Radiomic features derived from pretherapeutic MRI predict chemoradiation response in locally advanced rectal cancer.

BACKGROUND: The standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant concurrent chemoradiotherapy (CRT) followed by surgical excision. Current evidence suggests a favorable prognosis for those with pathological complete response (pCR), and surgery may be spared for them. We trained and validated regression models for CRT response prediction with selected radiomic features extracted from pretreatment magnetic resonance (MR) images to recruit potential candidates for this watch-and-wait strategy. METHODS: We retrospectively enrolled patients with LARC who underwent pre-CRT MR imaging between 2010 and 2019. Pathological complete response in surgical specimens after CRT was defined as the ground truth. Quantitative features derived from both unfiltered and filtered images were extracted from manually segmented region of interests on T2-weighted images and selected using variance threshold, univariate statistical tests, and cross-validation least absolute shrinkage and selection operator (Lasso) regression. Finally, a regression model using selected features with high coefficients was optimized and evaluated. Model performance was measured by classification accuracies and area under the receiver operating characteristic (AUROC). RESULTS: We extracted 1223 radiomic features from each MRI study of 133 enrolled patients. After tumor excision, 34 (26 %) of 133 patients had pCR in resected specimens. When 25 image-derived features were selected from univariate analysis, classification AUROC was 0.86 and 0.79 with the addition of six clinical features on the hold-out internal validation dataset. When 11 image-derived features were used, the optimized linear regression model had an AUROC value of 0.79 and 0.65 with the addition of six clinical features on the hold-out dataset. Among the radiomic features, texture features including gray level variance, strength, and cluster prominence had the highest coefficient by Lasso regression. CONCLUSION: Radiomic features derived from pretreatment MR images demonstrated promising efficacy in predicting pCR after CRT. However, radiomic features combined with clinical features did not result in remarkable improvement in model performance.

Taiwan Society of Colon and Rectal Surgeons Consensus on mCRC Treatment.

Therapeutic options for metastatic CRC (mCRC) have changed significantly in recent years, greatly increasing the complexity of therapeutic decision-making. Although oncology guidelines have helped improve the care process, guidelines may also limit the flexibility to individualize in-clinic decision-making. This consensus paper addresses specific gaps in the current international guidelines to assist Taiwanese colon and rectal experts make specific therapeutic choices. Over 3 years and three meetings with selected experts on "real-world" Taiwanese practice patterns for mCRC, consensus was achieved. The experts also discussed specific questions during in-depth one-on-one consultation. Outcomes of the discussion were then correlated with published evidence by an independent medical writer. The final consensus includes clinically implementable recommendations to provide guidance in treating Taiwanese mCRC patients. The consensus includes criteria for defining fit and unfit intensive treatment patients, treatment goals, treatment considerations of molecular profiles, treatment consideration, and optimal treatment choices between different patient archetypes, including optimal treatment options based on RAS, BRAF, and microsatellite instability (MSI) status. This consensus paper is the second in the Taiwan Society of Colon and Rectal Surgeons (TSCRS) Consensus series to address unmet gaps in guideline recommendations in lieu of Taiwanese mCRC management. Meticulous discussions with experts, the multidisciplinary nature of the working group, and the final drafting of the consensus by independent medical professionals have contributed to the strong scientific value of this consensus.

Harnessing stemness and PD-L1 expression by AT-rich interaction domain-containing protein 3B in colorectal cancer.

Background and Aims: Cancer stem cells (CSCs) have been shown to be responsible for the tumor initiation, metastasis, and therapeutic resistance of colorectal cancer (CRC). Recent studies have also indicated the importance of CSCs in escaping immune surveillance. However, the coordinated epigenetic control of the stem cell signature and the key molecule(s) involved in immunosurveillance of colorectal CSCs (CRCSCs) are unclear. Here, we investigated the role of a histone modifier, AT-rich interaction domain-containing protein 3B (ARID3B), in CRC. Methods: CRC patient-derived xenografts (PDXs) with knockout of ARID3B induced by CRISPR/Cas9 in vivo were used. Molecular/cellular biology assays were performed. Clinical data obtained from The Cancer Genome Atlas, as well as from our cohort (Taipei Veterans General Hospital), were analyzed. Results: ARID3B was crucial for the growth of CRC, and ARID3B promoted the stem-like features of CRC. Mechanistically, ARID3B activated Notch target genes, intestinal stem cell (ISC) genes, and programmed death-ligand 1 (PD-L1) through the recruitment of lysine-specific demethylase 4C (KDM4C) to modulate the chromatin configuration for transcriptional activation. Clinical sample analyses showed that the coexpression of ARID3B and the Notch target HES1 correlated with a worse outcome and that ARID3B and PD-L1 were highly expressed in the consensus molecular subtype 4 of CRC. Pharmacological inhibition of KDM4 activity reversed the ARID3B-induced signature. Conclusion: We reveal a noncanonical Notch pathway for activating Notch target genes, ISC genes, and PD-L1 in CRC. This finding explains the immune escape of CRCSCs and indicates a potential group that may benefit from immune checkpoint inhibitors. Epigenetic drugs for reversing stem-like features of CRC should also be investigated.

Robotic transanal total mesorectal excision assisted by laparoscopic transabdominal approach: A preliminary twenty-case series report.

BACKGROUND: Laparoscopy-assisted robotic transanal total mesorectal excision is a novel surgical technique for rectal cancer resection. Compared to prior DaVinci Si system case series, this case series is the first to report robotic taTME assisted by laparoscopy (r-taTME) in which the "transanal team" operates via the DaVinci Xi system. As a result, we aim to delineate and discuss preliminary findings from our robotic taTME experiences. METHODS: A total of twenty patients (twelve males) who underwent robotic taTME assisted by laparoscopy (r-taTME) between January 2016 and November 2016 at a single institution were documented. Surgical outcomes, including complications, pathological outcomes, and short-term results, were then retrospectively analyzed. RESULTS: All patients underwent r-taTME via a two-team approach. The "abdominal team" operated via a single port method (ileostomy site), while the "transanal team" operated via the DaVinci Xi system. The mean patient age was 56.7 ± 14.3 years (range 31-79), and the mean distance from tumor to anal verge was 6.0 ± 2.7 cm (range 2-10). The mean estimated intraoperative blood loss was 88 ± 107 ml (range 30-500), and circular stapling was utilized to restore continuity in 80% of study patients. The overall postoperative complication rate was 35%, and the mean distal margin length was 3.1 ± 1.3 cm. There were three patients who had a circumferential margin (CRM) involved by cancer cells (≤1 mm). CONCLUSION: Our preliminary series report demonstrates that utilization of r-taTME assisted by laparoscopy is safe and feasible. Development of a novel transanal approach that allows single-port access alongside a multi-arm robotic system may increase the convenience and efficiency of future operation.

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.

Author Correction: MicroRNA-146a directs the symmetric division of Snail-dominant colorectal cancer stem cells.

In the version of Supplementary Fig. 6c originally published with this Article, the immunoprecipitation (IP) and immunoblotting (IB) tags in the top panel were mislabelled. In addition, in Supplementary Fig. 6e, the blot of the IP: Numb; IB: ß-Trcp panel for HCT15 was mistakenly duplicated for HCT116. The correct versions of these figures are shown below. An independent repeat of the experiments presented in Supplementary Fig. 6c and e, showing results that are consistent with those reported in the unprocessed blots, have been deposited in figshare ( 10.6084/m9.figshare.7570685 ).

Aminopeptidase A initiates tumorigenesis and enhances tumor cell stemness via TWIST1 upregulation in colorectal cancer.

Metastasis accounts for the high mortality rate associated with colorectal cancer (CRC), but metastasis regulators are not fully understood. To identify a novel gene involved in tumor metastasis, we used oligonucleotide microarrays, transcriptome distance analyses, and machine learning algorithms to determine links between primary and metastatic colorectal cancers. Aminopeptidase A (APA; also known as ENPEP) was selected as our focus because its relationship with colorectal cancer requires clarification. Higher APA mRNA levels were observed in patients in advanced stages of cancer, suggesting a correlation between ENPEP and degree of malignancy. Our data also indicate that APA overexpression in CRC cells induced cell migration, invasion, anchorage-independent capability, and mesenchyme-like characteristics (e.g., EMT markers). We also observed TWIST induction in APA-overexpressing SW480 cells and TWIST down-regulation in HT29 cells knocked down with APA. Both APA silencing and impaired APA activity were found to reduce migratory capacity, cancer anchorage, stemness properties, and drug resistance in vitro and in vivo. We therefore suggest that APA enzymatic activity affects tumor initiation and cancer malignancy in a TWIST-dependent manner. Results from RT-qPCR and the immunohistochemical staining of specimens taken from CRC patients indicate a significant correlation between APA and TWIST. According to data from SurvExpress analyses of TWIST1 and APA mRNA expression profiles, high APA and TWIST expression are positively correlated with poor CRC prognosis. APA may act as a prognostic factor and/or therapeutic target for CRC metastasis and recurrence.

Transanal Total Mesorectal Excision Versus Laparoscopic Surgery for Rectal Cancer Receiving Neoadjuvant Chemoradiation: A Matched Case-Control Study.

BACKGROUND: Neoadjuvant chemoradiation therapy (nCRT) has been indicated for locally advanced rectal cancer. While utilization of laparoscopy in rectal cancer surgery has been popular in recent years, tumors receiving nCRT is still a surgical challenge. Transanal total mesorectal excision (TaTME) has emerged as a focused area of laparoscopic surgery that is becoming an increasingly acceptable approach in the field of rectal surgery. METHODS: Between December 2013 and April 2015, a total of 50 patients (38 males) with post-nCRT middle or lower rectal cancer who then underwent TaTME at two separate institutions were prospectively documented. Overall, 100 matched control cohorts who received conventional laparoscopic rectal surgery (LapTME) were simultaneously retrieved from a prospectively registered database. Four parameters of sex, age, clinical stage, and American Society of Anesthesiologists (ASA) score were matched for surgical outcomes, and short-term oncological results, including complications and pathological outcomes, were analyzed. RESULTS: Both the TaTME and LapTME groups received 5-fluorouracil-based chemotherapy and 5 weeks of long-course radiation therapy. Mean operative time for the TaTME group was 182.1 ± 55.4 min (156.6 ± 37.8 min in two-team-approach cases) and 178.7 ± 34.8 min for the LapTME group. The TaTME group yielded longer distal margin lengths. No significant differences were observed in blood loss, intraoperative complication rate, conversion rate, anastomosis type, and free circumferential margin rate. CONCLUSION: This matched case-control study demonstrated that TaTME is safe and feasible. Compared with LapTME, TaTME not only achieves identical circumferential margin status without compromising other operative and quality parameters but also benefits patients by achieving a longer distal margin. Thus, TaTME has the potential to become an option in managing irradiated rectal cancer.

The evolving practice of hybrid natural orifice transluminal endoscopic surgery (NOTES) for rectal cancer.

BACKGROUND: Natural orifice transluminal endoscopic surgery (NOTES) has emerged as the area of focus in laparoscopic surgery. Hybrid NOTES (hNOTES) has some potential advantages for treating rectal cancer. METHODS: Between May 2013 and November 2013, a total of 20 patients (11 males) who received hNOTES at two institutes participating in the study were documented and reviewed. Surgical outcomes, including complications and pathological outcomes, were analyzed. RESULTS: The mean age of patients was 57.8 ± 10.1 years (range 34-78). Eleven patients received preoperative neoadjuvant chemoradiotherapy, with the mean distance between tumor and anal verge being 5.9 ± 1.7 cm (mean 2-8). The mean estimated intraoperative blood loss was 68 ± 106 ml (range 30-500), with one case converted to open procedure due to uncontrolled bleeding. Eight cases underwent simultaneous two-team approach. The mean operative time was 200.8 ± 47.7 min (range 110-285). Circular stapling was performed for 14 cases (70 %) as the anastomosis, and protective stoma performed for 17 cases (85 %). The overall postoperative complication rate was 25 %. Two cases (10 %) develop pelvic abscess due to leakage, which were controlled by medical treatments. The distal and circumferential margins were all free of tumor cells, and the mean distal margin length was 2.4 ± 0.98 cm (range 0.5-4). CONCLUSIONS: Hybrid NOTES for rectal cancer is safe and feasible. Rapid experience-building accelerates its evolution, as reflected here by the high stapling rate and the idea of a two-team approach. It has the potential to become an option of treating rectal cancers.

MicroRNA-146a directs the symmetric division of Snail-dominant colorectal cancer stem cells.

Asymmetrical cell division (ACD) maintains the proper number of stem cells to ensure self-renewal. In cancer cells, the deregulation of ACD disrupts the homeostasis of the stem cell pool and promotes tumour growth. However, this mechanism is unclear. Here, we show a reduction of ACD in spheroid-derived colorectal cancer stem cells (CRCSCs) compared with differentiated cancer cells. The epithelial-mesenchymal transition (EMT) inducer Snail is responsible for the ACD-to-symmetrical cell division (SCD) switch in CRCSCs. Mechanistically, Snail induces the expression of microRNA-146a (miR-146a) through the ß-catenin-TCF4 complex. miR-146a targets Numb to stabilize ß-catenin, which forms a feedback circuit to maintain Wnt activity and directs SCD. Interference with the Snail-miR-146a­ß-catenin loop by inhibiting the MEK or Wnt activity reduces the symmetrical division of CRCSCs and attenuates tumorigenicity. In colorectal cancer patients, the Snail(High)Numb(Low) profile is correlated with cetuximab resistance and a poorer prognosis. This study elucidates a unique mechanism of EMT-induced CRCSC expansion.

Carcinoembryonic antigen (CEA) level, CEA ratio, and treatment outcome of rectal cancer patients receiving pre-operative chemoradiation and surgery.

BACKGROUND: To investigate serum carcinoembryonic antigen (CEA) as a prognostic factor for rectal cancer patients receiving pre-operative chemoradiotherapy (CRT). METHODS: Between 2000 and 2009, 138 patients with advanced rectal cancer receiving CRT before surgery at our hospital were retrospectively classified into 3 groups: pre-CRT CEA <6 ng/ml (group L; n = 87); pre-CRT CEA ≥ 6 ng/ml and post-CRT CEA <6 ng/ml (group H-L; n = 32); and both pre- and post-CRT CEA ≥ 6 ng/ml (group H-H; n = 19). CEA ratio (defined as post-CRT CEA divided by pre-CRT CEA), post-CRT CEA level and other factors were reviewed for prediction of pathologic complete response (pCR). RESULTS: Five-year disease-free survival (DFS) was better in groups L (69.0%) and H-L (74.5%) than in group H-H (44.9%) (p = 0.024). Pathologic complete response was observed in 19.5%, 21.9% and 5.3% of groups L, H-L and H-H respectively (p = 0.281). Multivariate analysis showed that ypN stage and pCR were independent prognostic factors for DFS and that post-CRT CEA level was independently predictive of pCR. As a whole, post-CRT CEA <2.61 ng/ml predicted pCR (sensitivity 76.0%; specificity 58.4%). For those with pre-CRT CEA ≥6 ng/ml, post-CRT CEA and CEA ratio both predicted pCR (sensitivity 87.5%, specificity 76.7%). CONCLUSIONS: In patients with pre-CRT serum CEA ≥6 ng/ml, those with "normalized" CEA levels after CRT may have similar DFS to those with "normal" (<6 ng/ml) pre-CRT values. Post-CRT CEA level is a predictor for pCR, especially in those with pre-CRT CEA ≥6 ng/ml.

Differences in clinicopathological characteristics of colorectal cancer between younger and elderly patients: an analysis of 322 patients from a single institution.

BACKGROUND: The prognosis of patients with colorectal cancer (CRC) of different onset ages is controversial. METHODS: Data were obtained from a prospective database at Taipei Veterans General Hospital. There were 2,738 newly diagnosed patients with CRC from 2001 to 2006. Two extreme age groups, younger (≤40 years) and elderly (≥80 years), were analyzed to compare clinicopathologic characteristics and prognosis after exclusion of specific cancer syndrome. RESULTS: A total of 322 patients were enrolled in this prospective study. The younger group consisted of 69 patients with mean age of 33.5 years, and the elderly group consisted of 253 patients with mean age of 83.4 years. Younger patients had a higher incidence of mucinous cell type (14.5% vs 6.3%, P = .05), poorly differentiated adenocarcinoma (26.1% vs 6.3%, P < .001), more advanced disease (82.6% vs 41.9%, P < .001), poorer disease-free survival (67.2% vs 79.3%, P = .048), and cancer-specific survival (44.1% vs 73.1%, P < .001) than elderly patients. CONCLUSIONS: In patients with CRC of younger onset, without relevant predisposing risk factors, younger patients have more advanced stages of disease, more aggressive histopathologic characteristics, and poorer prognoses compared with older patients.

Effects of S/B remedy containing Scutellaria baicalensis and Bupleurum scorzonerifolfium on hepatic interleukin-6 related signal transducer and activator of transcription 3 activation in mice through cell-cell interaction.

Signal transducer and activator of transcription 3 (STAT3) plays an important role in regulating interleukin 6 (IL-6) related growth control of the liver. Our previous study demonstrated that a mixture containing Scutellaria baicalensis and Bupleurum scorzonerifolfium (S/B remedy) modulated the growth of hepatocytes during liver regeneration after 2/3 partial hepatectomy. The aim of this study was to investigate whether S/B remedy induced mouse hepatic STAT3 activation directly in hepatocytes or indirectly via non-parenchymal cell-hepatocyte interaction. Direct S/B remedy effects were studied using primarily isolated hepatocytes; while C57BL/6J mice were used to study indirect effects of S/B remedy using gadolinium chloride to deplete Kupffer cells' function. The results showed that S/B remedy and its active constituents did not directly activate growth-related signaling in primarily isolated hepatocytes. However, S/B remedy induced STAT3 and subsequently suppressor of cytokine signaling (SOCS3) activation in mouse liver and increased serum IL-6 level in a dose-dependent manner, which could be partially blocked by pretreatment with gadolinium chloride. Oligonucloetide microarray analysis from S/B remedy-treated peripheral blood leukocytes demonstrated an up-regulation of IL-6 gene expression. We conclude that S/B remedy did not directly induce STAT3 activation in vitro, but induced hepatic IL-6 related STAT3 activation through non-parenchymal cell-hepatocyte interaction in vivo. The results provide important information on the molecular mechanisms of S/B remedy for treatment of human liver diseases.

Influence of GSTP1 I105V polymorphism on cumulative neuropathy and outcome of FOLFOX-4 treatment in Asian patients with colorectal carcinoma.

Glutathione S-transferase P1 (GSTP1) participates in detoxification of potentially genotoxic compounds that may alter the efficacy and toxicity of platinum-based chemotherapy. We analyzed the influence of I105V polymorphism of GSTP1 on clinico-pathological features and outcomes in 166 Chinese patients with metastatic colorectal carcinoma who had been treated with first-line FOLFOX-4. Combined analysis of GSTP1 I105V, ERCC1-118, and XPD-751 polymorphisms was also conducted. The results showed that, in comparison with Caucasian populations, a remarkably lower prevalence of Val105 allele variants was noted (24.7%). Patients with Val105 allele variants had a higher response to FOLFOX-4 (56.1%vs 37.6%, P = 0.04), and a longer progression-free (P < 0.01) as well as overall (P < 0.01) survival. By adjusted analysis, this polymorphism was identified as an independent prognostic factor (P = 0.01). In combined analysis, patients without any risk genotype, including GSTP1-105 Ile/Ile, ERCC1-118 C/T or T/T, and XPD-751 Lys/Gln, had significantly longer progression-free and overall survivals (P < 0.01). In addition, patients with Val105 allele variants had a higher incidence of grade 3/4 cumulative neuropathy after different cycles of treatment. These data suggest that Asian populations have a lower prevalence of I105V polymorphism in GSTP1. I105V polymorphism in GSTP1, by reducing its enzymatic activity and consequential detoxification to oxaliplatin, could be a key determinant for a better outcome, but more neurotoxicity, to FOLFOX-4 treatment.

Very low prevalence of XPD K751Q polymorphism and its association with XPD expression and outcomes of FOLFOX-4 treatment in Asian patients with colorectal carcinoma.

Xeroderma pigmentosum group D (XPD) participates in DNA unwinding during nucleotide excision repair, which may alter the efficacy of platinum-based chemotherapy. We analyzed the influence of codon 751 Lys-->Gln polymorphism of XPD on its protein expression levels, clinico-pathological features, and outcome of 188 Chinese patients with metastatic colorectal carcinoma (CRC) that had been treated with first-line Oxaliplatin + Leucovorin + 5-Fluorouracil (FOLFOX-4) chemotherapy. The results showed that in comparison with Caucasian populations, a remarkably lower prevalence of Lys/Gln genotype was noted (16%, n = 30). No between-group difference in XPD protein expression of patients with or without this polymorphism was noted (56.5%vs 59.7%; P = 0.783). Patients with Gln751 allele have a significantly lower response to FOLFOX-4 treatment (36.7%vs 58.2%, P = 0.03), and shorter progression-free (7 vs 11 months; P < 0.01) and overall (14 vs 22 months; P < 0.01) survivals. The incidence of grade 3/4 oxaliplatin-neuropathies was very similar in both groups (13.3%vs 16.5%; P = 0.67). By adjusted analysis, this polymorphism was further identified as an independent prognostic factor (P = 0.03). These data suggest that Asian populations have a significantly lower prevalence of codon 751 Lys/Gln polymorphism in XPD, which could be a key determinant for good response to oxaliplatin-based treatment and favorable outcomes.

ERCC1 codon 118 C→T polymorphism associated with ERCC1 expression and outcome of FOLFOX-4 treatment in Asian patients with metastatic colorectal carcinoma.

We analyzed the influence of codon 118 C→T polymorphism of ERCC1 on its protein expression levels, clinicopathological features, and outcome of 168 Chinese patients with metastatic colorectal carcinoma that had been treated with first-line FOLFOX-4 chemotherapy. A high prevalence of C/C genotype was noted (47.6%, n = 80; 168 patients in total). A marked increase of ERCC1 protein expression levels was also noted in patients with C/T or T/T genotypes (70%vs 20%; P < 0.01), which was associated with significantly lower response to FOLFOX-4 (36.4%vs 57.5%; p = 0.01), and shorter progression-free (7 months vs 13 months; P < 0.01) and overall (16 months vs 25 months; P < 0.01) survival times. By multivariate analysis, this polymorphism was also identified as an independent prognostic factor (P = 0.02). These data suggest that Asian populations have a significantly higher prevalence of the C/C genotype in ERCC1 codon 118, which could be a key determinant for good responses to oxaliplatin-based treatment and favorable outcomes.

UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities without affecting treatment outcome and survival in patients with metastatic colorectal carcinoma.

BACKGROUND: It is known that the uridine-diphosphoglucuronosyl transferase 1A1 (UGT1A1)*28 polymorphism reduces UGT1A1 enzyme activity, which may lead to severe toxicities in patients who receive irinotecan. This study was conducted to assess the influence of this polymorphism on the efficacy and toxicity of irinotecan treatment in Chinese patients with metastatic colorectal carcinoma (CRC). METHODS: In total, 128 patients with metastatic CRC who had received previous treatment with irinotecan plus 5-fluorouracil/leucovorin were analyzed retrospectively. Genomic DNA samples were obtained from patients' leukocytes, and genotypes were determined by analyzing the sequence of TATA boxes in the UGT1A1 gene. The influence of the UGT1A1*28 polymorphism on toxicity and treatment outcome was analyzed. RESULTS: Approximately 20% of patients were identified with the UGT1A1*28 polymorphism, including 15.6% (n = 20 patients) with the thymine-adenine (TA)6/TA7 genotype and 4.7% (n = 6 patients) with the TA7/TA7 genotype. The remaining 79.7% of patients (n = 102) had wild type TA6/TA6. Marked increases in grade 3 or 4 neutropenia (53.8% vs 4.9%; P < .01), neutropenic fever (38.5% vs 3.9%; P < .01), diarrhea (26.9% vs 5.9%; P < .01), and pretreatment bilirubin level (23.1% vs 8.8%; P = .04) were observed in patients who had the TA6/TA7 or TA7/TA7 genotypes. Patients' pretreatment bilirubin levels correlated well with irinotecan-induced neutropenia (P < .01). It was noted that, although the requirement for irinotecan dose reduction was significantly greater in patients who had this genetic variant (42.3% vs 12.7%; P < .01), it did not affect the response rate to irinotecan-based chemotherapy (42.3% vs 45.1%; P = .80), and it did not significantly affect progression-free survival (10 months vs 11 months; P = .94) or overall survival (19 months vs 18 months; P = .84). CONCLUSIONS: The current data suggested that the UGT1A1*28 polymorphism may be a key determinant for predicting irinotecan-induced severe toxicities without affecting treatment outcome for patients with metastatic CRC. Further prospective studies are warranted for using this polymorphism to optimize irinotecan-based chemotherapy.

Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients.

Oxaliplatin is effective in the treatment of metastatic colorectal cancer (MCRC) patients; however, severe neurotoxicity develops frequently. To assess the efficacy of oral glutamine for preventing neuropathy induced by oxaliplatin, a pilot study was performed. A total of 86 patients with MCRC treated at Taipei Veterans General Hospital were enrolled. Oxaliplatin (85 mg/m(2), days 1 and 15) plus weekly bolus 5-fluorouracil (5-FU; 500 mg/m(2)) and folinic acid (FA; 20 mg/m(2)) on days 1, 8, and 15 were given every 28 days as first-line treatment. Patients were randomized to receive (glutamine group; n = 42) or not receive (control group; n = 44) glutamine (15 g twice a day for seven consecutive days every 2 weeks starting on the day of oxaliplatin infusion). Efficacy of chemotherapy, neurological toxicity, and electrophysiological alterations were assessed. A lower percentage of grade 1-2 peripheral neuropathy was observed in the glutamine group (16.7% versus 38.6%) after two cycles of treatment, and a significantly lower incidence of grade 3-4 neuropathy was noted in the glutamine group after four cycles (4.8% versus 18.2%) and six cycles (11.9% versus 31.8%). By adding glutamine, interference with activities of daily living was lower (16.7% versus 40.9%), and need for oxaliplatin dose reduction was lower (7.1% versus 27.3%). There were no significant between-group differences in response to chemotherapy (52.4% versus 47.8%), electrophysiological abnormalities, grade 3-4 non-neurological toxicities (26.2% versus 22.8%), or survival. These data indi-cate that oral glutamine significantly reduces the incidence and severity of peripheral neuropathy of MCRC patients receiving oxaliplatin without affecting response to chemotherapy and survival.

Is decrease of tumor volume correlated with stage change after preoperative concurrent chemoradiotherapy?

BACKGROUND/AIMS: The significance of tumor volume and its change after concurrent chemoradiotherapy (CCRT) was evaluated. METHODOLOGY: Standard-dose external radiation and oral UFUR plus leucovorin were used to treat 30 middle and lower rectal adenocarcinoma patients. Volume of tumor calculated from images obtained by dynamic MRI of the rectum before and after CCRT was compared to pathological results after definite resection and other clinical data. RESULTS: The T-stage in 15 patients (50%), the N-stage in 13 (72.2%), and overall, the TNM stage in 18 (60%), were downstaged, including 7 (23.3%) with complete responses (CR). Volume of tumor before CCRT (Vpre) and after CCRT (VPost) was 10.3+/-6.1cm3 and 4.2+/-2.2cm3, respectively, and VPre correlated with initial T stage, N stage, age, and location. The net decrease ratio (NDR) of tumor volume was related to Vpre and initial T stage. As to the downstaging effect, VPre was related to incidence of CR; NDR was related to the downstaging of the N stage. CONCLUSIONS: All tumors showed volume reduction after CCRT, but the downstaging benefits were not in proportion to the size change. Initially larger tumors had higher ratios of volume reduction, and smaller tumors had higher chance of CR.

Is it reasonable to add preoperative serum level of CEA and CA19-9 to staging for colorectal cancer?

BACKGROUND: Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are the most common tumor markers for colorectal cancer. The aim of this study was to evaluate the possibility of adding them into the current staging system by analyzing their prognostic significance. MATERIALS AND METHODS: The study population was patients (n = 574, 67.1 +/- 11.3 years old, 397 males) who received potentially curative resection of colorectal adenocarcinoma (stage I-III) between January 1994 and August 2002, including preoperative measurements of CEA and CA19-9. Clinicopathological characteristics and associated follow-up data were retrospectively collected by reviewing available medical charts. CEA higher or equal to 5 ng/ml was defined as abnormal (CEA+). The CA19-9 level was set at 37 U/ml (CA19-9+). Patients were further divided into four groups (1, 2, 3, 4) according to the results of these two markers (CEA/CA19-9: -/-, -/+, +/-, and +/+). Survival was analyzed for AJCC staging, CEA (+) versus (-), CA19-9 (+) versus (-), and four groups. RESULTS: CEA and CA19-9 survival curves were not significantly different. However, the combined use of the two markers revealed a significant survival benefit (P = 0.035) of group 1 ("-" for both markers) over 4 ("+" for both) in stage II. CONCLUSIONS: Patients with an elevated level of both CEA and CA19-9 in stage II of colorectal cancer have a significantly poorer prognosis than those with normal levels of these markers. We recommend adding both CEA and CA19-9 to the current staging system.