CIP2A expression was an independent prognostic marker in patients with wild-type KRAS metastatic colorectal cancer after colorectal liver metastasectomy (relative risk = 1.873, P = 0.019). Targeted silencing of CIP2A in Caco-2 cells (wild-type KRAS) led to decreased expression of pERK/ERK and decreased cell proliferation. Overexpression of mutant KRAS G12D in Caco-2 cells led to an increase in CIP2A expression and cell proliferation. In Caco-2 cells with the KRAS G12D, KRAS overexpression preserved the regulation effect of CIP2A in KRAS and abrogated the impact of CIP2A regulation on pERK/ERK and cell proliferation. CIP2A inhibition also increased the efficacy of cetuximab in Caco-2 cells. CONCLUSIONS: CIP2A is an independent prognostic marker in patients with wild-type KRAS metastatic colorectal cancer after colorectal liver metastasectomy.

Interferon Gamma Induces Higher Neutrophil Extracellular Traps Leading to Tumor-Killing Activity in Microsatellite Stable Colorectal Cancer.

Many patients with colorectal cancer do not respond to immune checkpoint blockade (ICB) therapy, highlighting the urgent need to understand tumor resistance mechanisms. Recently, the link between the IFNγ signaling pathway integrity and ICB resistance in the colorectal cancer tumor microenvironment has been revealed. The immunosuppressive microenvironment poses a significant challenge to antitumor immunity in colorectal cancer development. Tumor-associated neutrophils found in tumor tissues exhibit an immunosuppressive phenotype and are associated with colorectal cancer patient prognosis. Neutrophil extracellular traps (NET), DNA meshes containing cytotoxic enzymes released into the extracellular space, may be promising therapeutic targets in cancer. This study showed increased NETs in tumor tissues and peripheral neutrophils of high levels of microsatellite instability (MSI-H) patients with colorectal cancer compared with microsatellite stable (MSS) patients with colorectal cancer. IFNγ response genes were enriched in MSI-H patients with colorectal cancer compared with patients with MSS colorectal cancer. Co-culturing neutrophils with MSI-H colorectal cancer cell lines induced more NET formation and higher cellular apoptosis than MSS colorectal cancer cell lines. IFNγ treatment induced more NET formation and apoptosis in MSS colorectal cancer cell lines. Using subcutaneous or orthotopic CT-26 (MSS) tumor-bearing mice models, IFNγ reduced tumor size and enhanced PD-1 antibody-induced tumor-killing activity, accompanied by upregulated NETs and cellular apoptosis. These findings suggest that IFNγ could be a therapeutic strategy for MSS colorectal cancer.

The survival outcome differs between left-sided colon cancer and middle/low rectal cancer after colorectal hepatic metastasectomy.

BACKGROUND: The clinical outcomes between left-sided colon cancer and middle/low rectal cancer seem to be different. This study aimed to examine the effect of primary tumor location regarding the left-sided colon and middle/low rectum on the overall survival (OS) of patients who underwent colorectal hepatic metastasectomy. METHODS: Patients who underwent colorectal hepatic metastasectomy were retrospectively enrolled. Patients were classified into 2 groups according to the primary tumor location (left-sided colon and middle/low rectum). Categorical variables were compared using the chi-square test or Fisher exact test, and continuous variables were analyzed using the Student t test. Survival was analyzed using the Kaplan-Meier method and log-rank test. The prognostic factors were analyzed by univariate and multivariate analyses using Cox proportional hazards regression models. RESULTS: Overall, 365 patients were enrolled. Patients with left-sided colon cancer had significantly better OS than those with middle/low rectal cancer (hazard ratio [HR], 0.725; P = .018), with median OS estimates of 48 and 38 months, respectively. In the subgroup analysis of RAS mutations, patients with left-sided colon cancer had significantly prolonged OS compared with those with middle/low rectum cancer (HR, 0.608; P = .034), with median OS estimates of 49 and 26 months, respectively. This observation was limited to patients with RAS mutations. CONCLUSION: According to our findings, patients with middle/low rectal cancer had poorer survival outcome and should not be categorized together with patients with left-sided colon cancer in terms of OS after colorectal hepatic metastasectomy.

The salvage lenvatinib-based regimen provides survival benefit in patients with refractory metastatic colorectal cancer.

Salvage treatment for refractory metastatic colorectal cancer (mCRC) has yet to be identified. We aimed to evaluate the efficacy of a salvage lenvatinib-based regimen for refractory mCRC. In total, 371 patients were categorized into lenvatinib-based and non-lenvatinib-based groups. In the lenvatinib-based group, patients who received lenvatinib at a dosage of 10 mg/day were categorized into lenvatinib/chemotherapy and lenvatinib/immunotherapy subgroups. We reported overall survival (OS) and progression-free survival (PFS) using the Kaplan-Meier method. OS1 was used to measure the time from disease progression after TAS-102 and regorafenib treatment to death, while OS2 was used to measure the time from TAS-102 or regorafenib treatment to death. Propensity score matching analysis was employed to compare the characteristics between the lenvatinib-based and non-lenvatinib-based groups. Next-generation sequencing (NGS) information was analyzed using R software. The lenvatinib-based group exhibited longer OS than did the non-lenvatinib-based group (OS1, 11.4 vs. 3.7 months; OS2, 27.2 vs. 8.2 months). The disease control rate (DCR) and objective response rate (ORR) of the lenvatinib-based regimens were 69.4% and 6.1%, respectively. Lenvatinib/chemotherapy and lenvatinib/immunotherapy had similar PFS, OS, DCR, and ORR. The adverse effects were manageable. After propensity score matching, the lenvatinib-based group continued to exhibit significantly longer OS1 and OS2 than did the non-lenvatinib-based group. NGS analysis revealed that GNAS and KRAS alterations were associated with a worse treatment response and prolonged survival, respectively. In conclusion, a moderate-dose salvage lenvatinib-based regimen demonstrated promising clinical activity and tolerability in treating refractory mCRC.

Lenvatinib Plus Pembrolizumab Versus Standard of Care for Previously Treated Metastatic Colorectal Cancer: Final Analysis of the Randomized, Open-Label, Phase III LEAP-017 Study.

PURPOSE: Treatment options are limited for patients with previously treated metastatic colorectal cancer (mCRC). In the LEAP-017 study, we evaluate whether lenvatinib in combination with pembrolizumab improves outcomes compared with standard of care (SOC) in previously treated mismatch repair proficient or not microsatellite instability high (pMMR or not MSI-H) mCRC. METHODS: In this international, multicenter, randomized, controlled, open-label, phase III study, eligible patients age 18 years and older with unresectable, pMMR or not MSI-H mCRC, that had progressed on or after, or could not tolerate, standard treatment, were randomly assigned 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 400 mg intravenously once every 6 weeks or investigator's choice of regorafenib or trifluridine/tipiracil (SOC). Randomization was stratified by presence or absence of liver metastases. The primary end point was overall survival (OS). LEAP-017 is registered at ClinicalTrials.gov (NCT04776148), and has completed recruitment. RESULTS: Between April 8, 2021, and December 21, 2021, 480 patients were randomly assigned to lenvatinib plus pembrolizumab (n = 241) or SOC (n = 239). At final analysis (median follow-up of 18.6 months [IQR, 3.9]), median OS with lenvatinib plus pembrolizumab versus SOC was 9.8 versus 9.3 months (hazard ratio [HR], 0.83 [95% CI, 0.68 to 1.02]; P = .0379; prespecified threshold P = .0214). Grade ≥3 treatment-related adverse events occurred in 58.4% (lenvatinib plus pembrolizumab) versus 42.1% (SOC) of patients. Two participants died due to treatment-related adverse events, both in the lenvatinib plus pembrolizumab arm. CONCLUSION: In patients with pMMR or not MSI-H mCRC that had progressed on previous therapy, there was no statistically significant improvement in OS after lenvatinib plus pembrolizumab treatment versus SOC. No new safety signals were observed.

Anti-VEGF Therapy Possibly Extends Survival in Patients With Colorectal Brain Metastasis by Protecting Patients From Neurologic Disability.

BACKGROUND: Colorectal brain metastases (CBMs) are rare with poor prognosis. There is still no standard systemic treatment for multiple or unresectable CBM. our study aimed to explore the impact of anti-VEGF therapy on overall survival, brain-specific disease control, and neurologic symptom burden in patients with CBM. METHODS: A total of 65 patients with CBM under treatment were retrospectively enrolled and divided into anti-VEGF based systemic therapy or non-anti-VEGF based therapy. A total of 25 patients who received at least 3 cycles of anti-VEGF agent and 40 patients without anti-VEGF therapy were analyzed by endpoints of overall survival (OS), progression-free survival (PFS), intracranial PFS (iPFS) and neurogenic event-free survival (nEFS). Gene expression in paired primary metastatic colorectal cancer (mCRC), liver, lung and brain metastasis from NCBI data was analyzed using top Gene Ontology (GO) and cBioPortal. RESULTS: Patients who treated with anti-VEGF therapy had significantly longer OS (19.5 vs. 5.5 months, P = .009), iPFS (14.6 vs. 4.1 months, P < .001) and nEFS (17.6 vs. 4.4 months, P < .001). Patients who received anti-VEGF therapy beyond any disease progression presented with superior OS (19.7 vs. 9.4 months, P = .039). Top GO and cBioPortal analysis revealed a stronger molecular function of angiogenesis in intracranial metastasis. CONCLUSIONS: Anti-VEGF based systemic therapy showed favorable efficacy that was reflected in longer overall survival, iPFS and NEFS in patients with CBM.

Surgical strategy for colorectal cancer with synchronous liver and extrahepatic metastases: A scoring system and decision tree model.

BACKGROUND: The role of hepatectomy in a specific group of patients with synchronous colorectal cancer with liver metastases (SCRLM) and synchronous extrahepatic disease (SEHD) is still unclear. The aim of this study was to evaluate the efficacy of liver surgery and define the selection criteria for surgical candidates in patients with SCRLM + SEHD. METHODS: Between July 2007 and October 2018, 475 patients with colorectal cancer with liver metastases (CRLM) who underwent liver resection were retrospectively reviewed. Sixty-five patients with SCRLM + SEHD were identified and included in the study. Clinical pathological data of these patients were analyzed to evaluate the influence on survival. Important prognostic factors were identified by univariate and multivariate analyses. The risk score system and decision tree analysis were generated according to the important prognostic factors for better patient selection. RESULTS: The 5-year survival rate of patients with SCRLM + SEHD was 21.9%. The most important prognostic factors were SCRLM number of more than five, site of SEHD other than the lung only, inability to achieve SCRLM + SEHD R0 resection, and BRAF mutation of cancer cells. The proposed risk score system and decision tree model easily discriminated between patients with different survival rates and identified the profile of suitable surgical patients. CONCLUSION: Liver surgery should not be a contraindication for patients with SCRLM + SEHD. Patients with complete SCRLM + SEHD R0 resection, SCRLM number less than or equal to five, SEHD confined to the lung only, and wild-type BRAF could have favorable survival outcomes. The proposed scoring system and decision tree model may be beneficial to patient selection in clinical use.

SNAIL regulates interleukin-8 expression, stem cell-like activity, and tumorigenicity of human colorectal carcinoma cells.

BACKGROUND & AIMS: Some cancer cells have activities that are similar to those of stem cells from normal tissues, and cell dedifferentiation correlates with poor prognosis. Little is known about the mechanisms that regulate the stem cell-like features of cancer cells; we investigated genes associated with stem cell-like features of colorectal cancer (CRC) cells. METHODS: We isolated colonospheres from primary CRC tissues and cell lines and characterized their gene expression patterns by microarray analysis. We also investigated the biological features of the colonosphere cells. RESULTS: Expanded CRC colonospheres contained cells that expressed high levels of CD44 and CD166, which are markers of colon cancer stem cells, and had many features of cancer stem cells, including chemoresistance and radioresistance, the ability to initiate tumor formation, and activation of epithelial-mesenchymal transition (EMT). SNAIL, an activator of EMT, was expressed at high levels by CRC colonospheres. Overexpression of Snail in CRC cells induced most properties of colonospheres, including cell dedifferentiation. Two hundred twenty-seven SNAIL-activated genes were up-regulated in colonospheres; gene regulatory networks centered around interleukin (IL)-8 and JUN. Blocking IL-8 expression or activity disrupted SNAIL-induced stem cell-like features of colonospheres. We observed that SNAIL activated the expression of IL8 by direct binding to its E3/E4 E-boxes. In CRC tissues, SNAIL and IL-8 were coexpressed with the stem cell marker CD44 but not with CD133 or CD24. CONCLUSIONS: In human CRC tissues, SNAIL regulates expression of IL-8 and other genes to induce cancer stem cell activities. Strategies that disrupt this pathway might be developed to block tumor formation by cancer stem cells.

Evaluation of prognosis for carcinoma of unknown origin in elderly patients.

PURPOSE: Carcinoma of unknown origin has a poor outcome and usually occurs in elderly patients. In this article, we analyzed the prognostic factors in elderly patients with cancer of unknown primary site (CUP) for treatment considerations. PATIENTS AND METHODS: Patients >70 years old with histologically proven carcinoma were retrospectively reviewed. The prognostic factors were analyzed with univariate and multivariate Cox regression. RESULTS: We included 63 patients aged 70-79 years and 51 patients ≥80 years old. The results of multivariate Cox regression in the 70-79 years age group revealed white blood cell count ≤10(4)/ml [p = 0.033; hazard ratio (HR) 2.51, range 1.079-5.840] and albumin ≥3.5 g/dl (p = 0.007; HR 3.38, range 1.398-8.177) as independent factors. In the group of patients ≥80 years old, Eastern Cooperative Oncology Group performance status <1 (p = 0.020), white blood cell count ≤10(4)/ml (p = 0.001), albumin ≥3.5 g/dl (p = 0.006), lactate dehydrogenase (LDH) ≤250 U/l (p = 0.002) and non-chest metastasis (p = 0.043) were significantly better with univariate analysis. Multivariate Cox regression revealed albumin ≥3.5 g/dl (p = 0.007; HR 3.28, range 1.389-7.745) and LDH ≤250 U/l (p = 0.045; HR 3.18, range 1.026-9.848) as independent factors. CONCLUSIONS: For elderly patients with CUP, the serum albumin level seems to be a consistently independent prognostic factor. In patients >80 years old, serum LDH plays an important role in prognosis. This study is helpful in predicting the outcome and management for this group of patients.

International Staging System predicts prognosis of Chinese patients with multiple myeloma across different calendar periods with application of novel agents.

The applicability of the International Staging System (ISS) for Chinese patients with multiple myeloma (MM) has not been demonstrated, especially with respect to treatments with novel agents. Newly diagnosed MM patients at Taipei Veterans General Hospital were enrolled between 1996 and 2007. Data regarding clinical features, laboratory tests, and outcome at last follow-up were collected. A total of 389 MM patients (71% male) were enrolled, with median age of 71 years. At diagnosis, 72.7% had Durie-Salmon (DS) stage III disease, 56.2% had ISS stage III disease, and 34% had serum creatinine ≧2.0 mg/dL. Compared with patients diagnosed in the first calendar period 1996-2001, the patients of the second calendar period 2002-2007 were older and more of these patients had received novel agents, especially thalidomide. The median overall survival period was 20.5 months, with a significant increase of patients in the second calendar period (15.3 and 28.2 months, respectively; P = 0.002), especially for those with ISS stages I and II. In the Cox proportion model, elevated serum ß(2) microglobulin at diagnosis (≧3.5 mg/L), old age (≧65 years), and impaired renal function were found to be independently associated with poor survival. Over the entire period, the ISS was found to be effective in providing an accurate prognosis with respect to different ages and calendar periods. This is the first study to show the applicability of ISS for Chinese patients with MM, especially for those who had received thalidomide.

BRAF mutation is a prognostic biomarker for colorectal liver metastasectomy.

BACKGROUND AND OBJECTIVES: In metastatic colorectal cancer, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is a predictive biomarker for anti-epidermal growth factor receptor (EGFR) treatment and V-raf murine sarcoma viral oncogene homolog B1 (BRAF) is a prognostic biomarker. We aimed to determine the impact of KRAS and BRAF mutation as determined from liver metastases specimens on overall survival (OS) in patients following colorectal liver metastasectomy. METHODS: Liver metastases specimens (n = 292) obtained from patients after liver metastasectomy were used to determine the KRAS/BRAF genotype. Associations between clinicopathological parameters and KRAS/BRAF genotype were identified by univariate and multivariate analyses using the Cox proportional hazards model. The impact of KRAS/BRAF genotype on survival was analyzed using the Kaplan-Meier method. RESULTS: The 5-year survival rate of the cohort was 55.8%. The KRAS and BRAF mutation rates were 38.0 and 2.1%, respectively. BRAF genotype, but not KRAS, was found to be an independent prognostic biomarker (HR = 5.181, P = 0.002) after adjustment for other significant confounding clinicopathological variates: Number of liver metastases (HR = 1.983, P = 0.009), concomitant extrahepatic disease (HR = 1.858, P = 0.014), and surgical margin (HR = 3.241, P < 0.001). BRAF genotype was an independent prognostic biomarker in patients with liver metastases only after metastasectomy (HR = 6.245, P < 0.003). CONCLUSIONS: BRAF mutation is an independent prognostic biomarker for colorectal liver metastasectomy.

Duloxetine improves oxaliplatin-induced neuropathy in patients with colorectal cancer: an open-label pilot study.

BACKGROUND: This open-label pilot study is aimed to evaluate the efficacy and tolerability of the antidepressant duloxetine, which is effective for diabetic neuropathic pain, in the treatment of chronic oxaliplatin-induced peripheral neuropathy (OIPN). METHODS: We enrolled a total of 39 patients with stage III or IV colorectal cancer with chronic OIPN. They were treated with duloxetine by increasing the dose from 30 mg/day to 60 mg/day. Patients' pain intensity was rated at baseline and 12 weeks after duloxetine administration. The severity of neuropathic pain was evaluated using the visual analog scale (VAS) score and the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3 (NCI-CTCAE v3.0). RESULTS: Nine patients (23.1%) discontinued duloxetine before the end of treatment because of adverse events. Of the remaining 30 patients, 19 patients (63.3%) had a VAS score improvement. Among them, nine (47.4%) showed a simultaneous grade improvement, and the other 10 patients (52.6%) had a stable grade according to NCI-CTCAE v3.0. Treatment with duloxetine did not impair renal or liver function and did not interfere with chemotherapy. CONCLUSIONS: Duloxetine is feasible in treating chronic OIPN with tolerable toxicity at a daily dose of 60 mg/day.

Molecular actions of exosomes and their theragnostics in colorectal cancer: current findings and limitations.

Extracellular vesicles (EVs) are cell-released, membranous structures essential for intercellular communication. The biochemical compositions and physiological impacts of exosomes, lipid-bound, endosomal origin EVs, have been focused on, especially on the tumor-host interactions in a defined tumor microenvironment (TME). Despite recent progress in targeted therapy and cancer immunotherapy in colorectal cancer (CRC), cancer patients still suffer from distal metastasis and tumor relapse, suggesting unmet needs for biomarkers directing therapeutic interventions and predicting treatment responsiveness. As exosomes are indispensable for intercellular communication and high exosome abundance makes them feasible biomarker molecules, this review discusses exosome heterogeneity and how exosomes orchestrate the interplay among tumor cells, cancer stem cells (CSCs) and host cells, including stromal cells, endothelial cells and immunocytes, in the CRC TME. This review also discusses mechanisms for loading exosomal contents and potential exosomal DNA, RNA and protein biomarkers for early CRC detection. Finally, we summarize the diagnostic and therapeutic exosomes in clinical trials. We envision that detecting and targeting cancer-specific exosomes could provide therapeutic advances in developing personalized cancer medicine.

A Long-Term and Large-Scale Real-World Study in Taiwan: Efficacy of Target Therapy in Stage IV Colorectal Cancer.

This study expands the understanding of the role of target therapy in improving survival of patients with mCRC based on real-world study results. These data represent potential survival outcomes of Taiwanese patients with mCRC in clinical practice. CRC is the most commonly diagnosed cancer and the third leading cause of cancer-related death in Taiwan. The aim of this study was to evaluate the efficacy of target therapy in combination with chemotherapy for mCRC in Taiwan. This was a real-world, retrospective, observational study in patients diagnosed with mCRC (N=1583). A total of 792 patients received chemotherapy plus target therapy (anti-EGFR therapy, n=180; anti-VEGF therapy, n=612) and 791 patients who received chemotherapy alone. Overall survival (OS) and progression-free survival (PFS) were examined. For RAS wild-type patients, the median OS (mOS) was 34.3 months in the EGFR L (left-sided colon) group, 27.3 months in the VEGF L group, 18.4 months in VEGF R (right-sided colon) group, and 13.8 months in EGFR R group (P<0.001). Median PFS (mPFS) was 9.8 months in the EGFR L group, 8.9 months in the VEGF L group, 6.8 months in VEGF R group, and 5.8 months in EGFR R group. In patients with a RAS mutation, mOS was 25.4 months in the VEGF L group and 19.4 months in the VEGF R group (P=0.167). Judicious treatment allocation in Taiwanese patients with mCRC can result in an mOS of 34.3 months using cetuximab plus chemotherapy for left-sided tumors. An mOS of 48.5 months can be achieved using cetuximab plus chemotherapy in the neoadjuvant setting in mCRC patients with left-sided tumors. This study expands our understanding of the role of target therapy in improving survival of mCRC patients based on real-world study results.

Low absolute lymphocyte count and addition of rituximab confer high risk for interstitial pneumonia in patients with diffuse large B-cell lymphoma.

Several small-scale studies have reported pulmonary toxicity among patients with diffuse large B-cell lymphoma (DLBCL) receiving rituximab-containing chemotherapy, though whether the use of rituximab predisposes to interstitial pneumonia (IP) remains unclear. This retrospective study was intended to identify the characteristics and risk factors of IP in patients with DLBCL. Between 2000 and 2009, 529 consecutive patients with DLBCL receiving first-line tri-weekly COP- or CHOP-based chemotherapy with or without rituximab were enrolled as subjects. IP was defined as diffuse pulmonary interstitial infiltrates found on computed tomography scans in conjunction with respiratory symptoms. IP was observed in 26 patients (4.9%), six of whom were confirmed with Pneumocystis jirovecii pneumonia. The median number of chemotherapy courses before IP was four cycles. Using multivariate analysis, absolute lymphocyte count less than 1×10(9)/l at diagnosis [odds ratio (OR) 2.75, p=0.014] and the addition of rituximab to chemotherapy (OR 4.56, p=0.003) were identified as independent risk factors for IP. In conclusion, the incidence of IP is increased in patients with DLBCL receiving rituximab-containing chemotherapy. Specific subgroups with lymphopenia at diagnosis may justify close scrutiny to detect pulmonary complications.

Prevalence and prognostic influence of genomic changes of EGFR pathway markers in synovial sarcoma.

BACKGROUND: We aimed to study the prevalence and prognostic influence of epidermal growth factor receptor (EGFR) and its downstream effectors in synovial sarcoma (SS). OBJECTIVES AND METHODS: The tissue blocks from 30 patients were obtained. Expression of EGFR and phosphatase and tensin homolog (PTEN) were examined by immunohistochemistry, and mutation status of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) exon 2, V-raf murine sarcoma viral oncogene homolog B1 (BRAF) exon 15, phosphoinositide-3-kinase, catalytic, alpha polypeptide (PI3KCA) exons 9, 20, and PTEN exons 5-9 were analyzed by direct sequencing. RESULTS: EGFR overexpression and PTEN deletion were found in 63.3% and 46.7% of patients. Sequence analysis failed to demonstrate mutations of KRAS and BRAF. However, an E545A point mutation in exon 9 of PI3KCA was found in 2 of the 30 (6.7%) cases and 4 point mutations in exon 5 (E99K, D106N), intro 6 to exon 7 (AATA(G)), and exon 9 (A359T) of PTEN were found in 2 of the 30 (6.7%) cases. PTEN loss was significantly more frequent in cases of trunk tumors, and the overexpression of EGFR was significantly more prevalent in patients who were 35 or older. CONCLUSIONS: PTEN deletion was associated with poor survival.