Background/Objectives: Pembrolizumab demonstrates a high response rate in patients with mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC), with responses often sustained even after treatment cessation. However, the pathological complete response (pCR) rate in clinically responding cases remains unknown. This study aimed to evaluate the relationship between the radiological and pathological responses in patients with dMMR mCRC who responded to pembrolizumab. Methods: This retrospective study included 27 patients with dMMR mCRC treated with pembrolizumab. The radiological response was assessed using RECIST version 1.1 criteria. The pathological response was evaluated in patients who underwent metastasectomy, with pCR defined as the absence of residual cancer cells. Results: The median progression-free survival (PFS) of the cohort was 19 months. Among the 27 patients, 3 achieved clinical complete response (cCR), and 10 had clinical partial response (cPR), resulting in a response rate of 48%. All three patients with cCR maintained their responses without metastasectomy (2-year PFS: 100%). Among patients with cPR, eight maintained their responses, while two experienced progression (2-year PFS: 75%). Five patients with cPR underwent curative-intent metastasectomy, and four of them (80%) achieved pCR. Thus, at least 40% of patients with cPR in this cohort had no residual cancer histologically. Conclusions: Our findings demonstrate the significant discordance between the radiological and pathological responses to pembrolizumab in dMMR mCRC patients, with 80% of those with cPR achieving pCR upon metastasectomy. These observations highlight the need for improved response assessment methods for precision immunotherapy.

To evaluate the outcomes of laparoscopic resection of colorectal cancer in non-elite cases. We defined patients whose clinical characteristics conformed to the criteria of the JCOG0404 trial as “elite” and those whose clinical characteristics did not conform to these criteria as “non-elite”. Patients with Stage II/III colorectal cancer (n = 450) were analyzed. The elite (E) and non-elite (NE) groups were further divided into open (E-Open, NE-Open) and laparoscopic (E-Lap, NE-Lap) surgery groups. We compared the short- and long-term outcomes of these groups. Propensity score matching (PSM) was performed when comparing the NE groups. The E group included 163 patients and the NE group included 287 patients. Before and after PSM, the NE-Lap group had significantly longer operative times, lower postoperative complication rates, earlier recovery of bowel function, and shorter postoperative hospital stays than the NE-Open group. After PSM, the Clavien–Dindo classification Grade ≥ III complications and reoperation rates in the NE-Lap group were significantly lower than those in the NE-Open group. The short-term outcomes of the NE-Lap group were comparable with those of the E-Lap group. The 5-year overall survival rates were not significantly different among the groups. Laparoscopic resection of colorectal cancer is effective and safe, even in non-elite cases.

Background Although treatment outcomes for metastatic colorectal cancer (mCRC) have dramatically improved over the past few decades, drug costs have also significantly increased. This study aimed to investigate which first-line treatment regimens for mCRC are actually used (frequency) in Japanese practice and at what cost. Methods We collected data on patients with mCRC who received first-line treatment at 37 institutions of the Japan Clinical Oncology Group Colorectal Cancer Study Group from July 2021 to June 2022, and calculated the cost of regimens. The cost per month of each regimen was estimated based on standard usage, assuming a patient with a weight of 70 kg and a body surface area of 1.8 m2. We categorized the regimens into very high-cost (>= 1 000 000 Japanese yen [JPY]/month), high-cost (>= 500 000 JPY/month), and others (<500 000 JPY/month). Results The study included 1880 participants, 24% of whom were >= 75 years. Molecular targeted containing regimens were received by 78% of the patients. The most frequently used regimen was the doublet regimen (fluoropyrimidine with either oxaliplatin or irinotecan) plus bevacizumab (43%), followed by doublet plus cetuximab or panitumumab (21%). The cost of molecular targeted drugs-containing regimens (ranging from 85 406 to 843 602 JPY/month) is much higher than that of only cytotoxic drug regimens (ranging from 17 672 to 51 004 JPY/month). About 16% received high-cost treatments that included panitumumab-containing regimens and pembrolizumab (17% of patients aged <= 74 years and 11% of patients aged >= 75 years). Conclusion About 16% of mCRC patients received first-line treatment with regimens costing >500 000JPY/month, and molecular targeted drugs being the main drivers of cost.

Abstract Background: Metastasectomy is an important treatment to improve survival outcomes in metastatic colorectal cancer (mCRC). However, the evidence regarding the significance of metastasectomy in selected patients with tumors deficient in mismatch repair (dMMR) has been lacking. We aimed to describe the significance of metastasectomy in patients with dMMR mCRC, and the pathological complete response (pCR) rate of patients who underwent metastasectomy after pembrolizumab treatment. Methods: This retrospective analysis included 42 patients with dMMR mCRC treated at Niigata University Medical and Dental Hospitaland its affiliated hospitals. Clinicopathological characteristics, including metastasectomy, were analyzed to evaluate overall survival (OS). Moreover, pCR rate after pembrolizumab treatment was evaluated in patients who underwent metastasectomy. Results: The sites of metastases were lymph node in 17, peritoneum in 16, and liver in seven patients. Metastasectomy was performed in 18 (43%) of the 42 patients. The five-year OS for patients who underwent metastasectomy was 100%, and metastasectomy was an independent prognostic factor for OS (P = 0.009). Three patients underwent metastasectomy with curative intent after pembrolizumab treatment, and pCR was achieved in all three patients (100%). Conclusions: For this small retrospective study, the data suggest that metastasectomy is an important treatment for patients with dMMR mCRC, and patients treated with pembrolizumab show an excellent pCR rate.

Abstract Background The lymph node metastasis rate in right‐sided colon cancer is unknown, and the optimal central vascular ligation level remains controversial. We aimed to determine the lymph node metastasis rate and short‐term results of radical surgery with extended lymph node dissection in right‐sided colon cancer. Methods This prospective multicenter observational study included patients with stage II/III right‐sided colon cancer from five cancer hospitals. The metastasis rate of each node station was analyzed according to tumor location and main feeding artery. Results Between April 2018 and August 2021, 208 patients underwent dissection around the superior mesenteric artery (SMA) and vein (SMV). In transverse colon cancer, 7.5% and 2.5% of metastases occurred around the SMV and SMA at the root of the middle colic artery (MCA), respectively; 6.7% and 6.7% at the root of the right colic artery. In caecal cancer, 1.9% of metastases occurred around the SMV and 1.9% around the SMA. In ascending colon cancer, the rate was 1.1% around the SMV. Of the tumors, 17% fed mainly by the ileocolic artery had node metastases along the middle or right colic artery, as did 66.7% fed mainly by the right colic artery and 41.2% fed by the MCA (p = 0.01). Postoperative complications occurred in 42 patients (20.2%). Conclusion Routine prophylactic extended lymphadenectomy around the SMA might not be necessary in caecum and ascending colon cancer. Dissection around the SMA may be necessary in cases of transverse colon cancer or when the feeding artery is the MCA.

Metastatic choroidal carcinoma is rare and generally has a poor prognosis. The present case report describes a case of choroidal metastasis from distal cholangiocarcinoma, which was successfully managed using stereotactic radiotherapy (SRT). A 67-year-old Japanese man underwent pancreaticoduodenectomy for distal cholangiocarcinoma. The pathological stage was T2N0M0 stage IIA, according to the Union for International Cancer Control 8th edition. After surgery, the patient received adjuvant chemotherapy with oral TS-1® for 1 month. A total of 2 months after surgery, the patient was readmitted to hospital due to decreased visual acuity. Fundoscopy revealed a macular hole in the right eye that accounted for the decreased visual acuity. Additionally, Goldmann three-mirror contact lens examination revealed a 4-mm choroidal mass with a yellowish color situated at a considerable distance from the optic nerve. Magnetic resonance imaging revealed an enhanced choroidal mass. Based on the findings of ophthalmologic examinations and the patient's history of cholangiocarcinoma, they were diagnosed with choroidal metastasis from distal cholangiocarcinoma. SRT was administered at a total dose of 40 Gy divided into 8 Gy fractions. A total of 1 year after SRT, the patient achieved complete remission without decreased visual acuity. The patient remains alive and in good health without recurrence, 4 years after the diagnosis of choroidal metastasis. To the best of our knowledge, this is the second reported case of intraocular metastasis from cholangiocarcinoma. In conclusion, SRT may provide an opportunity to control metastatic choroidal carcinoma without decreasing visual acuity.

BackgroundAlthough previous studies have demonstrated that tumor deposits (TDs) are associated with worse prognosis in colon cancer, their clinical significance in rectal cancer has not been fully elucidated, especially in the lateral pelvic lymph node (LPLN) area. This study aimed to clarify the clinical significance of TDs, focusing on the number of metastatic foci, including lymph node metastases (LNMs) and TDs, in the LPLN area.MethodsThis retrospective study involved 226 consecutive patients with cStage II/III low rectal cancer who underwent LPLN dissection. Metastatic foci, including LNM and TD, in the LPLN area were defined as lateral pelvic metastases (LP-M) and were evaluated according to LP-M status: presence (absence vs. presence), histopathological classification (LNM vs. TD), and number (one to three vs. four or more). We evaluated the relapse-free survival of each model and compared them using the Akaike information criterion (AIC) and Harrell's concordance index (c-index).ResultsForty-nine of 226 patients (22%) had LP-M, and 15 patients (7%) had TDs. The median number of LP-M per patient was one (range, 1-9). The best risk stratification power was observed for number (AIC, 758; c-index, 0.668) compared with presence (AIC, 759; c-index, 0.665) and histopathological classification (AIC, 761; c-index, 0.664). The number of LP-M was an independent prognostic factor for both relapse-free and overall survival, and was significantly associated with cumulative local recurrence.ConclusionThe number of metastatic foci, including LNMs and TDs, in the LPLN area is useful for risk stratification of patients with low rectal cancer.

Quantitative structure activity relationships (QSARs) have been derived relating skin corrosivity data of organic acids, bases and phenols to their log(octanol/water partition coefficient), molecular volume, melting point and pKa. Datasets were analysed using principal components analysis; plots of the first 2 principal components of the above parameters, which broadly model skin permeability and cytotoxicity, for each group of chemicals showed that the analysis was able to discriminate well between corrosive and non-corrosive chemicals. The derived QSARs should be useful for the prediction of the skin corrosivity potential of new or untested chemicals.

Purpose Despite marked recent advances in chemotherapy, few reports have focused on the prognosis for patients with metastatic colorectal cancer (mCRC) achieving complete response (CR) after systemic chemotherapy. This study investigated the clinical course of mCRC patients achieving CR and evaluated the role of chemotherapy in CR. Methods This retrospective study searched a prospectively maintained database at the author’s institute to identify medical records for mCRC patients achieving CR after systematic chemotherapy from January 2007 to March 2020. Results The search yielded 23 patients with confirmed CR to systemic chemotherapy. Median time to CR from treatment initiation was 6.8 months. Maintenance chemotherapy was continued for 22 of 23 patients. Median duration of maintenance chemotherapy was 11.1 months. Disease progression occurred for 17 (73.9%) patients at a median 48.1-month follow-up. Median progression-free survival was 26.6 months. Median overall survival was 91.7 months. Conclusions Patients with CR to chemotherapy had a high probability of disease progression, but a relatively long-term prognosis. Treatment strategies after achievement of CR should be based an understanding of the high potential that tumor cells will remain. Use of maintenance chemotherapy after achievement of CR is still unclear, and the recent data do not demonstrate a negative impact for continuing maintenance chemotherapy after CR.

Ramucirumab (RAM) plus paclitaxel (PTX) therapy has shown promising results as a standard second-line treatment for advanced gastric cancer patients. Recently, combined docetaxel (DOC) plus S-1 (DS) therapy could be regarded as the new standard adjuvant chemotherapy for patients with curatively resected stage III gastric cancer. However, the efficacy and safety of RAM plus PTX therapy in patients treated previously with DOC-containing therapy remains unclear. This study assessed the clinical outcomes of RAM plus PTX therapy in advanced gastric cancer patients with or without a previous history of treatment with a DOC-containing regimen. In a series of 107 consecutive patients enrolled for this study, the median PFS and OS were 4.2 and 6.2 months, respectively. Fifty-five patients had a history of prior therapy with DOC and 52 did not. There was no significant difference between with and without DOC groups in the ORR (22.2% vs. 23.5%), PFS (4.2 vs. 5.3 months), or OS (7.2 vs. 6.4 months). In a comparison taking into account the interval from the DOC-containing therapy to the RAM plus PTX therapy, the number of treatment courses was significantly smaller and the PFS significantly shorter in the patient group with an interval of ≤ 6 months (median, 2 vs 4.5 courses, P = 0.033; 3.4 months vs. 5.1 months, P = 0.043). RAM plus PTX therapy in patients with advanced gastric cancer is effective even in patients who have previously received DOC-containing chemotherapy, especially if the interval is > 6 months.

Primary synovial sarcoma of the spermatic cord is quite rare and has not been reported in Japanese literature. We report a case of primary synovial sarcoma of the spermatic cord and localized dissemination of the tumor in a patient who experienced recurrence of intra-abdominal bleeding 7 years after curative resection of the primary lesion. A 70-year-old man was admitted with disturbance on urination and lower abdominal pain. Computed tomography (CT) of the abdomen revealed two lesions:a 10-cm intrapelvic tumor with hemorrhage and a 4-cm tumor adjacent to the bladder. Curative excision of the tumors was performed. Histological examination revealed that the larger lesion was a primary tumor of the spermatic cord with proliferation of spindle cells in cellular fascicles in a monotonous pattern, which was compatible with histologic findings of monophasic fibrous synovial sarcoma. The smaller lesion was a disseminated tumor. The diagnosis of synovial sarcoma was confirmed by the detection of a SS18 (SYT) -SSX1 fusion gene. After discharge, the patient received adjuvant chemotherapy, including ifosfamide and doxorubicin. No recurrence was evident thereafter. Seven years after the operation, the patient experienced sudden abdominal pain and swelling and was transferred to our hospital. CT showed a 17-cm tumor with massive hemorrhage in the omental bursa. Through catheterization of the superior mesenteric artery, bleeding from a branch of the dorsal pancreatic artery was identified. Because of the difficulty of catheterizing the bleeding branch, he underwent emergency resection of the tumor and partial resection of the colon. Histologic examination and genetic testing revealed that the tumor was a recurrence of the synovial sarcoma. After discharge, the patient received treatment with gemcitabine and docetaxel. However, 7 months after the second surgery, intraperitoneal manifestations recurred. The patient died 14 months after the second resection. This case suggests that curative surgical resection of the primary synovial sarcoma of the spermatic cord contributes to prolonged survival. However, because the recurrence rate of synovial sarcoma is high, multidisciplinary treatment, including chemotherapy and radiotherapy, might be necessary.

Right-sided colorectal cancer (RCRC) demonstrates worse survival outcome compared with left-sided CRC (LCRC). Recently, the importance of RNF43 mutation and BRAF V600E mutation has been reported in the serrated neoplasia pathway, which is one of the precancerous lesions in RCRC. It was hypothesized that the clinical significance of RNF43 mutation differs according to primary tumor sidedness. To test this hypothesis, the clinicopathological characteristics and survival outcome of patients with RNF43 mutation in RCRC and LCRC were investigated. Stage I-IV CRC patients (n=201) were analyzed. Genetic alterations including RNF43 using a 415-gene panel were investigated. Clinicopathological characteristics between RNF43 wild-type and RNF43 mutant-type were analyzed. Moreover, RNF43 mutant-type was classified according to primary tumor sidedness, i.e., right-sided RNF43 mutant-type or left-sided RNF43 mutant-type, and the clinicopathological characteristics between the two groups were compared. RNF43 mutational prevalence, spectrum and frequency between our cohort and TCGA samples were compared. RNF43 mutation was observed in 27 out of 201 patients (13%). Multivariate analysis revealed that age (>= 65), absence of venous invasion, and BRAF V600E mutation were independently associated with RNF43 mutation. Among the 27 patients with RNF43 mutation, 12 patients were right-sided RNF43 mutant-type and 15 left-sided RNF43 mutant-type. Right-sided RNF43 mutant-type was significantly associated with histopathological grade 3, presence of lymphatic invasion, APC wild, BRAF V600E mutation, microsatellite instability-high (MSI-H), and RNF43 nonsense/frameshift mutation compared with left-sided RNF43 mutant-type. Similarly, RNF43 nonsense/frameshift mutations were more frequently observed in RCRC compared with LCRC in the TCGA cohort (P=0.042). Right-sided RNF43 mutant-type exhibited significantly worse overall survival than RNF43 wild-type and left-sided RNF43 mutant-type (P=0.001 and P=0.023, respectively) in stage IV disease. RNF43 mutation may be a distinct molecular subtype which is associated with aggressive tumor biology along with BRAF V600E mutation in RCRC.

症例は69歳の女性で，胸部中下部食道癌の診断で術前化学療法後PRと判定し，右開胸食道切除，胃管再建術を施行した．病理検査では低分化型の扁平上皮癌で，pT3N2M0，pStage IIIの診断であった．術後9か月で縦隔内リンパ節再発を認め，化学放射線療法を施行しCRと判定した．術後2年2か月の定期CTで左副腎腫瘤が出現，転移性副腎腫瘍と診断し，化学療法を導入，継続し一旦は縮小したものの，その後再増大を認めた．PET-CTでは，副腎以外には縦隔を含め明らかなFDG集積を認めず，左副腎への単発転移と診断し，外科的切除の方針とした．初回手術後4年で左副腎摘出術を施行，術後は追加治療を行わず経過観察し，現在再発なく6年の長期生存中である．食道癌術後の血行性再発は一般に予後不良であるが，単発の転移と考えられる場合には時期を逃さない積極的な外科的治療が予後の向上に寄与する可能性が示唆された．

Treatment strategies of rectal cancer differ between tumors located above (RS/Ra) and below (Rb) the peritoneal reflection. Based on the extent of distal spread (DS), the Japanese Society for Cancer of Colon and Rectum proposed an optimal distal margin in RS/Ra and Rb tumors. In this study, we investigated the clinical significance of DS between RS/Ra and Rb tumors. We analyzed 287 stage I–III rectal cancer patients who underwent curative intent resection without preoperative therapy. DS and other pathological factors were evaluated using whole-mount sections. To investigate the clinical significance of DS in RS/Ra and Rb tumors, clinicopathological variables, including DS, were analyzed for the survival outcome according to the tumor group. DS was detected in 20 out of 185 (11%) patients with RS/Ra tumors and 8 out of 102 (8%) patients with Rb tumors. DS was not significantly associated with the overall survival (OS) or relapse-free survival (RFS) in RS/Ra tumors, but was an independent prognostic factor for the OS and RFS in Rb tumors (P = 0.002 and 0.007, respectively). The clinical significance of DS differs between RS/Ra and Rb tumors. DS is associated with a worse survival in Rb tumors, but not in RS/Ra tumors.

A 78-year-old man was admitted with diarrhea. Colonoscopy and computed tomography(CT)revealed rectal cancer with multiple liver metastases. Low anterior resection was performed for local control. After the operation, 5 courses of mFOLFOX6 plus bevacizumab chemotherapy were administered as first-line systemic therapy, but CT showed progressive disease with liver metastases. After the first-line systemic therapy, 2 courses of FOLFIRI plus bevacizumab chemotherapy were performed as second-line systemic therapy, but CT also revealed progressive disease with liver metastases. We retrospectively performed comprehensive genomic sequencing with a 415-gene panel and found that the patient had a hypermutation subtype. Interestingly, the panel also revealed that he had mismatch-repair(MMR)deficiency with MSH2 mutation, which is reported as a possible cause of resistance to 5-fluorouracil in colorectal cancer.

e15101 Background: Although the difference in right vs. left sidedness of colorectal cancer (CRC) in response to targeted therapy has been reported, we hypothesized that right-sided colorectal cancer (RCC) is more likely to have genetic alterations associated with resistance of anti-EGFR therapy. We tested this hypothesis using comprehensive genomic sequencing (CGS) on a set of samples from well-characterized CRC patients. Methods: Two-hundred-one primary colon cancer patients with either RCC or left-sided colorectal cancer (LCC) were analyzed. We investigated gene alterations using 415 gene panel, which includes the gene alterations associated with resistance of anti-EGFR therapy: TK receptors ( ERBB2, MET, EGFR, FGFR1, and PDGFRA), RAS pathway ( KRAS, NRAS, HRAS, BRAF, and MAPK2K1), and PI3K pathway ( PTEN and PIK3CA). We defined the patients who had no alterations in any of the genes as “all wild-type”, who are theoretically considered as responders of anti-EGFR therapy. Other patients with genetic alterations in resistance pathways were defined as “mutant-type”. Results: Fifty-six patients (28%) and 145 patients (72%) had RCC and LCC, respectively. Mutation of PIK3CA, BRAF, ACVR2A, MSH6, and CTNNB1 were significantly associated with RCC. Conversely, mutation of APC and TP53 were significantly associated with LCC. Regarding the gene alterations associated with anti-EGFR therapy, only 6 of 56 patients (11%) of RCC were “all wild-type”; in contrast to 41 of 145 patients (28%) of LCC that were “all wild-type” ( P = 0.009). In 45 Stage IV patients treated with anti-EGFR therapy, RCC showed significantly worse progression-free survival (PFS) than LCC ( P = 0.019), and “mutant-type” RCC showed worse PFS compared to the others ( P = 0.018). Conclusions: RCC is more likely to have the genetic alterations associated with resistance of anti-EGFR therapy compared to LCC. Primary tumor sidedness is a surrogate for the non-random distribution of molecular subtypes in CRC.

Objectives Anti-epidermal growth factor receptor (EGFR) therapy has been found to be more effective against left-sided colorectal cancer (LCRC) than right-sided colorectal cancer (RCRC). We hypothesized that RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy and tested this using comprehensive genomic sequencing. Materials and methods A total of 201 patients with either primary RCRC or LCRC were analyzed. We investigated tumors for genetic alterations using a 415-gene panel, which included alterations associated with resistance to anti-EGFR therapy: TK receptors (ERBB2, MET, EGFR, FGFR1, and PDGFRA), RAS pathway (KRAS, NRAS, HRAS, BRAF, and MAPK2K1), and PI3K pathway (PTEN and PIK3CA). Patients whose tumors had no alterations in these 12 genes, theoretically considered to respond to anti-EGFR therapy, were defined as “all wild-type”, while remaining patients were defined as “mutant-type”. Results Fifty-six patients (28%) and 145 patients (72%) had RCRC and LCRC, respectively. Regarding genetic alterations associated with anti-EGFR therapy, only 6 of 56 patients (11%) with RCRC were “all wild-type” compared with 41 of 145 patients (28%) with LCRC (P = 0.009). Among the 49 patients who received anti-EGFR therapy, RCRC showed significantly worse progression-free survival (PFS) than LCRC (P = 0.022), and “mutant-type” RCRC showed significantly worse PFS compared with “all wild-type” LCRC (P = 0.004). Conclusions RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy compared with LCRC. Furthermore, our data shows primary tumor sidedness is a surrogate for the non-random distribution of genetic alterations in CRC.

We herein report the case of a rapidly progressive sporadic mesenteric desmoid tumor (DT). A 62-year-old woman presented with a 4-cm-diameter palpable mass in the left supraumbilical area. The mass showed an ill-defined margin with heterogeneous delayed enhancement on computed tomography and heterogeneous high intensity on T2-weighted magnetic resonance imaging. Sixteen months after the initial observation, the mass had grown in size, reaching 13 cm in diameter. The resected mass was histologically confirmed as a DT of the mesentery. Since DT often has an unpredictable clinical course, clinicians should bear in mind the need for imaging follow-up.

Case 1: A 61-year-old man who had a diagnosis of low rectal cancer with lateral pelvic lymph node (LPLN) metastasis and multiple liver metastases underwent low anterior resection with LPLN dissection. The initial surgery was followed by chemotherapy, and then an extended right hepatectomy with partial resection of the liver was performed. Subsequently, a lung metastasis was detected, and the lung was partially resected. The patient was alive 9 years and 6 months after the initial operation. Case 2: A 53-year-old man had a diagnosis of low rectal cancer. After 5 courses of mFOLFOX6 plus bevacizumab, he underwent low anterior resection with LPLN dissection and resection of the peritoneal metastasis. The patient was alive 6 years and 3 months after the surgery without any signs of recurrence. Case 3: A 48-year-old man had a diagnosis of low rectal cancer and multiple liver metastases. He underwent low anterior resection with LPLN dissection and right hepatic lobectomy. He subsequently showed liver and lung metastases. The patient received systemic chemotherapy, and is alive with recurrent disease. We report 3 cases of Stage Ⅳ low rectal cancer with LPLN metastasis, and propose that LPLN dissection is important as a part of R0 resection for Stage Ⅳ low rectal cancer.