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Background: There are no standardised criteria for the determination of the ‘regional’ pericolic node in colon cancer surgery, which represents a major cause of the international uncertainty regarding the optimal bowel resection margin. This prospective cohort study aimed to determine ‘regional’ pericolic nodes based on detailed mapping for feeding arteries and lymph nodes. Methods: In all, 2,996 patients with stages I–III colon cancer who underwent curative surgery between June 2013 and December 2017 at 25 institutions in Japan were included. The anatomical distributions of the feeding artery and lymph nodes were determined in resected fresh surgical specimens based on in vivo measurements of the bowel. Findings: The mean number of retrieved pericolic nodes was 20·9 per patient. In all patients except seven (0·2%), the primary feeding artery was distributed within 10 cm of the primary tumour. The metastatic pericolic node location most distant from the primary tumour was within 3 cm in 837 patients, 3–5 cm in 130 patients, 5–7 cm in 39 patients and 7–10 cm in 34 patients. Only four patients (0·1%) had pericolic lymphatic spread beyond 10 cm; all of whom had T3/4 tumours accompanying extensive mesenteric lymphatic spread, and three developed systemic recurrence. The positive pericolic node distance from the primary tumour did not differ depending on the primary tumour location or the distribution of the feeding arteries. Postoperatively, none of the 2996 patients developed recurrence in the remaining pericolic nodes. Interpretation: Based on the distribution of metastatic lymph nodes and prognostic outcomes, the pericolic nodes designated as ‘regional’ were those located within 10 cm of the primary tumours. Despite the fact that surgeons tend to prefer complete mesocolic excision, these findings should be fully considered when determining the bowel resection margin. Funding: Japanese Society for Cancer of the Colon and Rectum Declaration of Interest: All authors declare no competing interests. Ethical Approval: This study was conducted according to the Declaration of Helsinki and comparable Japanese ethical standards. The study was approved by the Institutional Review Boards of the JSCCR and each participating institution. Written informed consent was obtained from all study participants

Background Irinotecan (CPT-11)-induced neutropenia is associated with UDP-glucuronosyltransferase (UGT) 1A1*6 and *28 polymorphisms. This prospective study investigated whether using these polymorphisms to adjust the initial dose of CPT-11 as part of FOLFIRI treatment in colorectal cancer patients might improve safety. Methods All data were collected by a physician. The relationship between UGT1A1 polymorphisms and first-cycle neutropenia, reasons for treatment discontinuation, and time-to-treatment failure were evaluated. Multivariate analysis was used to assess the risk of neutropenia. Results A total of 795 patients were divided into wild-type (*1/*1) (50.1 %), heterozygous (*28/*1, *6/*1) (41.1 %), and homozygous (*28/*28, *6/*6, *28/*6) (8.which are associated with a decrease in the8 %) groups, in which the median starting dose of CPT-11 was 143.0, 143.0, and 115.0 mg/m2, respectively. First-cycle grade ≥3 neutropenia occurred in 17.3, 25.4, and 28.6 % of these patients, respectively. Multivariate analysis revealed that the incidence of grade ≥3 neutropenia was significantly greater in the heterozygous and homozygous groups than in the wild-type group [odds ratio (OR) 1.67; 95 % confidence interval (CI) 1.16–2.42; p = 0.0060, and OR 2.22; 95 % CI 1.22–4.02; p = 0.0088, respectively]. Age (OR 1.77; 95 % CI 1.24–2.53; p = 0.0017), coelomic fluid (OR 1.84; 95 % CI 1.05–3.25; p = 0.0343), and non-reduction in starting dose (OR 1.53; 95 % CI 1.08–2.18; p = 0.0176) were also identified as significant risk factors. Conclusion The risk of neutropenia was higher in the heterozygous and homozygous groups at initiation of CPT-11 treatment. This suggests that when a reduction in dose is required in patients harboring two variant alleles, the decrease should be approximately 20 %.

This study investigated the diagnostic accuracy of hybrid positron-emission tomography/computed tomography (PET/CT) for lymph node (LN) metastasis of esophageal cancer. We also investigated the correlation between the size of metastatic nests and the detection by PET/CT. Two hundred and fifty-eight patients with esophageal squamous cell carcinoma who underwent esophagectomy with two- or three-field radical lymphadenectomy were analyzed retrospectively. We compared the diagnosis of preoperative PET/CT to the postoperative histopathological examination by each anatomical field (n = 1,231) in all 258 patients. The metastatic LNs resected from PET/CT positive fields were classified as belonging to the PET/CT-N-positive group (n = 229) and those from negative fields as belonging to the PET/CT-N-negative group (n = 352). The cross-sectional areas of metastatic nests were measured in each metastatic LN. Of the 1,231 fields, 275 (22 %) were positive for metastasis, including 581 LNs from 408 regional LN stations. The sensitivity and specificity of PET/CT examined by each anatomical field were 25.8 and 97.8 %, respectively. The median area of metastatic nests was 17.7 mm2 in the PET/CT-N-positive group, and 7.7 mm2 in the PET/CT-N-negative group (p

The histogenesis of the pattern of cancer spread along Auerbach's plexus (myenteric spread: MS) remains unclear and its prognostic value in colorectal cancer (CRC) has not been thoroughly investigated.Pathology slides of 2845 pT2/pT3/pT4 CRCs stained with hematoxylin-eosin (HE) were reviewed at 10 institutions. MS was classified into 2 groups depending on whether it was accompanied by the finding of perineural invasion (PN) within the lesion. In addition, immunohistochemical staining (D2-40, S100, CD56, synaptophysin) was performed for serially sectioned specimens from 50 CRCs diagnosed as having PN-negative MS.MS was observed in 504 patients (17.7 %); 360 patients were classified as having PN-positive MS and 144 as having PN-negative MS. The 5-year disease-free survival rate of patients with MS was lower than that of patients without MS (63.3 vs 82.7 %, P0.0001); however, there was no significant difference in survival outcome according to the presence or absence of intralesion PN in MS. Multivariate analysis showed that the prognostic impact of MS was independent of conventional prognosticators including T and N stages, vascular invasion and extramural PN. In all the tumors having PN-negative MS, remnants of neural tissue were identified within or around cancer nests located at the leading edge of MS.MS is an important prognostic factor for CRC. This feature is the result of cancer development with replacement of Auerbach's plexus and can be classified as intramural PN. The clinical significance of "Pn1" in the UICC/AJCC TNM classification could be enhanced by individual assessment both intramurally and extramurally.

After approval of bevacizumab in Japan, post-marketing surveillance studies reported on safety. However, few reports have shown the efficacy of bevacizumab as used in daily practice. We evaluated the efficacy and safety of bevacizumab for metastatic colorectal cancer patients in daily practice.All unresectable metastatic colorectal cancer patients who began receiving bevacizumab in participating facilities from June 2007 to October 2008 were retrospectively analyzed for safety and efficacy. Adverse events were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events. Response Evaluation in Solid Tumors criteria, version 1.0, was used for the tumor response rate.A total of 212 patients from 17 institutions were assessed. Grade 3 or higher adverse events related to bevacizumab included gastrointestinal perforation in 3, thrombosis in 7, hypertension in 30 and gastrointestinal bleeding in 2. Response rates were 62.5, 30.1 and 11.8% overall among patients receiving bevacizumab as first-, second- and third-line or greater therapy. Median progression-free survival was 14.4 [95% confidence interval (CI): 10.8-18.1], 7.8 (95% CI: 6.5-9.1) and 6.0 (95% CI: 4.6-7.3) months, and median overall survival was 32.5 (95% CI: 24.6-40.3), 16.4 (95% CI: 14.4-18.5) and 11.8 (95% CI: 8.6-15.0) months, respectively.The general cohort of patients in HGCSG0801 showed a similar efficacy and safety profile of bevacizumab as seen in clinical trials. Although the sample size was small and there were several study limitations, these results suggest that colorectal cancer patients in Japan might safely receive and benefit from bevacizumab in combination with chemotherapy in daily practice, as is seen in patients in other countries.

特発性腸間膜静脈硬化症は，稀な疾患であるが，近年報告が増加してきている．病因は不明とされているが，我々は漢方薬の長期服用歴を認めた4例を経験した．症例1：58歳，男性．黄連解毒湯を17年間内服．主訴は便潜血陽性．右半結腸粘膜は暗青色，浮腫状であったがCTで石灰化を認めず，IMPの初期像と考えられた．症例2：69歳，女性．五淋散を内服．腹痛を主訴に受診．大腸内視鏡，CTにて異常なく経過観察となったが，8年後，典型的なIMPに進展した．症例3：53歳，女性．加味逍遥散，十味敗毒湯を19年間内服．主訴は右下腹部違和感．右半結腸の粘膜は暗青色，浮腫状で，管腔狭小化，潰瘍形成とCTにて石灰化を認めた．症例4：48歳，女性．加味逍遥散，安中散内服．便潜血陽性で大腸内視鏡を施行し異常を認めなかったが，9年後に右側腹部痛が出現しIMPに進展したため右半結腸切除術を施行した．IMPの病因の一つとして漢方薬が考えられるため，詳細な薬剤投与歴の聴取が重要である．

食道原発のGISTは全消化管GISTの2％以下とされ1)稀な疾患である．今回われわれは食道GIST4例を経験したので報告する．症例1は69歳，男性．3年前より指摘されていた食道粘膜下腫瘍が7cmに増大したため中下部食道切除胃管後縦隔再建を施行した．術後3年3カ月で肝転移にて再発したがメシル酸イマチニブの内服を開始し以後無再発生存中である．症例2は76歳，女性．下部食道に5cm径の粘膜下腫瘍と上縦隔リンパ節の腫大があったため胸部食道亜全摘・胸骨後胃管再建を施行した．術後27カ月無再発生存中である．症例3は52歳，男性．検診にて3cm径の食道粘膜下腫瘍を指摘され胸腔鏡補助下核出術を施行した．術後23カ月無再発生存中である．症例4は53歳，男性．下部食道に7cm径の粘膜下腫瘍があり，中下部食道切除胃管後縦隔再建を施行した．術後8カ月無再発生存中である．全4例でCD34(+) c-Kit(+) α-SMA(-) S100(-)で狭義のGISTであり，高リスクに分類された．

ABSTRACT Aim: We planned a randomized, open-label trial to evaluate differences between pre-emptive and reactive skin treatment for panitumumab (Pmab)-associated skin toxicities in Japanese patients with metastatic colorectal cancer. Patients & methods: Patients receiving third-line Pmab-containing regimens were randomized to pre-emptive or reactive treatment. The primary end point was the cumulative incidence of ≥grade 2 skin toxicities during 6 weeks. Retrospectively, a dermatologist reviewed skin toxicities, in a blinded manner. Results: A total of 95 patients were enrolled (pre-emptive: 47, reactive: 48). The primary end point was achieved (21.3 and 62.5% [risk ratio: 0.34; p < 0.001], for pre-emptive and reactive treatment, respectively). A similar trend was observed in central review. Conclusion: Pre-emptive skin treatment could reduce the severity of Pmab-associated skin toxicities in Japanese metastatic colorectal cancer patients.

Background: The population in Japan is aging more rapidly than in any other country. However, no studies have determined the characteristics of the large population of elderly patients with colorectal tumors. Therefore, we examined the clinicopathological and molecular features of these tumors in elderly patients. Methods: In total, 1,627 colorectal tumors (393 serrated lesions, 277 non-serrated adenomas and 957 colorectal cancers) were acquired from patients. Tumor specimens were analyzed for BRAF and KRAS mutations, CpG island methylator phenotype-specific promoters (CACNA1G, CDKN2A, IGF2 and RUNX3), IGFBP7, MGMT, MLH1 and RASSF2 methylation, microsatellite instability (MSI) and microRNA- 31 (miR-31). Results: The frequency of elderly patients (aged ≥75 years) with sessile serrated adenomas (SSAs) with cytological dysplasia was higher than that of those with other serrated lesions and non-serrated adenomas (p < 0.0001). In elderly patients, all SSAs were located in the proximal colon (particularly the cecum to ascending colon). High miR-31 expression, MLH1 methylation and MSI-high status were more frequently detected in SSAs from elderly patients than in those from non-elderly patients. In contrast, no significant differences were found between older age of onset and high-grade dysplasia for traditional serrated adenomas or non-serrated adenomas in any of these molecular alterations. Conclusion: In elderly patients, all SSAs were located in the proximal colon. Furthermore, cytological dysplasia and molecular alterations were more frequently detected in elderly patients with SSAs than in non-elderly patients. Thus, careful colonoscopic examinations of the proximal colon are necessary for elderly patients because SSAs in those patients may exhibit malignant potential.

Background. The aims of this study were to determine the recommended dose (RD) in combination chemotherapy of S-1 and carboplatin in recurrent and/or metastatic head and neck cancer (phase I) and to examine response rate and toxicities at RD (phase II). Methods. S-1 was given orally at a fixed dose of 40, 50, or 60 mg twice daily based on the patient's body surface area for 21 days followed by a 14-day rest. In phase I, carboplatin was given intravenously to a cohort of three patients on day 8 at a dose of 2.5, 3.0, 3.5, or 4.0 area under the curve (AUC) values, depending on the dose-limiting toxicities (DLTs). Results. In phase I, the RD was estimated as 2.5 AUC. In phase II, thrombocytopenia and leukopenia were most commonly found as hematologic DLTs, which were manageable without hospitalization. The response rate was 40.9%. Conclusions. This regimen is considered to be active against recurrent and/or metastatic head and neck cancer in an outpatient setting. © 2006 Wiley Periodicals, Inc. Head Neck, 2006

Background: The aim of the present study is to symptomatically analyze the extent to which pelvic nerve-sparing radical surgery for rectal cancer impacts on long-term voiding and male sexual function. Methods: A self-administered questionnaire was mailed to 68 patients who underwent pelvic nerve-sparing radical surgery for invasive rectal cancer with 52 responses (28 men and 24 women; 27 complete and 25 incomplete preservation; response rate 76.5%). Each patient was asked to record if there had been any changes in lower urinary tract symptoms after surgery. Sexual function was also investigated in men. Results: Of the 52 patients, 48 (92%) maintained voluntary voiding without catheterization in the long term. Clean intermittent self-catheterization was performed in only four patients with incomplete preservation because of persistent voiding dysfunction. Subjectively, approximately 60% of the patients remained unchanged in lower urinary tract symptoms after surgery. The satisfaction rate regarding the current voiding status was significantly higher in women than in men (83% versus 61%, P = 0.0294), but was not significantly different between those with complete (76%) and incomplete preservation (64%). Despite the acceptable urinary status, 88% of men had some deterioration in the erectile function, regardless of the types of surgical procedures. Overall, 64% of men were unsatisfied with the current sexual function. Conclusions: Pelvic nerve-sparing radical surgery for rectal cancer preserved the long-term voiding function in the majority of patients. In completely preserved patients and in women, symptomatic outcomes were more satisfactory. Postoperative erectile dysfunction was found to be a serious problem, even in complete nerve-sparing procedure.

当院で経験した4例の特発性食道破裂について検討した.年齢は35～72歳,いずれも男性.全例飲酒を契機とした嘔吐により発症し,胸部下部食道左壁の破裂を認めた.破裂長径は1.5～5.0cm (中央値3.7cm)で,全例前医にて診断を得て紹介され,入院同日に手術を行った.発症から手術開始までに要した経過時間は,順に17, 12, 48, 19時間であった.全例一期的縫合閉鎖を施行,それに加え横隔膜被覆を行ったものが1例, pericardial fat padを被覆したものが1例, fundic patch & fundoplicationを行ったものが1例であった.全例救命しえたが,術後2例に胃食道逆流症状を認めた. fundic patch & fundoplicationを行った症例は,最も経過良好であった.本疾患は,術後晩期合併症である胃食道逆流症状(gastro-esophageal reflex disease:以下GERDと略記)を訴える症例が少なからずみうけられる.このため救命はもちろん, QOLを考慮した治療法を選択しなければならない.食道裂孔付近の破裂で長径5 cm以上もしくは発症後12時間以上経過した症例などでは,縫合不全およびGERD予防の点からもfundic patchおよびfundoplicationを行うことが有効と考える.

症例は45歳,男性.前胸部不快感の増強を主訴に近医受診.内視鏡検査にて下部食道表在癌ならびに噴門部に巨大な腫瘤性病変を認め,加療目的に当院紹介入院.精査にて食道表在癌・胃壁内転移と診断し,左開胸開腹下部食道胃全摘術を施行.切除標本組織診断では下部食道IIc+IIb病変の大きさは4.5×4.0cm,深達度m2癌, ly3, v0, n2で胃噴門部に大きさ6.5×6.0cmの壁内転移巣を認め,進行度TIaN2M0IM1-Stp10→StageIIであった.術後8年9ヵ月経過した現在,再発は認められていない.外科的切除を施行した自験例m2癌52例のうち脈管侵襲が認められた症例は3例(5.8%)であり,リンパ節転移を認めたものは本症例1例(1.9%)のみであった. m2癌症例においても脈管侵襲が認められることがあり,リンパ節転移の有無・壁内転移などを十分に検索したうえ治療方針を決定する必要があると考えられた.

Gene mutations in the pathway downstream of epidermal growth factor receptor (EGFR) are considered to induce resistance to anti-EGFR therapy in colorectal cancer (CRC). We recently reported that microRNA-31 (miR-31)-5p may regulate BRAF activation and play a role in the signaling pathway downstream of EGFR in CRC. Therefore, we hypothesized that miR-31-5p can be a useful biomarker for anti-EGFR therapy in CRC. We evaluated miR-31-5p expression and gene mutations [KRAS (codon 61 or 146), NRAS (codon 12, 13, or 61), and BRAF (V600E)] in the EGFR downstream pathway in 102 CRC patients harboring KRAS (codon 12 or 13) wild-type who were treated with anti-EGFR therapeutics. Progression-free survival (PFS) and overall survival (OS) were evaluated. KRAS (codon 61 or 146), NRAS, and BRAF mutations were detected in 6.9, 6.9, and 5.9 % patients, respectively. Compared with CRCs with at least one mutation (n = 20), significantly better PFS (P = 0.0003) but insignificantly better OS were observed in CRCs harboring all wild-type genes (KRAS, NRAS, and BRAF). High miR-31-5p expression was identified in 11 % (n = 11) patients and was significantly associated with shorter PFS (P = 0.003). In CRCs carrying all wild-type genes, high miR-31-5p was associated with shorter PFS (P = 0.027). High miR-31-5p expression was associated with shorter PFS in patients with CRC treated with anti-EGFR therapeutics. Moreover, in CRCs carrying all wild-type genes, high miR-31-5p was associated with shorter PFS, suggesting that it may be a useful and additional prognostic biomarker for anti-EGFR therapy.

Background.The purpose of this study was to clarify the incidence and risk factors for incisional surgical site infections (SSI) in patients undergoing elective open surgery for colorectal cancer.Methods.We conducted prospective surveillance of incisional SSI after elective colorectal resections performed by a single surgeon for a 1-year period. Variables associated with infection, as identified in the literature, were collected and statistically analyzed for their association with incisional SSI development.Results.A total of 224 patients were identified for evaluation. The mean patient age was 67 years, and 120 (55%) were male. Thirty-three (14.7%) patients were diagnosed with incisional SSI. Multivariate analysis suggested that incisional SSI was independently associated with TNM stages III and IV (odds ratio [OR], 2.4) and intraoperative hypotension (OR, 3.4).Conclusions.The incidence of incisional SSI in our cohort was well within values generally reported in the literature. Our data suggest the importance of the maintenance of intraoperative normotension to reduce the development of incisional SSI.

肺Langerhans細胞組織球症 (pulmonary Langerhans'cell histiocytosis) は, 通常はびまん性肺疾患であり, 単発性の病変は稀である.今回我々は孤立性肺結節として発見された肺Langerhans細胞組織球症の一切除例を経験したので報告する.症例は73歳, 男性.約3年前に当院で結腸癌の手術を受け, 定期的に外来通院中であった.定期検査として施行した胸部CTで, 右肺S3bに径0 .5cmの小結節を認めた.結腸癌の肺転移を疑い, 肺部分切除を行った.切除標本は, Langerhans細胞, 好酸球, 好中球, 小型リンパ球などの集簇からなり, S100蛋白による免疫染色に陽性を示し, 病理組織学的に肺Lan gerhans細胞組織球症と診断した.

症例は62歳, 男性.約1年前より慢性腎不全にて週3回の血液透析を施行されていた.定期の胸部単純X線で左肺上葉の無気肺を指摘され, 精査の結果, 左上葉入口部原発の扁平上皮癌で下葉支への浸潤が認められた.週3回の維持透析により患者の全身状態は良好にコントロールされており, 術前3日間連日透析施行後に, 左肺摘除術, 縦隔リンパ節郭清術を行った.術後は1日目より2日間透析を施行した後, 術前の透析スヶジュールに戻した.グルコース・インスリン療法を併用することにより術後の血清K値は良好に維持され, 術後18日目に退院した.

We inserted Dumon stent to 13 patients with tracheobronchial stenosis due to advanced or recurrent esophageal carcinoma. Severe dyspnea was improved in 11 patients except for 2 patients with bilateral recurrent nerve palsy. 3 cases who had radiation therapy or chemotherapy lived over 150 days. We inserted esophageal stent in 4 cases. 2 patients died due to hemoptysis after 156 days and 35 days. We conclude that Dumon stent is one of the useful treatments in order to improve quality of life and prognosis of advanced or recurrent esophageal carcinoma.

BRAF is an important gene in colorectal cancers (CRCs) that is associated with molecular characterization and resistance to targeted therapy. Although microRNAs (miRNAs) are useful biomarkers of various cancers, the association between miRNA and BRAF in CRCs is undefined. Therefore, this study was conducted to identify a relationship between specific miRNA molecules and BRAF mutation in CRCs and serrated lesions. miRNA array was used for the measurement of 760 miRNAs in 29 CRCs. To assess the identified miRNAs, quantitative reverse transcription-PCR was performed on 721 CRCs, 381 serrated lesions and 251 non-serrated adenomas. Moreover, proliferation and invasion assays were conducted using cell lines. miRNA array analysis revealed that microRNA-31 (miR-31)-5p was the most up-regulated miRNA in CRCs with mutated BRAF (V600E) compared with CRCs possessing wild-type BRAF (including cases with KRAS mutation). High miR-31 expression was associated with BRAF and KRAS mutations and proximal location (P < 0.0001). High miR-31 expression was related to cancer-specific mortality [multivariate hazard ratio = 2.06, 95% confidence interval: 1.36-3.09, P = 0.0008]. Functional analysis demonstrated that miR-31 inhibitor decreased cell invasion and proliferation. With regard to serrated lesions, high miR-31 expression was less frequently detected in hyperplastic polyps compared with other serrated lesions. In conclusion, associations were identified between miR-31, BRAF and prognosis in CRC. Transfection of miR-31 inhibitor had an antitumour effect. Thus, miR-31 may be a promising diagnostic biomarker and therapeutic target in colon cancers. Moreover, high miR-31 expression in serrated lesions suggested that miR-31 may be a key molecule in serrated pathway.

Perineural invasion (PN) in colorectal cancer (CRC) is a site-specific prognostic marker, as mentioned by the AJCC Cancer Staging Manual, but it remains to be clearly defined. We aimed to identify an optimal characterization of PN as a component of cancer staging. On the basis of the anatomic features of the nervous system of the large bowel, site-specific pathologic criteria were assigned to PN according to the location of PN. Multi-institutional pathologic review based on these criteria was performed for 962 patients with stage I to III CRC at 2 institutions (1999 to 2004, cohort 1) and 1883 patients from 8 other institutions (2000 to 2004, cohort 2). In cohort 1, intramural and extramural PN were observed in 152 and 101 patients, respectively, which had a different impact on disease-free survival (hazard ratio, 2.6 [1.9 to 3.5] vs. 4.7 [3.4 to 6.5], respectively). A 3-tiered grading system (Pn0; Pn1a, intramural PN; Pn1b, extramural PN) distinguished 5-year disease-free survival as 88%, 70%, and 48%, respectively; and multivariate analysis identified PN grade as a significant prognostic marker independent of T or N stage. These results were similar in cohort 2. Interinstitutional difference of the prognostic impact of PN grade was acceptably small among all institutions. Interobserver study among 6 gastrointestinal pathologists showed superior judgment reproducibility for PN compared with vascular invasion. The results of our study indicate that PN is an important prognostic marker in CRC. The value of cancer staging could be enhanced by PN assessment using site-specific criteria and a simple grading system based on PN location within the bowel.

This study investigated the diagnostic accuracy of hybrid positron-emission tomography/computed tomography (PET/CT) for lymph node (LN) metastasis of esophageal cancer. We also investigated the correlation between the size of metastatic nests and the detection by PET/CT.Two hundred and fifty-eight patients with esophageal squamous cell carcinoma who underwent esophagectomy with two- or three-field radical lymphadenectomy were analyzed retrospectively. We compared the diagnosis of preoperative PET/CT to the postoperative histopathological examination by each anatomical field (n = 1,231) in all 258 patients. The metastatic LNs resected from PET/CT positive fields were classified as belonging to the PET/CT-N-positive group (n = 229) and those from negative fields as belonging to the PET/CT-N-negative group (n = 352). The cross-sectional areas of metastatic nests were measured in each metastatic LN.Of the 1,231 fields, 275 (22 %) were positive for metastasis, including 581 LNs from 408 regional LN stations. The sensitivity and specificity of PET/CT examined by each anatomical field were 25.8 and 97.8 %, respectively. The median area of metastatic nests was 17.7 mm2 in the PET/CT-N-positive group, and 7.7 mm2 in the PET/CT-N-negative group (p0.001).A significant correlation was suggested between the nest size and detection by PET/CT. Because of its low sensitivity, PET/CT alone is insufficient to determine the surgical procedures, especially when considering reduction surgery.

Background & Aims More information is needed on the long-term outcomes of patients who undergo endoscopic resection of colorectal tumors. We evaluated recurrence of colorectal cancer (CRC) after endoscopic resection or a combination of endoscopic research and surgery for T1 colorectal tumors. Methods We conducted a retrospective study of 389 patients with T1 CRC treated by endoscopic resection from January 1989 to December 2008 in Sapporo, Japan. We compared outcomes between patients who underwent subsequent surgery (ER + SURG, n=205) and those who did not (ER only, n=184) and statistically adjusted baseline differences between the groups according to the propensity scores. Results There was almost no risk of cancer recurrence among patients without indications for surgery recommended by the Japanese Society for Cancer of the Colon and Rectum (these indications include tumors with vertical margins, deep submucosal invasion, lymphatic or venous invasion, poor differentiation, or high-grade budding). Among patients with indications for surgery, the cumulative risks of recurrence (CRRs) were 3.7% in the ER + SURG group and 20.1% in the ER only group (P = .001). However, the patients with only deep submucosal invasion had a low CRR, even without surgery (2.3% in the ER + SURG group and 3.4% in the ER only groups, P = .867). In contrast, patients with indications for surgery other than deep submucosal invasion (high-risk patients) had much better outcomes when they also underwent surgery (CRRs: 5.8% in the ER + SURG group vs 58.0% in the ER only group, P Conclusions On the basis of a retrospective study of patients who underwent endoscopic resection for T1 CRC, those with tumors with only submucosal invasion are at low risk for cancer recurrence. However, patients with other high-risk tumor features have greater risks for cancer recurrence and benefit from subsequent surgery.

Purpose Histologic components of the TNM classification system have been repeatedly revised since the fifth edition (TNM5). TNM classification revisions provide different criteria for categorizing tumor nodules without residual lymph node structure (ND). However, there are few systematic evaluations regarding the effectiveness of these revisions. Patients and Methods A multicenter pathologic review for ND in colorectal cancer (CRC) was performed. Tumor staging defined by TNM5, sixth edition (TNM6), and seventh edition (TNM7) were compared on the basis of Akaike information criterion (AIC) and Harrell's concordance index (c-index). Moreover, TNM7's prognostic value was compared between the original ND and modified criteria, which considered all regional NDs as lymph node metastasis (LNM) irrespective of the original structure. Results In 1,716 treated patients with CRC (1994 to 1998), tumor stages (I/II/III) exhibited better prognoses in TNM7 (AIC, 3055.1; c-index, 0.7215) than in TNM6 (AIC, 3063.7; c-index, 0.7149), but not better than in TNM5 (AIC, 3051.6; c-index, 0.7240). Comparing the original TNM7 and modified criteria, 4.2% of patients were classified in different N stages (N0/N1/N2a/N2b); both AIC and the c-index were superior in the modified criteria (AIC, 3029.40; c-index, 0.7271) compared with the original criteria (AIC, 3040.58; c-index, 0.7230). Modified criteria were also associated with improved prognostic power of tumor stages (I/IIA/IIB/IIC/IIIA/IIIB/IIIC). These results were similar in another cohort of 2,242 treated patients with CRC (1999 to 2003). Conclusion The prognostic value of TNM7 is better than that of TNM6; however, improvement over TNM5 is insignificant. By considering all regional NDs as LNM irrespective of their morphology, TNM classification can be simplified and its prognostic value improved.

This study aimed to determine the optimal categorization of extramural tumor deposits lacking residual lymph node (LN) structure (EX) in colorectal cancer staging.The TNM classification system categorizes EX on the basis of their contour characteristics (the contour rule).We conducted a multicenter, retrospective, pathological review of 1716 patients with stage I to III curatively resected colorectal cancer who were treated at 11 institutions (1994-1998). In addition, 2242 patients from 9 institutions (1999-2003) were enrolled as a second cohort for validating results. EX were classified as isolated foci confined to vascular or perineural spaces (ie, lymphatic, venous, or perineural invasion) or as tumor nodules (ND). N- and T-staging systems employing different categories for staging were compared in terms of their prognostic power. In addition, the diagnoses of extramural, discontinuously spreading lesions made by 11 observers from different institutions were assessed for interobserver agreement.EX were observed in 18.2% of patients in the first cohort. The method of categorization of EX in tumor staging has a stronger impact on N than T staging. The N-staging system in which all ND types were classified as N factor (the ND rule) could more effectively stratify the survival outcome than the contour rule (Akaike information criterion, 3040.8 vs 3059.5; the Harrell C-index, 0.7255 vs 0.7103). EX were observed in 16.9% of patients in the second cohort. Statistically, the ND rule was more informative than the contour rule for N staging. The Fleiss kappa coefficient for distinguishing LN metastases from EX (0.74) was lower than expected for complete agreement, and it decreased further to 0.51 when calculated for the judgment of ND with smooth contours.Classifying all ND types as N factors irrespective of contours can simplify the tumor staging system by enhancing diagnostic objectivity, resulting in improved prognostic accuracy.

Purpose To clarify the prognostic impact of tumor nodules without residual lymph node (LN) structure (ND) in colorectal cancer and to determine optimal categorization of ND in tumor staging. Patients and Methods A multicenter, retrospective pathologic review was performed for 1,716 patients with stages I to III curatively resected colorectal cancer treated at 11 institutions between 1994 and 1998. An additional 2,242 patients from nine institutions were enrolled between 1999 and 2003 as a second cohort to validate the results. Results LN metastasis (LNM) and ND were observed in 33.7% and 16.0% (smooth-contour nodule [S-ND], 8.2%; irregular-contour nodule [I-ND], 10.7%) of patients in the first cohort. S-ND and I-ND were similarly distributed in the regional area. There was no considerable difference in the impact on survival between S-ND (hazard ratio [HR], 2.7; 95% CI, 1.9 to 3.8) and I-ND (HR, 4.3; 95% CI, 3.3 to 5.8) or between LNM (HR, 4.5; 95% CI, 3.4 to 6.0) and ND (HR, 4.0; 95% CI, 3.1 to 5.3). LNM and ND were similarly associated with the mode of recurrence. Tumor nodules ≥ 5 mm growing with venous/perineural invasion (ND [v/pni+]), judged with 0.61 κ value among 11 observers, had an independent prognostic value for 5-year survival of 42%; similar results were observed in the second cohort. Conclusion These results do not support the TNM system in which S-ND is treated differently from I-ND in tumor staging; LNM and ND should be considered together in the same category. The presence of ND (v/pni+) has a considerable adverse prognostic effect.

701 Background: Oxaliplatin-containing regimen is a standard adjuvant chemotherapy for resected stage III colon cancer. Oxaliplatin-containing regimens were investigated for their efficacy in patients with resected stage III colon cancer in MOSAIC and XELOXA studies. Since these two international randomized studies were performed outside of Japan, we conducted a phase II study (NORTH/HGCSG1003) to assess the efficacy and safety of FOLFOX as adjuvant chemotherapy in Japanese patients (pts) with resected stage III colon cancer (UMIN ID: 000004590). Methods: This phase II study enrolled patients with resected stage III colon cancer. Patients received 12 biweekly cycles of FOLFOX4 or mFOLFOX6. Sample size was determined to be 243 pts. Primary endpoint was DFS. Secondary endpoints included overall survival (OS) and safety. Results: From September 2010 to March 2013, 273 pts were enrolled at 28 institutions. Safety analysis included 265 patients who received FOLFOX. Patients characteristics were as follows: median age, 65 (33-84); male/female: 131/134; PS 0/1:258/7; stage IIIA/IIIB/IIIC: 37/197/31; colon/rectosigmoid: 214/51. The most common grade 3-4 adverse events were neutrophil count decreased (48.1%), platelet count decreased (2.3%), and allergic reaction (1.5%). The incidence of peripheral sensory neuropathy (PSN) was 41.9% (grade 1), 38.1% (grade 2), and 6.4% (grade 3). PSN tended to be serious depending on the cumulative dose of oxaliplatin (table 1). Median cumulative dose of oxaliplatin at which PSN occurred were as follows: grade 1; 170 mg/m2, ≥ grade 2; 850 mg/m2, ≥ grade 3; (-). The median number of cycles of chemotherapy was 12, and the completion treatment rate was 80.4%. There was no treatment-related death. Conclusions: In Japanese patients with stage III colon cancer, FOLFOX is a well-tolerable regimen as adjuvant chemotherapy. Clinical trial information: 000004590. [Table: see text]

Ectopic (heterotopic) gastric mucosa (EGM) of the upper esophagus, referred as inlet patch, is an asymptomatic benign lesion that is often detected during endoscopic examination. Although it is considered a source of adenocarcinoma in the upper esophagus, only 17 cases of adenocarcinoma have been reported previously. We report a rare case of adenocarcinoma arising in EGM of the cervical esophagus.

Background: The optimum management of esophageal cancers with synchronous second primary cancer (SPC) has not been determined. The aim of this study was to evaluate the efficacy of intense screening and treatment for esophageal cancers with synchronous SPC. Methods: Between 1981 and 1997, 1479 patients with esophageal cancers were screened for synchronous SPC during the process of initial staging. Radical treatment was recommended for esophageal cancer and synchronous SPC in cases for whom both cancers were curable. Treatment results for esophageal cancer patients with or without synchronous SPC were compared. Results: Among 1479 patients, 155 (10.5%) were found to have 166 synchronous SPC. Primary sites included the stomach in 65, the head and neck in 44, the colon/rectum in 27, the lung in 14 and other sites in 16 patients. Clinical stages of synchronous SPC were stage I in 41%, stage II in 20%, stage III in 25% and stage IV in 14%. The 5-year overall survival rates by clinical stages of esophageal cancers (stage 0, I, II, III, IV) in patients with synchronous SPC were 51% (95% CI, 23–78%), 43% (95% CI, 18–68%), 11% (95% CI, 0–22%), 14% (95% CI, 0–28%) and 12% (95% CI, 1–22%), respectively. The 5-year overall survival rate for patients with or without synchronous SPC were 20% (95% CI, 13–28%) and 32% (95% CI, 29–35%), respectively. No significant difference was observed between both groups (p = 0.2562). Conclusions: Intense screening and treatment may be justifiable in the light of the high detection rate of curable SPC and the reasonable survival of patients with synchronous SPC. However, a prospective study including cost–benefit analysis is needed to provide the evidence to justify the intense screening and treatment.

3587 Background: Panitumumab (Pmab) has demonstrated efficacy in patients with KRAS wild-type metastatic colorectal cancer (mCRC). Although the STEPP study (Lacouture M. E. et al. J Clin Oncol. 201...

541 Background: Panitumumab (Pmab), a fully human monoclonal antibody targeting the EGFR, has been demonstrated the efficacy in patients with KRASwild-type metastatic colorectal cancer (mCRC). Though STEPP study (Lacouture et al, JCO 2010) showed that pre-emptive skin treatment reduced skin toxicities compared with reactive treatment among patients receiving Pmab, the data of Asians has not been reported. We planned a randomized controlled open-label trial to verify the differences between pre-emptive and reactive treatment for skin toxicities in Japanese patients. Methods: Patients receiving Pmab-containing treatments as third line regimen for mCRC were randomly assigned 1:1 to pre-emptive or reactive skin treatment group. In the pre-emptive treatment group, patients received skin moisturizers, sunscreen, topical steroid and minocycline. In the reactive treatment group, patients received only skin moisturizers. The primary endpoint was the cumulative incidence of ≥ grade 2 skin toxicities during the 6-week treatment period. Retrospectively, dermatologist reviewed skin toxicities with photographs in blinded manner. Results: Out of 95 enrolled patients, 47 patients were randomly assigned to pre-emptive group, and 48 to reactive group. The incidence of ≥ grade 2 skin toxicities during the 6-week treatment period (according to investigator’s assessment) was 21.3% and 62.5% (risk ratio [RR] = 0.34, 95% CI 0.19 - 0.62; p

634 Background: In the treatment for mCRC, it is essential for understanding the prognosis of each individual patient. Köhne’s index (KI) based on performance status, white blood cell count, alkaline phosphatase and number of metastatic sites has been previously proposed. However, in the salvage setting, the validity of KI has not been reported in patients treated by cetuximab-based chemotherapy. Methods: 269 patients with mCRC treated by cetuximab contained chemotherapy were retrospectively registered from 27 centers in Japan. This analysis was included in the KRAS wild-type patients who were refractory to or intolerant for 5-FU/irinotecan/oxaliplatin and were never administered anti-EGFR-antibody. Univariate and multivariate analysis for overall survival were performed using patient characteristics. Survival analyses were performed with Kaplan-Meier method, log-rank test and Cox proportional hazards model. The analysis was also designed to determine whether the Köhne’s classification could be extended to other endpoints such as progression-free survival. Results: All data were available for prognostic categorization in 127 patients. Median overall and progression-free survival was 9.8 and 4.2 months. The distribution and median survival / progression-free survival for KI were as follows: low risk (L) (n = 40; 13.1/5.1 months), intermediate risk (I) (n = 17; 9.6/3.5 months), and high risk (H) (n = 70; 7.6/4.1 months). For overall survival, there was significant difference between L and H (p = 0.004), but not between L and I (p = 0.213), and between I and H (p = 0.321). For progression-free survival, there was tended to difference between L and H (p = 0.083), but not between L and I (p = 0.392), and between I and H (p = 0.630). In Cox multivariate analysis, KI showed an independent prognostic impact (HR 1.370, p = 0.010), but not predictive impact (HR 1.147, p = 0.212). Conclusions: In this analysis, KI might be a prognostic factor in salvage treatment with cetuximab-based regimen, but no effect predicted impact. Moreover, the prospective evaluation is needed for the further validation.

3638 Background: Study showed that the oral anticancer agent UFT/LV is useful as postoperative adjuvant chemotherapy for stage III colorectal cancer. PSK, a protein-bound polysaccharide extracted from the mycelia of Coriolus versicolor, is an immunomodulator widely used in gastric, colorectal and lung cancers. Methods: Patients aged 20-80 years with stage III colorectal cancer registered in 35 facilities were randomized to: group A (UFT/LV 28 days/5 weeks for 6 months); group B (UFT+LV 28 days/5 weeks for 6 months, then UFT for 12 months); and group C (UFT+LV+PSK 28 days/5 weeks for 6 months, then UFT+PSK for 12 months). Treatment was started within 6 months after curative resection. Outcome measures were relapse-free survival (RFS), overall survival (OS), incidence and severity of adverse events, and QOL. Results: Of 342 patients registered, 340 eligible patients were analyzed (84 in group A, 85 in group B, and 171 in group C). At baseline, variation in QOL score was observed but histopathological parameters were not different among 3 groups. Median observation period was 36 months. 3-year RFS was 73.8%, 77.6% and 73.9% in groups A, B, and C [A vs C: hazard ratio (HR) 0.960, 95% confidence interval (CI) 0.575-1.601; B vs C: HR 0.837, CI 0.488-1.433; A vs B: HR 1.151, CI 0.623-2.126]. 3-year OS was 95.2%, 91.8% and 89.9% in groups A, B, and C (A vs C: HR 0.460, CI 0.155-1.367; B vs C: HR 0.814, CI 0.338-1.963 A vs B: HR 0.570, CI 0.167-1.947). Adverse events ≥grade 3 included gastrointestinal symptoms and general status. There was no treatment-related death. Excluding high fatigue score in QOL scale that showed pretreatment variation, stratification analysis showed interaction between family score and group, and efficacy was suggested especially in group C with high score (3-yesr RFS: 66.7%, 68.2% and 88.1% in groups A, B, and C. A vs C: HR 3.289, CI 0.951-11.375, B vs C: HR 3.070, CI 0.973-9.685, A vs B: HR 1.084, CI 0.344-3.417). Conclusions: A significant difference in primary endpoint was not detected. Variation in QOL at treatment initiation probably greatly affected outcome. Clinical trial information: NCT00209742.

541 Background: In the previous studies, panitumumab (Pmab) has been demonstrated the efficacy for patients with metastatic colorectal cancer (mCRC) in all treatment lines. It is still controversial about the efficacy of Pmab for patients that had progressed on prior cetuximab (Cmab), though there had been a few reports (from Metges et al. and Wadlow et al.) regarding the efficacy of Pmab after Cmab refractory or intolerance. To evaluate the efficacy and safety of Pmab in patients with cetuximab-refractory mCRC, in comparison with anti-EGFR antibody naïve patients (Cmab-naïve) and Cmab-refractory or intolerance patients (prior-Cmab). Methods: Two hundred patients with mCRC treated by Pmab contained chemotherapy were retrospectively registered from 20 centers in Japan (HGCSG 1002 study). Of these, the patients that were refractory to or intolerant for 5-FU/ irinotecan/ oxaliplatin, and were administered Pmab monotherapy were included in this analysis. Results: Of 93 patients (44 prior-Cmab and 49 Cmab-naïve) were evaluated. There were no significant differences in the baseline characteristics of the patients in each group. The incidence of Grade 3 or higher any skin toxicities were higher in the Cmab-naïve (26.5.%) than in the prior-Cmab (11.4%). The overall response rate (RR) was not significantly difference (prior-Cmab/ Cmab-naïve, 9.1%/ 10.2%), but the disease control rate (DCR) was slightly higher in Cmab-naïve group (38.6%/ 55.1%, p=0.15). Progression free survival (PFS) and overall survival (OS) were follows: prior-Cmab/ Cmab-naïve, 2.8m/ 3.1m, 6.8m / 9.5m. There was a significant difference between the two groups in OS curve (p=0.04). Conclusions: Pmab was safely administered to heavily pretreated mCRC patients in daily practice. Although there were no significant differences in RR, DCS and PFS between prior-Cmab and Cmab-naïve, but the median OS was longer for the Cmab-naïve group compared with the prior-Cmab group. Therapeutic efficacies of Pmab for prior-Cmab patients did not comparable to those for Cmab-naïve patients. We are now performing a phase II trial on the efficacy of Pmab for Cmab-refractory mCRC patients.

593 Background: Inhibition of the EGFR pathway has become a key part in the treatment of colorectal cancer. There were few studies for clinical early predictive markers. To investigate the early magnesium (Mg2+), calcium (Ca2+), albumin (Alb), CEA and CA 19-9 plasma level reductions as a predictor for clinical outcome in terms of progression free survival (PFS) and overall survival (OS). Methods: 200 patients (pts) with mCRC treated by Pmab contained chemotherapy were retrospectively registered from 20 centers in Japan (HGCSG 1002 study). Of these, the pts that were refractory to or intolerant for 5-FU/ irinotecan/ oxaliplatin, and were never administered anti-EGFR-antibody, were included in this analysis. Mg2+, Ca2+, Alb, CEA and CA19-9 plasma levels were obtained from medical records. The differences in terms of PFS and OS according to the presence of Mg2+, Ca2+, Alb, CEA and CA19-9 reductions were evaluated by the log-rank test. Results: Of 67 pts were able to evaluate for this analysis. Pts’ characteristics were as follows: male/female 38/29, median age 64 (range 45-81), ECOG PS (0/1/2- ) 45/17/5. Response rate and disease control rate were 16.4% and 65.7%, PFS and OS were 4.3 m and 12.4 m, respectively. There were no correlations between Ca/Alb plasma level reductions and PFS/OS. Mg2+ reduction of at least 50% respect to the basal value during the course of treatment was significantly correlated with improved OS and PFS (OS, P=0.03; PFS, P=0.01), but the early reduction (until the 4th week or the 8th week after start of chemotherapy) was not correlated with OS and PFS. An early CEA serum level reduction of at least 40% until the 8th week was significantly correlated with improved OS and PFS (OS, P=0.04; PFS, P=0.07), moreover of at least 30% until the 4th week was correlated to longer PFS (P=0.053). Similar results were seen in CA19-9. Conclusions: An early CEA plasma level reduction of at least 30% or 40% was suggested to be a predictor for PFS in Pmab containing chemotherapy for mCRC pts. Although Mg2+ serum level reduction was correlated to clinical outcome, but could not show that is an early predictor for PFS and OS in our study.

684 Background: Bevacizumab (BV) is widely used in first-line chemotherapy for metastatic colorectal cancer in Japan, but the use of beyond bevacizumab first progression (BBP) has been controversial yet. Methods: Of patients treated with first-line BV in our retrospective cohort study (HGCSG0801), patients treated with BBP (n=22) and those without BBP ( n=19) in second-line setting were analyzed. The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used to assess adverse events. The Response Evaluation in Solid Tumors (RECIST) criteria version 1.0 was used to assess tumor response. The Kaplan–Meier method was used to determine PFS and OS. Log-rank test was used to compare each group in terms of PFS and OS. All statistical tests were performed using SPSS. Results: PS (0/1/2) before second line chemotherapy was 18/3/1 in BBP and 10/8/1 in NBBP, respectively. In the safety analysis, five patients in BBP showed a worsening/newer hypertension, which wasn’t a clinical problem. In the efficacy analysis, the response rate was 22.8% in BBP and 0% in NBBP. The median PFS was better in BBP (6.7 months in BBP and 2.7 months in NBBP), but there was no significant difference in median OS from first BV administration between two groups (27.3 months in BBP and 22.2 months in NBBP). Conclusions: We analyzed BBP in daily practice in Japan. Adverse events were well tolerated, but survival advantage of BBP was not suggested. About the efficacy of BBP, we are waiting the results of ongoing Phase III trials.