The efficacy of simple oral nutritional supplements versus usual care in postoperative patients with gastric cancer: study protocol for a multicenter, open-label, parallel, randomized controlled trial.

BACKGROUND: Body weight loss (BWL) after gastrectomy impact on the short- and long-term outcomes. Oral nutritional supplement (ONS) has potential to prevent BWL in patients after gastrectomy. However, there is no consistent evidence supporting the beneficial effects of ONS on BWL, muscle strength and health-related quality of life (HRQoL). This study aimed to evaluate the effects of ONS formulated primarily with carbohydrate and protein on BWL, muscle strength, and HRQoL. METHODS: This will be a multicenter, open-label, parallel, randomized controlled trial in patients with gastric cancer who will undergo gastrectomy. A total of 120 patients who will undergo gastrectomy will be randomly assigned to the ONS group or usual care (control) group in a 1:1 ratio. The stratification factors will be the clinical stage (I or ≥ II) and surgical procedures (total gastrectomy or other procedure). In the ONS group, the patients will receive 400 kcal (400 ml)/day of ONS from postoperative day 5 to 7, and the intervention will continue postoperatively for 8 weeks. The control group patients will be given a regular diet. The primary outcome will be the percentage of BWL (%BWL) from baseline to 8 weeks postoperatively. The secondary outcomes will be muscle strength (handgrip strength), HRQoL (EORTC QLQ-C30, QLQ-OG25, EQ-5D-5L), nutritional status (hemoglobin, lymphocyte count, albumin), and dietary intake. All analyses will be performed on an intention-to-treat basis. DISCUSSION: This study will provide evidence showing whether or not ONS with simple nutritional ingredients can improve patient adherence and HRQoL by reducing BWL after gastrectomy. If supported by the study results, nutritional support with simple nutrients will be recommended to patients after gastrectomy for gastric cancer. TRIAL REGISTRATION: jRCTs051230012; Japan Registry of Clinical Trails. Registered on Apr. 13, 2023.

Limited Oncological Benefits of Laparoscopic Total Gastrectomy With Splenectomy for Patients With Type 4 or Large Type 3 Gastric Cancer.

BACKGROUND/AIM: Total gastrectomy with splenectomy (TGS) is routinely performed in patients with type 4 or large type 3 gastric cancer (GC), which sometimes metastasize to splenic hilar lymph nodes (LNs). However, the indication for and significance of TGS remain controversial. This multicenter retrospective study aimed to evaluate the oncological feasibility of laparoscopic TGS (LTGS) in patients with advanced proximal GC. PATIENTS AND METHODS: We retrospectively studied patients with type 4 or large type 3 GC who underwent LTGS at three Institutes between January 2010 and December 2018. RESULTS: We identified 26 consecutive eligible patients for analysis. Large type 3/type 4 were observed in 10 (38.5%)/16 (61.5%) cases. Involvement of the greater curvature was observed in 19 cases (73.1%), and GC spread to the whole stomach was observed in 12 cases (46.2%). R0 resection was achieved in 23 cases (88.5%). The median number of retrieved splenic hilar LNs was 4.0 (1-15), and the number of cases with splenic hilar LN metastasis was 3 (11.5%). Postoperative grade II intra-abdominal abscess was observed in 1 case (3.8%), and pancreatic fistula was not observed in any patient. Recurrence was observed in 18 cases (69.2%), of which 16 (88.9%) presented peritoneal recurrence. The median overall survival (OS) was 40.6 months, and the 5-year OS rate was 30.3%. The 5-year survival rate of patients with splenic hilar LN metastasis was 33.3% and the therapeutic value of splenectomy was 3.83. CONCLUSION: LTGS was performed safely, but the oncological benefit of the procedure for type 4 or large type 3 GC was very limited.

Is D2 laparoscopic gastrectomy essential for elderly patients with advanced gastric cancer? A propensity score matched analysis.

Background: The necessity of the standard D2 gastrectomy for elderly patients with advanced gastric cancer (GC) is controversial because only limited data are available to demonstrate its oncological benefit for them. Our aim was to compare the outcomes of D2 and Non-D2 and to evaluate the survival benefit of D2 laparoscopic gastrectomy (LG) in elderly patients. Methods: We retrospectively identified 865 patients with GC who underwent radical LG at our hospital between 2011 and 2017. Patients aged ≥75 years who were diagnosed with clinical T1N+ or clinical T2-4 were eligible. The primary outcome was the 3-year overall survival (OS) rate. The confounding factors were minimized using propensity score matching. Results: This study included 119 patients (63 D2 LG and 56 Non-D2 LG), and 52 patients (26 each for D2 LG and Non-D2 LG) were analyzed after matching. Although no significant difference was found in overall major complications (P=1.00), complications tended to occur in the D2 group (D2 vs. Non-D2 =3.9% vs. 0%). No differences in the 3-year OS were noted between the two groups (68.8% vs. 68.8%; HR 1.53, 95% CI: 0.56-3.19). Conclusions: This study demonstrated the possible association between D2 LG and increased complication rate and no survival benefit of D2 LG in elderly patients.

Side-overlap esophagogastric tube (SO-EG) reconstruction after minimally invasive Ivor Lewis esophagectomy or laparoscopic proximal gastrectomy for cancer of the esophagogastric junction.

PURPOSE: Both laparoscopic proximal gastrectomy with lower esophagectomy (extended LPG) and minimally invasive Ivor Lewis esophagectomy (MIILE) are acceptable treatments for adenocarcinoma of the esophagogastric junction (AEG), but the optimal reconstruction technique for mediastinal esophagogastrostomy (one that provides adequate reflux prevention) has not been established. We devised a novel side-overlap esophagogastric-tube (SO-EG) reconstruction. METHODS: We performed a retrospective review of patient records after LPG or MIILE. In each patient, we created a 3-cm wide gastric tube, overlapping the esophagus by 5 cm. A linear stapler was inserted into the left side of the esophageal stump and the anterior gastric wall along the greater curvature. The entry hole was closed to make a slit-like anastomosis, and the right side of the esophageal wall was fixed to the anterior gastric wall. RESULTS: Ten consecutive patients underwent this procedure between June 2020 and July 2021. Five patients had Siewert type II AEG: 4 with lower thoracic esophageal cancer and 1 with benign lower esophageal stenosis. A total of 3 patients underwent extended LPG, and 7 underwent MIILE. The median operative time was 352 min (range, 221-556 min). The postoperative course was uneventful in 9 patients; a single patient developed pneumonia. Seven patients underwent follow-up endoscopy at 6 months. One patient with anastomotic stenosis and 2 with mild reflux esophagitis were treated conservatively. CONCLUSION: Our novel SO-EG reconstruction is simple and feasible, with acceptable results for preventing reflux esophagitis. This technique can be performed with either extended LPG or MIILE.

Functional Outcomes of Delta-Shaped Anastomosis After Laparoscopic Distal Gastrectomy.

BACKGROUND: We invented a simple and secure method of intracorporeal gastroduodenostomy, the delta-shaped anastomosis (DA), using endoscopic linear stapler only and standardized the DA procedure by resecting two-thirds of the stomach based on the anatomical landmarks. This study aimed to evaluate the feasibility of the standardized DA as the standard reconstruction procedure after a laparoscopic distal gastrectomy assessing functional outcomes including postoperative complications, body weight loss, nutritional status, and endoscopic findings. METHODS: The medical records of 349 patients with gastric cancer who underwent laparoscopic distal gastrectomy from April 2011 to December 2017 at our hospital were retrospectively reviewed. Functional outcomes were assessed according to nutritional status and endoscopic findings. RESULTS: The operation time was shorter and complication rate was lower in the standardized DA than those in Billroth-II (BII) and Roux-en-Y (RY). The body weight loss in DA was 10% 1 year postoperatively and remained stable during the follow-up period, which showed no significant difference. The endoscopic findings showed the ratio of residual food in DA was lower than that in RY (DA:RY = 13.3%:13.6% and 8.4%:33.3% at 1 and 3 years postoperatively, respectively). Severe gastritis was extremely rare in DA (6.7% at 1 year and 15.6% at 3 years postoperatively). Bile reflux was more often found in DA than RY (DA:RY = 19.9%:4.8% and 26.6%:0% at 1 and 3 years postoperatively, respectively). Reflux esophagitis was found 10% of DA only. CONCLUSIONS: Functional outcomes of the standardized DA were satisfactory and feasible. Our intracorporeal Billroth-I reconstruction, by resecting two-thirds of the stomach, can be one of the standard reconstruction methods after a laparoscopic distal gastrectomy.

Comparative Outcomes of Laparoscopic Gastrectomy and Open Gastrectomy for Scirrhous Gastric Cancer: A Multicenter Retrospective Cohort Study.

Objective: A multicenter retrospective cohort study was performed to compare the outcomes of laparoscopic gastrectomy (LG) versus open gastrectomy (OG) for scirrhous gastric cancer (GC) as a unique subtype also known as type 4 gastric cancer or linitis plastica. Background: Although data on the efficacy and safety of LG as an alternative to OG are emerging, the applicability of LG to scirrhous GC remains unclear. Methods: Patients with clinical type 4 GC undergoing gastrectomy at 13 hospitals from 2005 to 2015 were retrospectively reviewed. As the primary endpoint, we compared overall survival (OS) between the LG and OG groups. To adjust for confounding factors, we used multivariate Cox regression analysis for the main analyses and propensity-score matching for sensitivity analysis. Short-term outcomes and recurrence-free survival were also compared. Results: A total of 288 patients (LG, 62; OG, 226) were included in the main analysis. Postoperative complications occurred in 25.8% and 30.1%, respectively (P = 0.44). No significant difference in recurrence-free survival was observed (P = 0.72). The 5-year OS rates were 32.4% and 31.6% in the LG and OG groups, respectively (P = 0.60). The hazard ratio (LG/OG) for OS was 0.98 (95% confidence interval [CI], 0.65-1.43) in the multivariate regression analysis. In the sensitivity analyses after propensity-score matching, the hazard ratio for OS was 0.92 (95% CI, 0.58-1.45). Conclusions: Considering the hazard ratios and 95% CIs for OS, LG for scirrhous GC was not associated with worse survival than that for OG.

Laparoscopic en bloc lower mediastinal lymph node dissection via transhiatal approach for adenocarcinoma of esophagogastric junction.

INTRODUCTION: According to previous studies, transhiatal lower mediastinal lymph node (LMLN) dissection is recommended for patients with adenocarcinoma of esophagogastric junction (AEG) with esophageal involvement of <3.0 cm [1-3]. Herein, we reported our procedure and the short-term outcomes. SURGICAL PROCEDURE: The patient was placed in a supine position under general anesthesia, and five ports were placed into the upper abdomen. After radical suprapancreatic lymph node dissection, the center of the phrenic tendon was cut and each phrenic crus was retracted laterally to obtain good operative field. The ventral tissue along the lower esophagus was dissected from the pericardia. The dissection proceeded to the right atrium along the IVC. The dorsal tissue was dissected from the aorta. The remaining plate-like tissue was dissected from the pleura. Finally, the dissected tissue was peeled back from the esophagus. RESULTS: Twenty-four patients with Siewert type II/III AEG underwent this procedure at our hospital between April 2011 and December 2019. Two cases were administered with the right thoracic approach to secure proximal margin or perform anastomosis safely. All cases underwent R0 resection. Although the Clavien-Dindo grade IIIa anastomotic leakage was confirmed in two cases (8.3%), there were no complications associated with the procedure. The median number of retrieved LMLN was five (range 0-14). Two patients had metastatic LMLN. The length of esophageal involvement in patients with metastatic LMLN was longer than that in patients with nonmetastatic LMLN (26 mm vs 12.5 mm). CONCLUSION: Our procedure was safe and feasible for lymph node dissection in AEG.

Upper mediastinal lymph node dissection based on mesenteric excision in esophageal cancer surgery: confirmation by near-infrared image-guided lymphatic mapping and the impact on locoregional control.

BACKGROUND: We previously reported a novel method of mesenteric excision for esophageal cancer surgery. The esophagus, trachea, recurrent laryngeal nerves (RLNs), and surrounding lymph nodes (LNs) are contained in a common mesenterium, which we termed the "mesotracheoesophagus". In addition, near-infrared (NIR) image-guided lymphatic mapping has recently been used. The purpose of this study was to confirm the feasibility of NIR image-guided lymphatic mapping for upper mediastinal LN dissection, and to confirm the oncological feasibility of our surgical approach. METHODS: Fifteen patients with resectable esophageal cancer underwent submucosal injection of indocyanine green (ICG), and underwent robot-assisted esophagectomy. The frequency of ICG positivity in the LN basins along the RLNs, and metastatic frequency were assessed. Regarding the oncological feasibility of our thoracoscopic esophagectomy, the recurrence patterns and survival of 72 consecutive patients who underwent curative resection from 2011 to 2016 were analyzed. RESULTS: ICG-positive LN basins along the right and left RLNs were found in 12 (80% of 15) patients (3 patients positive for metastatic LNs) and 11 (73% of 15) patients (2 positive for metastatic LNs and 1 false-negative), respectively. All ICG-positive LN basins were found within the mesotracheoesophagus. The sensitivity was 5/6 (83%), and the negative predictive value was 6/7 (86%). Among the 72 patients, with a median follow-up period of 1644 days, only 3 (4.2%) patients developed locoregional recurrence. CONCLUSIONS: The NIR image-guided lymphatic mapping was feasible. Our results with no ICG-positive basins outside of the '"mesotracheoesophagus", supported our surgical approach. It might become standard, with acceptable locoregional control.

Laparoscopic surgery for ventrally located epiphrenic diverticulum with esophageal achalasia.

Epiphrenic diverticulum is frequently associated with esophageal motility disorder, including esophageal achalasia. Heller's myotomy should accompany diverticulectomy to reduce the bulging pressure in surgery for epiphrenic diverticulum with esophageal achalasia. In such cases, designing myotomy is sometimes difficult, depending on the size and location of the diverticulum. Ventrally located diverticula require special caution to spare some muscular tissue between the longitudinal staple line of the diverticulectomy and myotomy, which is a crucial step to prevent staple-line dehiscence. In this article, we describe a case with ventrally located epiphrenic diverticulum who underwent successful laparoscopic resection and myotomy for esophageal achalasia with an informative surgical video.

Iatrogenic diaphragmatic hernia as a late complication of laparoscopic excisional biopsy of peritoneal nodules: A case report.

INTRODUCTION: Iatrogenic diaphragmatic hernias have been reported as a rare complication of abdominal surgery, and only a few reports have suggested minimal intraoperative injury to the diaphragm as a cause. PRESENTATION OF CASE: We report a rare case of delayed diaphragmatic hernia caused by laparoscopic excisional biopsy of a peritoneal lesion on the diaphragmatic peritoneum. A 70-year-old woman with gastric gastrointestinal stromal tumor underwent laparoscopic partial gastrectomy and excisional biopsy for white nodules on the left diaphragmatic peritoneum using laparoscopic scissors. Slight bleeding that occurred after excisional biopsy was stopped using a soft-coagulation system. Six months after her first surgery, a left diaphragmatic defect and transverse colon migration into the thoracic cavity were detected on computed tomography. The patient subsequently underwent laparoscopic diaphragmatic hernia repair. The site at which the diaphragm defect occurred was consistent with the site of excisional biopsy. The defect was closed with interrupted suturing using non-absorbable threads, following which a composite mesh was applied above the suture site for reinforcement. DISCUSSION: This is the first report of an iatrogenic diaphragmatic hernia after diagnostic laparoscopy for peritoneal excision biopsy of the diaphragmatic surface. In the present case, the coagulation procedure for hemostasis after peritoneal resection was considered to be the cause of the diaphragmatic hernia. The heat generated by soft coagulation might have unexpectedly reached and damaged the deep areas of the diaphragmatic muscle. CONCLUSION: Surgeons performing laparoscopic excisional biopsy of the diaphragmatic peritoneum should consider the potential risk for iatrogenic diaphragmatic hernias.

MicroRNA-9-5p-CDX2 Axis: A Useful Prognostic Biomarker for Patients with Stage II/III Colorectal Cancer.

A lack of caudal-type homeobox transcription factor 2 (CDX2) protein expression has been proposed as a prognostic biomarker for colorectal cancer (CRC). However, the relationship between CDX2 levels and the survival of patients with stage II/III CRC along with the relationship between microRNAs (miRs) and CDX2 expression are unclear. Tissue samples were collected from patients with stage II/III CRC surgically treated at Kyoto University Hospital. CDX2 expression was semi-quantitatively evaluated by immunohistochemistry (IHC). The prognostic impacts of CDX2 expression on overall survival (OS) and relapse-free survival (RFS) were evaluated by multivariable statistical analysis. The expression of miRs regulating CDX2 expression and their prognostic impacts were analyzed using The Cancer Genome Atlas Program for CRC (TCGA-CRC). Eleven of 174 CRC tissues lacked CDX2 expression. The five-year OS and RFS rates of patients with CDX2-negative CRC were significantly lower than those of CDX2-positive patients. Multivariate analysis of clinicopathological features revealed that CDX2-negative status is an independent marker of poor prognosis in stage II/III CRC. miR-9-5p was shown to regulate CDX2 expression. TCGA-CRC analysis showed that high miR-9-5p expression was significantly associated with poor patient prognosis in stage II/III CRC. In conclusion, CDX2, the post-transcriptional target of microRNA-9-5p, is a useful prognostic biomarker in patients with stage II/III CRC.

Laparoscopic gastrectomy with and without prophylactic drains in gastric cancer: a propensity score-matched analysis.

BACKGROUND: The number of patients who are undergoing laparoscopic gastrectomy for treating gastric cancer is increasing. Although prophylactic drains have been widely employed following the procedure, there are few studies reporting the efficacy of prophylactic drainage. Therefore, this study assessed the efficacy of prophylactic drains following laparoscopic gastrectomy for gastric cancer. METHODS: Data of patients who received laparoscopic gastrectomy for treating gastric cancer in our institution between April 2011 and March 2017 were reviewed, and the outcomes of patients with and without a prophylactic drainage were compared. Propensity score matching was used to minimize potential selection bias. RESULTS: A total of 779 patients who underwent surgery for gastric cancer were reviewed; of these, 628 patients who received elective laparoscopic gastrectomy were included in this study. After propensity score matching, data of 145 pairs of patients were extracted. No significant differences were noted in the incidence of postoperative complications between the drain and no-drain groups (19.3% vs 11.0%, P = 0.071). The days after the surgery until the initiation of soft diet (6.3 ± 7.4 vs 4.9 ± 2.9 days, P = 0.036) and the length of postoperative hospital stay (15.7 ± 12.9 vs 13.0 ± 6.3 days, P = 0.023) were greater in the drain group than those in the no-drain group. CONCLUSIONS: This study suggests that routinely using prophylactic drainage following laparoscopic gastrectomy for treating gastric cancer is not obligatory.

Strategy for treatment of stage IV human epidermal growth factor 2-positive gastric cancer: a case report.

BACKGROUND: The prognosis of stage IV gastric cancer and human epidermal growth factor 2 (HER2)-positive gastric cancer is poor, although new drugs and regimens have been developed. We report a case of a patient with stage IV HER2-positive gastric cancer treated successfully by conversion therapy and trastuzumab. CASE PRESENTATION: The patient was a 73-year-old Japanese man diagnosed as L, type 3, circ, T4aNxCy1P1M1, stage IV (the Japanese classification of gastric carcinoma). The patient was treated with docetaxel, cisplatin, and TS-1 (DCS regimen). After two courses of the regimen, peritoneal dissemination disappeared, and peritoneal lavage cytology revealed no tumor cells in the abdominal cavity. Subsequently, he underwent laparoscopic distal gastrectomy with D1+. Pathological findings were ypT2(MP), ypN2(3/15), ypP0, ypCY0, M0, ypstage II. He received TS-1 as an adjuvant chemotherapy, but he had peritoneal recurrence. The original gastric cancer was HER2-positive. We therefore treated him with TS-1 with trastuzumab. This regimen was quite effective and achieved a complete response. After complete response, we switched the patient to trastuzumab monotherapy. He had no evidence of recurrence for 6 years, 3 months after surgery. CONCLUSION: DCS regimen, R0 resection, and adjuvant chemotherapy with trastuzumab can be a powerful strategy for stage IV HER2-positive gastric cancer.

Exosome miR-335 as a novel therapeutic strategy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common and deadly cancer. Most cases of HCC arise in a cirrhotic/fibrotic liver, indicating that environment may play a paramount role in cancer genesis. Previous studies from our group and others have shown that, in desmoplastic cancers, there is a rich intercellular communication between activated, cancer-associated fibroblasts and cancer cells. Moreover, extracellular vesicles (EVs), or exosomes, have been identified as an important arm of this intercellular communication platform. Finally, these studies have shown that EVs can carry microRNA (miR) species in vivo and deliver them to desmoplastic cancers. The precise role played by activated liver fibroblasts/stellate cells in HCC development is insufficiently known. Based on previous studies, it appears plausible that activated fibroblasts produce signals carried by EVs that promote HCC genesis. In the current study, we first hypothesized and then demonstrated that stellate cell-derived EVs 1) can be loaded with an miR species of choice (miR-335-5p); 2) are taken up by HCC cells in vitro and more importantly in vivo; 3) can supply the miR-335-5p cargo to recipient HCC cells in vitro as well as in vivo; and 4) inhibit HCC cell proliferation and invasion in vitro as well as induce HCC tumor shrinkage in vivo. Finally, we identified messenger RNA targets for miR-335 that are down-regulated after treatment with EV-miR-335-5p. This study informs potential therapeutic strategies in HCC, whereby stellate cell-derived EVs are loaded with therapeutic nucleic acids and delivered in vivo. (Hepatology 2018;67:940-954).

miR-137 Regulates the Tumorigenicity of Colon Cancer Stem Cells through the Inhibition of DCLK1.

UNLABELLED: miRNAs have important roles in regulating cancer stem cell (CSC) properties and are considered to be potential therapeutic targets. However, few studies have focused on miRNAs which are specifically related to colon CSCs. Here, a PCR-based miRNA profiling analysis of normal colon stem cells (NCSC) and colon CSCs (EpCAM⁺/CD44⁺/CD66a⁻) identified miRNAs which regulate colon CSC properties. Interestingly, miRNA-137 (miR-137) expression was downregulated in the colon CSCs compared with NCSCs, while doublecortin-like kinase 1(DCLK1) mRNA was highly expressed in the colon CSCs but low in the NCSCs. In fact, DCLK1-positive cancer cells were widely distributed in clinically resected colon cancer specimens, while DCLK1-positve epithelial cells were rarely detected in normal colon tissues including the crypt bottoms. Luciferase assay and immunoblot analysis revealed that miR-137 regulated DCLK1 gene expression. Transduction of exogenous miR-137 suppressed the development of colon cancer organoids in vitro and the tumorigenicity of colon cancer cells in vivo without affecting the growth of normal intestinal organoids. Furthermore, the suppression of miR-137 enhanced the organoid development of normal colon cells. These data demonstrate that miR-137 has the capacity to suppress the tumorigenicity of colon CSCs and that maintained expression of miR-137 in NCSCs contributes to suppressing uncontrolled cell proliferation through the inhibition of DCLK1 expression. IMPLICATIONS: The miR-137/DCLK1 axis as an important regulator in NCSCs and colon CSCs; further understanding of this axis may foster the development of potential gene therapeutic strategies targeting colon CSCs.

[Two cases of curative resection by laparoscopic surgery following preoperative chemotherapy with bevacizumab for locally advanced colon cancer].

Here we report 2 cases of curative resection following preoperative chemotherapy with bevacizumab for locally advanced colon cancer. Case 1 was a 62-year-old man admitted with constipation, abdominal distention, and abdominal pain. An abdominal computed tomography(CT)scan revealed an obstructive tumor of the sigmoid colon with invasion into the bladder. A diverting colostomy was performed, and chemotherapy with mFOLFOX6(infusional 5-fluorouracil/Leucovorin+ oxaliplatin) plus bevacizumab was initiated. The tumor shrunk markedly after 6 courses of this treatment. Thereafter, laparoscopy- assisted sigmoidectomy was successfully performed. Case 2 was a 61-year-old woman admitted with diarrhea, abdominal pain, and fever. An abdominal CT scan revealed an obstructive tumor of the sigmoid colon with invasion into the ileum, uterus and retroperitoneum. A diverting colostomy was performed, and chemotherapy with XELOX(capecitabine+ oxaliplatin)plus bevacizumab was initiated. The tumor shrunk markedly after 6 courses of this treatment. Thereafter, laparoscopy- assisted sigmoidectomy was successfully performed. Both cases demonstrated partial clinical responses to chemotherapy; thus, curative resection surgeries were performed. There were no perioperative complications. Therefore, we conclude that oxaliplatin-based chemotherapy plus bevacizumab and laparoscopic resection could be very effective for locally advanced colon cancer.