PEGylated chitosan-coated nanophotosensitizers for effective cancer treatment by photothermal-photodynamic therapy combined with glutathione depletion.

The combination of photothermal therapy (PTT) and photodynamic therapy (PDT) has emerged as a promising strategy for cancer treatment. However, the poor photostability and photothermal conversion efficiency (PCE) of organic small-molecule photosensitizers, and the intracellular glutathione (GSH)-mediated singlet oxygen scavenging largely decline the antitumor efficacy of PTT and PDT. Herein, a versatile nanophotosensitizer (NPS) system is developed by ingenious incorporation of indocyanine green (ICG) into the PEGylated chitosan (PEG-CS)-coated polydopamine (PDA) nanoparticles via multiple π-π stacking, hydrophobic and electrostatic interactions. The PEG-CS-covered NPS showed prominent colloidal and photothermal stability as well as high PCE (ca 62.8 %). Meanwhile, the Michael addition between NPS and GSH can consume GSH, thus reducing the GSH-induced singlet oxygen scavenging. After being internalized by CT26 cells, the NPS under near-infrared laser irradiation produced massive singlet oxygen with the aid of thermo-enhanced intracellular GSH depletion to elicit mitochondrial damage and lipid peroxide formation, thus leading to ferroptosis and apoptosis. Importantly, the combined PTT and PDT delivered by NPS effectively inhibited CT26 tumor growth in vivo by light-activated intense hyperthermia and redox homeostasis disturbance. Overall, this work presents a new tactic of boosting antitumor potency of ICG-mediated phototherapy by PEG-CS-covered NPS.

Light-Activatable MBD-Readers of 5-Methylcytosine Reveal Domain-Dependent Chromatin Association Kinetics In Vivo.

5-Methylcytosine (5mC) is the central epigenetic mark of mammalian DNA, and plays fundamental roles in chromatin regulation. 5mC is dynamically read and translated into regulatory outputs by methyl-CpG-binding domain (MBD) proteins. These multidomain readers recognize 5mC via an MBD domain, and undergo additional domain-dependent interactions with multiple additional chromatin components. However, studying this dynamic process is limited by a lack of methods to conditionally control the 5mC affinity of MBD readers in cells. Light-control of MBD association to chromatin by genetically encoding a photocaged serine at the MBD-DNA interface is reported. The authors study the association of MBD1 to mouse pericentromeres, dependent on its CxxC3 and transcriptional repressor domains (TRD) which interact with unmethylated CpG and heterochromatin-associated complexes, respectively. Both domains significantly modulate association kinetics, arguing for a model in which the CxxC3 delays methylation responses of MBD1 by holding it at unmethylated loci, whereas the TRD promotes responses by aiding heterochromatin association is studied. Their approach offers otherwise inaccessible kinetic insights into the domain-specific regulation of a central MBD reader, and sets the basis for further unravelling how the integration of MBDs into complex heterochromatin interaction networks control the kinetics of 5mC reading and translation into altered chromatin states.

Safety and Efficacy of Oral Nalbuphine on Postoperative Pain in Hemorrhoidectomy Patients: A Randomized, Double-blind, Placebo-controlled, Pivotal Trial.

OBJECTIVES: Severe postoperative pain requiring opioid treatment has been reported in 20% to 40% of hemorrhoidectomy patients. Compared with morphine, nalbuphine offers better hemodynamic stability, a lower risk of respiratory depression, and a lower potential for addiction. Nalbuphine was developed from the intravenous form into an oral form (PHN131) to alleviate moderate-to-severe pain. MATERIALS AND METHODS: A randomized, double-blind, placebo-controlled, multiple-dose, parallel-design trial was conducted to evaluate the safety and efficacy of PHN131 in patients undergoing hemorrhoidectomy. Eligible patients were randomly assigned to receive either PHN131 soft capsules containing nalbuphine hydrochloride 60 mg or placebo capsules. Intramuscular diclofenac was the rescue analgesic. Pain was measured by the area under the curve of mean Visual Analog Scale pain intensity scores. RESULTS: Visual Analog Scale results in patients receiving PHN131 were significantly lower than placebo group scores through 48 hours postoperatively (149.2±75.52 vs. 179.6±65.97; P =0.0301). According to Brief Pain Inventory Short-Form scores, the impact of pain on quality of life was significantly smaller for the PHN131 group than for the placebo group. Time to the first use of diclofenac postoperatively was significantly longer in the PHN131 group than in the placebo group. The cumulative dosage of diclofenac in the PHN131 group was only around half of that in the placebo group ( P <0.0001). Drug-related adverse events were mild-to-moderate and resolved by the treatment end. No drug-related severe adverse events were observed. DISCUSSION: Our findings demonstrate that PHN131 is effective and well-tolerated in the treatment of moderate-to-severe post hemorrhoidectomy pain and may provide another option for patients to control their pain.

Modeling the survival of colorectal cancer patients based on colonoscopic features in a feature ensemble vision transformer.

The prognosis of patients with colorectal cancer (CRC) mostly relies on the classic tumor node metastasis (TNM) staging classification. A more accurate and convenient prediction model would provide a better prognosis and assist in treatment. From May 2014 to December 2017, patients who underwent an operation for CRC were enrolled. The proposed feature ensemble vision transformer (FEViT) used ensemble classifiers to benefit the combinations of relevant colonoscopy features from the pretrained vision transformer and clinical features, including sex, age, family history of CRC, and tumor location, to establish the prognostic model. A total of 1729 colonoscopy images were enrolled in the current retrospective study. For the prediction of patient survival, FEViT achieved an accuracy of 94 % with an area under the receiver operating characteristic curve of 0.93, which was better than the TNM staging classification (90 %, 0.83) in the experiment. FEViT reduced the limited receptive field and gradient disappearance in the conventional convolutional neural network and was a relatively effective and efficient procedure. The promising accuracy of FEViT in modeling survival makes the prognosis of CRC patients more predictable and practical.

Optochemical Control of TET Dioxygenases Enables Kinetic Insights into the Domain-Dependent Interplay of TET1 and MBD1 while Oxidizing and Reading 5-Methylcytosine.

Methyl-CpG binding domain (MBD) proteins and ten-eleven-translocation (TET) dioxygenases are the readers and erasers of 5-methylcytosine (5mC), the central epigenetic mark of mammalian DNA. We employ light-activatable human TET1 controlled by a genetically encoded photocaged serine to enable in vivo kinetic studies of their interplay at the common substrate methylated cytosine-guanine (mCpG). We identify the multidomain reader MBD1 to negatively regulate TET1-catalyzed 5mC oxidation kinetics via its mCpG-binding MBD domain. However, we also identify the third Cys-x-x-Cys (CXXC3) domain of MBD1 to promote oxidation kinetics by TET1, dependent on its ability to bind nonmethylated CpG, the final product of TET-mediated mCpG oxidation and active demethylation. In contrast, we do not observe differences in TET1 regulation for MBD1 variants with or without the transcriptional repressor domain. Our approach reveals a complex, domain-dependent interplay of these readers and erasers of 5mC with different domain-specific contributions of MBD1 to the overall kinetics of TET1-catalyzed global 5mC oxidation kinetics that contribute to a better understanding of dynamic methylome shaping.

Planned Short-Course Radiation (scRT) is Superior to Upfront Concurrent Chemoradiation (CCRT) in Treating Metastatic Rectal Cancer.

BACKGROUND OR PURPOSE: To compare the cost-performance between planned short-course radiation and upfront concurrent chemoradiation on metastatic rectal cancer. METHODS: A total of 75 patients with metastatic rectal cancer who underwent planned short-course radiation or upfront concurrent chemoradiation were enrolled. The Kaplan-Meier method was used to compute the survival rates. The χ2 test was used to compare baseline characteristics. The Cox proportional hazards model was applied to determine the prognostic influence of clinicopathological factors. RESULTS: The planned short-course radiation is superior to upfront concurrent chemoradiation in overall survival for the patients with metastatic rectal cancer (34.8 vs. 20.2 months, P = 0.010). The planned short-course radiation was an independent prognostic factor (P = 0.009, HR (95% CI) = 0.319(0.135-0.752)). The efficacy of radiation on downstaging was similar between planned short-course radiation and upfront concurrent chemoradiation. The total cost of concurrent chemoradiation is 4.52-fold more expensive than that of short-course radiation (340,142 vs. 75,106 NT dollars, respectively). CONCLUSIONS: Based on the impressive cost-performance of planned short-course radiation compared with upfront concurrent chemoradiation (better OS, modest downstaging and lower cost), planned short-course radiation should be the preferred radiation approach for managing metastatic rectal cancer.

Risk factors for delayed perineal wound healing and its impact on prolonged hospital stay after abdominoperineal resection.

BACKGROUND: Perineal wound complications are a long-lasting issue for abdominoperineal resection (APR) patients. Complication rates as high as 60% have been reported, with the most common complication being delayed perineal wound healing. The aim of this study was to identify risk factors for delayed perineal wound healing and its impact on prolonged hospital stay. METHODS: We included low rectal tumor patients who underwent APR at a referral medical center from April 2002 to December 2017; a total of 229 patients were included. The basic characteristics and surgical outcomes of the patients were analyzed to identify risk factors for delayed perineal wound healing (> 30 days after APR) and prolonged hospital stay (post-APR hospital stay > 14 days). RESULTS: All patients received primary closure for their perineal wound. The majority of patients were diagnosed with adenocarcinoma (N = 213, 93.1%). In the univariate analysis, patients with hypoalbuminemia (albumin < 3.5 g/dL) had an increased risk of delayed wound healing (39.5% vs. 60.5%, P = 0.001), which was an independent risk factor in the multivariable analysis (OR 2.962, 95% CI 1.437-6.102, P = 0.003). Patients with delayed wound healing also had a significantly increased risk of prolonged hospital stay (OR 6.404, 95% CI 3.508-11.694, P < 0.001). CONCLUSIONS: Hypoalbuminemia was an independent risk factor for delayed wound healing, which consequently led to a prolonged hospital stay. Further clinical trials are needed to reduce the incidence of delayed perineal wound healing by correcting albumin levels or nutritional status before APR.

Prognosticators of Long-Term Outcomes of TNM Stage II Colorectal Cancer: Molecular Patterns or Clinicopathological Features.

BACKGROUND: Patients with stage II colorectal cancer (CRC) have a higher risk of recurrence when they have certain risk factors, including clinical and pathological patterns. However, as the prognostic role of molecular patterns for stage II disease is still unclear, this study aimed to investigate it. METHODS: A total of 509 patients with stage II CRC were enrolled, and all clinical, pathological, and molecular data were collected. Molecular patterns included microsatellite instability (MSI); elevated microsatellite alterations at selected tetranucleotides (EMAST) status; and expression of RAS/RAF genes, genes of the APC pathway, and other gene mutations. The endpoints were oncological outcomes, including overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), local recurrence (LR), and distant recurrence (DR). Cox regression analysis was used. RESULTS: Numerous molecular patterns influenced the oncological outcomes on univariate analysis, but no variable reached significance in LR. On multivariate analysis, a mucinous component (MC) > 50% (P < 0.01) was significant for OS and CSS. Lymphovascular invasion (LVI; P< 0.01), MC > 50% (P < 0.01), and EMAST-H (P = 0.02) significantly influenced DFS, whereas LVI (P < 0.01), MC > 50% (P < 0.01), and TP53 mutation (P = 0.02) were significant for DR. CONCLUSIONS: In this study, MSI, EMAST, and RAS/RAF alterations did not influence the oncological outcomes. Overall, LVI and MC were two significant prognostic factors for DFS and DR. Thus, the histopathology, rather than the genes, plays a major role in the prognosis of patients with stage II CRC.

Structure-guided development of purine amide, hydroxamate, and amidoxime for the inhibition of non-small cell lung cancer.

An 8-oxopurine-6-carboxamide compound (1a) was previously identified as an inhibitor of non-small cell lung cancer (NSCLC). In this study, more than 30 purine-6-carboxamide derivatives with variations at the C2, N7, C8, and N9 positions were synthesized to investigate the structure-activity relationship as a basis for the construction of an advanced pharmacophore model. This model suggests that purine-6-hydroxamate and purine-6-amidoxime analogs could form more hydrogen bonds with a target protein to enhance the inhibitory activities against H1975 cells. Among the series of analogs, hydroxamate 17 and amidoxime 19a exhibited excellent potency against H1975 cells (IC50 < 1.5 µM) and other lung cancer cells with either wild-type or mutated epidermal growth factor receptor (EGFR). Mouse experiments indicated that compounds 17 and 19a were efficient anticancer agents with no appreciable toxicity. The mechanisms of action for the induction of cell apoptosis were determined to involve microtubule fragmentation and p53-mediated signaling pathways.

Clinicopathological and molecular differences in colorectal cancer according to location.

PURPOSE: The incidence, pathogenesis, molecular pathways, and outcomes of colorectal cancer vary depending on the location of the tumor. This study aimed to compare the difference in tumor characteristics and the outcome between right-sided colon cancer and left-sided colorectal cancer (LCRC). MATERIALS AND METHODS: A total of 1503 patients with colorectal cancer who underwent surgery at the Taipei Veterans General Hospital between 2000 and 2010 were enrolled in this study. Right-sided colon cancer was defined as cancers in the cecum, ascending colon, and transverse colon, while LCRC was defined as cancers in the splenic flexure colon, descending colon, sigmoid colon, and rectum. The endpoint was overall survival. The mutations were detected via polymerase chain reaction and MASS array. The prognostic value was determined using the log-rank test and the Cox regression analysis. RESULTS: A total of 407 and 1096 cases were classified as right-sided colon cancer and LCRC, respectively. Compared to patients with LCRC, those with right-sided colon cancer had more mucinous type cancer (7.4% vs. 3.5%), poorly differentiated tumor (11.5% vs. 3.6%), and advanced tumor-node-metastasis stage. The risk for peritoneal tumor seeding was higher in the right-sided colon cancer group (12.8% vs. 5.7%). Overall survival was better in LCRC than in right-sided colon cancer ( P=0.036). CONCLUSIONS: In our study, right-sided colon cancer had a more advanced tumor stage, a higher risk of peritoneal metastasis, and a poorer outcome than LCRC. Moreover, right-sided colon cancer had more gene mutations in BRAF, KRAS, SMAD4, TGF-ß, PIK3CA, PTEN, AKT1, and high microsatellite instability.

Differences in gene mutations according to gender among patients with colorectal cancer.

BACKGROUND: The incidence, site distribution, and mortality rates of patients with colorectal cancer differ according to gender. We investigated gene mutations in colorectal patients and wanted to examine gender-specific differences. METHODS: A total of 1505 patients who underwent surgical intervention for colorectal cancer were recruited from March 2000 to January 2010 at Taipei Veterans' General Hospital and investigated for gene mutations in K-ras, N-ras, H-ras, BRAF, loss of 18q, APC, p53, SMAD4, TGF-ß, PIK3CA, PTEN, FBXW7, AKT1, and MSI. RESULTS: There were significant differences between male and female patients in terms of tumor location (p < 0.0001) and pathological stage (p = 0.011). The female patients had significantly more gene mutations in BRAF (6.4 vs. 3.3%, OR 1.985, p = 0.006), TGF-ß (4.7 vs. 2.5%, OR 1.887, p = 0.027), and revealed a MSI-high status (14.0 vs. 8.3%, OR 1.800, p = 0.001) than male patients. Male patients had significantly more gene mutations in N-ras (5.1 vs. 2.3%, OR 2.227, p = 0.012); however, the significance was maintained only for mutations in BRAF (OR 2.104, p = 0.038), MSI-high status (OR 2.003 p = 0.001), and N-ras (OR 3.000, p = 0.010) after the groups were divided by tumor site. CONCLUSION: Gene mutations in BRAF, MSI-high status, and N-ras differ according to gender among patients with colorectal cancer.

Metastatic Malignancy to the Colon and Rectum: A Report of 14 Cases from One Single Institute.

BACKGROUND: Metastatic malignancy occurs rarely in the colon or rectum. We presented 14 patients with colorectal metastasis (CRM). METHODS: A retrospective review was conducted on a computerized colorectal tumor database at the Taipei Veterans General Hospital from January 2000 to June 2013. RESULTS: The incidence of CRM was 0.19% (14 in 7,524 patients). There were 6 males and 8 females with a mean age of 66.9 ± 13.6 years. Origins of the CRM included lung cancers (n = 3), prostate cancers (n = 2), and others (n = 1, respectively). Clinical presentations were not specific and colonoscopic pictures were indistinguishable from primary colorectal cancers; 5 of the 9 biopsies identified metastasis. Eight patients had extracolonic metastasis and 6 patients had CRM only. Significantly better survival was observed in the CRM-only group (p = 0.037). The mean interval from the treatment of primary tumor to the diagnosis of CRM was 30.2 ± 49.0 months. The mean survival time after CRM was 24.9 ± 30.8 months. CONCLUSION: Clinical features and colonoscopic findings of CRM were indistinguishable from primary colorectal cancer. Histopathological review of the biopsy could be helpful in identifying the primary lesion. Surgical resection with curative intent provided longer survival in CRM-only patients.

Peramivir analogues bearing hydrophilic side chains exhibit higher activities against H275Y mutant than wild-type influenza virus.

Peramivir is an effective anti-influenza drug in the clinical treatment of influenza, but its efficacy toward the H275Y mutant is reduced. The previously reported cocrystal structures of inhibitors in the mutant neuraminidase (NA) suggest that the hydrophobic side chain should be at the origin of reduced binding affinity. In contrast, zanamivir having a hydrophilic glycerol side chain still possesses high affinity toward the H275Y NA. We thus designed five peramivir analogues (5-9) carrying hydrophilic glycol or glycerol side chains, and evaluated their roles in anti-influenza activity, especially for the H275Y mutant. The synthetic sequence involves a key step of (3 + 2) cycloaddition reactions between alkenes and nitrile oxides to construct the scaffold of peramivir carrying the desired hydrophilic side chains and other appropriate functional groups. The molecular docking experiments reveal that the hydrophilic side chain can provide extra hydrogen bonding with the translocated Glu-276 residue in the H275Y NA active site. Thus, the H275Y mutant may be even more sensitive than wild-type virus toward the peramivir analogues bearing hydrophilic side chains. Notably, the peramivir analogue bearing a glycerol side chain inhibits the H275Y mutant with an IC50 value of 35 nM, which is better than the WSN virus by 9 fold.

Building personalized treatment plans for early-stage colorectal cancer patients.

We developed a series of models to predict the likelihood of recurrence and the response to chemotherapy for the personalized treatment of stage I and II colorectal cancer patients. A recurrence prediction model was developed from 235 stage I/II patients. The model successfully distinguished between high-risk and low-risk groups, with a hazard ratio of recurrence of 4.66 (p < 0.0001). More importantly, the model was accurate for both stage I (hazard ratio = 5.87, p = 0.0006) and stage II (hazard ratio = 4.30, p < 0.0001) disease. This model performed much better than the Oncotype and ColoPrint commercial services in identifying patients at high risk for stage II recurrence. And unlike the commercial services, the robust model included recurrence prediction for stage I patients. As stage I/II CRC patients usually do not receive chemotherapy, we generated chemotherapy efficacy prediction models with data from 358 stage III patients. The predictions were highly accurate: the hazard ratio of recurrence for responders vs. non-responders was 4.13 for those treated with FOLFOX (p < 0.0001), and 3.16 (p = 0.0012) for those treated with fluorouracil. We have thus created a prognostic model that accurately identifies patients at high risk for recurrence, and the first accurate chemotherapy efficacy prediction model for individual patients. In the future, complete personalized treatment plans for stage I/II patients may be developed if the drug prediction models generated from stage III patients are verified to be effective for stage I and II patients in prospective studies.

Intraperitoneal ziv-aflibercept effectively manages refractory ascites in colorectal cancer patients.

Ascites related to metastatic colorectal cancer (mCRC) reduces patient survival and quality of life, and systemic chemotherapy is largely ineffective for managing ascites. Here, we examined the clinical efficacy of intraperitoneal (IP) ziv-aflibercept for managing refractory ascites in 15 mCRC patients who did not respond to standard chemotherapy. Fifty or 100 mg of ziv-aflibercept in 100 mL of saline solution were infused through a pigtail catheter and retained for 24 h. When the ascites drainage volumes were subsequently monitored, 73.3% of patients showed an objective response (OR) to IP ziv-aflibercept treatment. Patients with low Eastern Cooperative Oncology Group (ECOG) performance status or with serum ascites albumin gradients (SAAG) less than 1.1 g/dL had better responses to treatment, and 4 patients with SAAG less than 1.1 g/dL showed rapid objective responses (rOR). These findings indicate that intraperitoneal ziv-aflibercept therapy may be a highly effective means of treating refractory ascites in mCRC patients, and that SAAG may be predictive of a rapid response to this treatment.

Adjuvant FOLFOX treatment for stage III colon cancer: how many cycles are enough?

PURPOSE: Adjuvant FOLFOX (5-fluorouracil and oxaliplatin) chemotherapy benefits stage III colon cancer patients. However, it still results in side effects and increased cost. Reducing cycles had been thought to decrease these problems. This retrospective study aimed to find the appropriate number of treatment cycles that are sufficient for treating these patients. PATIENTS AND METHODS: A total of 213 stage III colon cancer patients receiving adjuvant FOLFOX therapy were retrospectively recruited. Demographic data were collected for analysis. Survival analyses were performed between all cases of patients receiving above and below a certain cycle number. If a significant difference was reached at that cycle number, multivariate Cox Regression was performed with those factors resulting in p < 0.2 to assess the independent prognostic factors. RESULTS: The 5-year overall survival rate of patients was 77.9 %, and the 3-year disease-free survival was 76.7 %. For overall survival, a significant benefit was noted for treatment of at least 8 cycles, for disease-free survival, significant differences were apparent from patient data of those who underwent from 7 to 12 treatment cycles. Multivariate survival analysis of that patient data at cycle 8 for overall survival and cycle 7 for disease free survival revealed cycle number as the only independent prognostic factor (p = 0.04, 0.048). CONCLUSION: Cycle number of adjuvant FOLFOX is a significant prognostic factor for stage III colon cancer patients. At least 8 cycles are needed to have an overall survival benefit, and 7 to disease-free survival.

Improved outcomes of colorectal cancer patients with liver metastases in the era of the multidisciplinary teams.

PURPOSE: The use of multidisciplinary teams (MDTs), which address colorectal cancer treatment planning through weekly regular group meetings, was begun in October 2007. We analyzed and compared the outcomes of colorectal cancer patients with metastatic disease before and after the era of MDTs. METHODS: From 2001 to 2010, 1075 patients who presented with stage IV disease and were treated in Taipei Veterans General Hospital were enrolled in the study. Among these patients, 439 (40.8%) were diagnosed after MDTs had been established. The percentage of patients receiving surgical treatment for metastatic disease was calculated and compared before and after MDTs were established, and the survival rate was compared using a log-rank test, with a significance of P < 0.05. RESULTS: A significantly improved survival rate in patients with stage IV disease was observed after establishment of MDTs, with the 3-year survival rate increasing from 25.6 to 38.2% (P < 0.001). Based on multivariate analysis, establishment of a MDT was an independent prognostic factor in patients with stage IV disease (hazard ratio = 0.74, 95% confidence interval = 0.624∼0.866, P < 0.001). The percentage of liver resection in patients with liver metastasis increased from 19.6 to 35.2% after the establishment of MDTs, whereas the percentage of lung resection in patients with lung metastasis remained stationary from 12.4 to 14.3%. CONCLUSIONS: In the era of MDTs, intensive cooperation between different specialists has increased the referral rate for metastasectomy, resulting in significantly improved outcomes of colorectal patients in initial stage IV disease.

Incidence of Second Primary Malignancies Following Colorectal Cancer: A Distinct Pattern of Occurrence Between Colon and Rectal Cancers and Association of Co-Morbidity with Second Primary Malignancies in a Population-Based Cohort of 98,876 Patients in Taiwan.

The purpose of this study is to determine the features of second primary malignancies (SPMs) among patients with prior colorectal cancer (CRC) using a nationwide population-based dataset.Patients with CRC newly diagnosed between 1996 and 2011, and >1 year of follow-up were recruited from the Taiwan National Health Insurance database. Standardized incidence ratios (SIRs) of SPMs in patients with CRC were calculated.During the 16-year study period, 4259 SPMs developed among 98,876 CRC patients. The median duration of follow-up was 4.03 years. The SIR for all SPMs was 1.13 (95% confidence interval = 1.10-1.17). Compared with the general population, a higher incidence of thyroid, prostate, ovarian, and hematologic malignancies developed among patients with colon cancer, whereas the risk for bone and soft tissue cancers increased among patients with rectal cancer. The risk for breast, bladder, kidney, lung, and uterine cancers was significantly higher in patients with colon and rectal cancers than the general population. The risk for liver and biliary tract cancers declined in patients with rectal cancer. Based on multivariate analysis among patients with CRC, age ≥70 years, men, chronic obstructive pulmonary disease (COPD), cirrhosis, and dyslipidemia were independent predictors of an SPM.In conclusion, patients with CRC were at increased risk for a second cancer. The pattern of SPMs was distinct between patients with colon and rectal cancer. Age, men, COPD, cirrhosis, and dyslipidemia were independent risk factors for SPMs. Surveillance and education should be provided for survivors with respect to risk for SPMs.

Synchronous and metachronous colorectal cancers: distinct disease entities or different disease courses?

BACKGROUND/AIMS: This study aimed to investigate the clinicopathological characteristics of synchronous and metachronous colorectal cancers (CRCs). METHODOLOGY: From January 1, 2001 to December 31, 2010, 5898 patients who underwent surgical resection for CRCs were enrolled. Synchronous CRC was defined as presence of more than one primary CRC within 6 months of resection of the primary tumor; while CRC that occurred at least 6 months later was regarded as metachronous CRC. RESULTS: 5346 patients were eligible for the study and divided into three groups: solitary, synchronous and metachronous CRC. The overall prevalence of the synchronous CRC was 2.2% and the 10-year cumulative incidence of metachronous cancer was 0.84%. 29 (64%) metachronous cancers were diagnosed within 3 years of the index cancer and the mean time interval was 3.2 years. Male gender and presence of associated adenoma were significant risk factors for both synchronous and metachronous CRC. Synchronous and metachronous CRC patients shared similar clinicopathological features except that the former were older than the latter by 3.7 years. The five-year survival rates were not different among the three groups. CONCLUSIONS: Our study indicates that synchronous and metachronous CRC might represent similar disease entity with different courses.

Mutations in the RAS and PI3K pathways are associated with metastatic location in colorectal cancers.

BACKGROUND AND OBJECTIVES: Identification of mutations in the downstream epidermal growth factor receptor (EGFR) signaling pathway could provide important insights of EGFR-targeted therapies in colorectal cancers. We analyzed the mutation spectra of the PI3K/PTEN/AKT and RAS/RAF/MAPK pathways in colorectal cancers and the associations of these mutations with sites of metastases or recurrence. METHODS: The study population comprised 1,492 retrospectively collected stages I-IV colorectal cancer specimens. Tissue was obtained between 2000 and 2010 at a single hospital. We analyzed 61 hot spots using MALDI-TOF mass spectrometry for nucleic acid analysis. RESULTS: Mutations were found in the RAS pathway in 47.3% of patients and in the PI3K pathway in 14.3% of patients, with 9.2% of patients carrying mutations in both pathways. Both the RAS and PI3K pathway mutations were significantly associated with proximal tumors, mucinous tumors, and microsatellite instability. Tumors carrying a RAS pathway mutation exhibited a higher frequency of lung and peritoneal metastasis than did tumors with a wild-type gene (P = 0.025 and 0.009, respectively). NRAS gene mutation was significantly associated with lung metastasis (P = 0.001). CONCLUSIONS: Somatic mutations in the RAS pathway of the primary tumor in colorectal cancer can influence patterns of metastasis and recurrence.