Prognostic Relevance of Primary Tumor Sidedness in Early-stage Colorectal Cancer: An Integrated Analysis of 4 Randomized Controlled Trials (JCOG2003A).

OBJECTIVE: The aim of this study was to determine the genuine prognostic relevance of primary tumor sidedness (PTS) in patients with early-stage colorectal cancer (CRC). BACKGROUND: The prognostic relevance of PTS in early-stage CRC remains a topic of debate. Several large epidemiological studies investigated survival only and did not consider the risk of recurrence so far. METHODS: Patients with stage II/III adenocarcinoma of the colon and upper rectum from 4 randomized controlled trials were analyzed. Survival outcomes were compared according to the tumor location: right-sided (cecum to transverse colon) or left-sided (descending colon to upper rectum). RESULTS: A total of 4113 patients were divided into a right-sided group (N=1349) and a left-sided group (N=2764). Relapse-free survival after primary surgery was not associated with PTS in all patients and each stage [hazard ratio (HR) adjusted =1.024 (95% CI: 0.886-1.183) in all patients; 1.327 (0.852-2.067) in stage II; and 0.990 (0.850-1.154) in stage III]. Also, overall survival after primary surgery was not associated with PTS in all patients and each stage [HR adjusted =0.879 (95% CI: 0.726-1.064) in all patients; 1.517 (0.738-3.115) in stage II; and 0.840 (0.689-1.024) in stage III]. In total, 795 patients (right-sided, N=257; left-sided, N=538) developed recurrence after primary surgery. PTS was significantly associated with overall survival after recurrence (HR adjusted =0.773, 95% CI: 0.627-0.954). CONCLUSIONS: PTS had no impact on the risk of recurrence for stage II/III CRC. Treatment stratification based on PTS is unnecessary for early-stage CRC.

How Does Omitting Additional Surgery After Local Excision Affect the Prognostic Outcome of Patients With High-risk T1 Colorectal Cancer?

OBJECTIVE: To investigate how omitting additional surgery after local excision (LE) affects patient outcomes in high-risk T1 colorectal cancer (CRC). BACKGROUND: It is debatable whether additional surgery should be performed for all patients with high-risk T1 CRC regardless of the tolerability of invasive procedures. METHODS: Patients who had received LE for T1 CRC at the Japanese Society for Cancer of the Colon and Rectum institutions between 2009 and 2016 were analyzed. Those who had received additional surgical resection and those who did not were matched one-on-one by the propensity score-matching method. A total of 401 propensity score-matched pairs were extracted from 1975 patients at 27 Japanese Society for Cancer of the Colon and Rectum institutions and were compared. RESULTS: Regional lymph node metastasis was observed in 31 (7.7%) patients in the LE + surgery group. Comparatively, the incidence of oncologic adverse events was low in the LE-alone group, such as the 5-year cumulative risk of local recurrence (4.1%) or overall recurrence (5.5%). In addition, the difference in the 5-year cancer-specific survival between the LE + surgery and LE-alone groups was only 1.8% (99.7% and 97.9%, respectively), whereas the 5-year overall survival was significantly lower in the LE-alone group than in the LE + surgery group [88.5% vs 94.5%, respectively ( P = 0.002)]. CONCLUSIONS: Those who had decided to omit additional surgery at the dedicated center for CRC treatment presented a small number of oncologic events and a satisfactory cancer-specific survival, which may suggest an important role of risk assessment regarding nononcologic adverse events to achieve a best practice for each individual with high-risk T1 tumors.

Long-term outcomes of additional surgery after endoscopic resection versus primary surgery for T1 colorectal cancer.

INTRODUCTION: There is considerable concern about whether endoscopic resection (ER) prior to additional surgery (AS) for T1 colorectal cancer (CRC) has oncologically potential adverse effects. Therefore, this study aimed to compare the long-term outcomes, including overall survival (OS), of patients treated with AS after ER versus primary surgery (PS) for T1 CRC using a propensity score-matched analysis from a large observational study. METHODS: This study investigated 6105 patients with T1 CRC treated with either ER or surgical resection between 2009 and 2016 at 27 high-volume Japanese institutions, with those undergoing surgery alone included in the PS group and those undergoing AS after ER included in the AS group. Propensity score matching was used for long-term outcomes of mortality and recurrence analysis. RESULTS: After propensity score matching, 1219 of 2438 patients were identified in each group. The 5-year OS rates in the AS and PS groups were 97.1% and 96.0%, respectively (hazard ratio: 0.72, 95% confidence interval [CI]: 0.49-1.08), indicating the non-inferiority of the AS group. Moreover, 32 patients (2.6%) in the AS group and 24 (2.0%) in the PS group had recurrences, with no significant difference between the two groups (odds ratio: 1.34, 95% CI: 0.76-2.40, p = 0.344). DISCUSSION: ER prior to AS for T1 CRC had no adverse effect on patients' long-term outcomes, including the 5-year OS rate. ER is a viable first-line treatment option for endoscopically resectable T1 CRC.

Treatment Decision for Locally Resected T1 Colorectal Carcinoma-Verification of the Japanese Guideline Criteria for Additional Surgery Based on Long-Term Clinical Outcomes.

INTRODUCTION: To verify the value of the pathological criteria for additional treatment in locally resected pT1 colorectal carcinoma (CRC) which have been used in the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines since 2009. METHODS: We enrolled 4,719 patients with pT1 CRC treated at 27 institutions between July 2009 and December 2016 (1,259 patients with local resection alone [group A], 1,508 patients with additional surgery after local resection [group B], and 1,952 patients with surgery alone [group C]). All 5 factors of the JSCCR guidelines (submucosal resection margin, tumor histologic grade, submucosal invasion depth, lymphovascular invasion, and tumor budding) for lymph node metastasis (LNM) had been diagnosed prospectively. RESULTS: Any of the risk factors were present in 3,801 patients. The LNM incidence was 10.3% (95% confidence interval 9.3-11.4) in group B/C patients with risk factors, whereas it was 1.8% (95% confidence interval 0.4-5.2) in those without risk factors ( P < 0.01). In group A, the incidence of recurrence was 3.4% in patients with risk factors, but it was only 0.1% in patients without risk factors ( P < 0.01). The disease-free survival rate of group A patients classified as risk positive was significantly worse than those of groups B and C patients. However, the 5-year disease-free survival rate in group A patients with no risk was 99.2%. DISCUSSION: Our large-scale real-world multicenter study demonstrated the validity of the JSCCR criteria for pT1 CRC after local resection, especially regarding favorable outcomes in patients with low risk of LNM.

Pharmacokinetics of L-theanine and the effect on amino acid composition in mice administered with L-theanine.

L-theanine, an amino acid component of the tea leaves of Camellia sinensis, is sold in Japan as a supplement for good sleep. Although several studies in humans and mice have reported the effects of L-theanine on brain function, only a few reports have comprehensively clarified the disposition of theanine administered to mice and its effects on concentrations of other blood amino acids. In this study, we aimed to determine the changes in the blood levels of L-theanine administered to mice and amino acid composition of the serum. L-theanine were administered to four-week-old Std-ddY male mice orally or via tail vein injection. L-theanine and other amino acids in serum prepared from blood collected at different time points post-dose were labeled with phenylisothiocyanate and quantified. The serum concentration of orally administered L-theanine peaked 15 min after administration. The area under the curve for tail vein injection revealed the bioavailability of L- theanine to be approximately 70%. L-theanine administration did not affect any amino acid levels in the serum, but a significant increase in the peak area overlapping the Glycine (Gly) peak was observed 30 min after administration. L-theanine administered to mice was rapidly absorbed and eliminated, suggesting that taking L-theanine as a supplement is safe without affecting its own levels or serum levels of other amino acids. However, considering that Gly, similar to L-theanine, is used as a dietary supplement for its anxiolytic effects and to improve sleep, determining the effects of L-theanine administration on Gly is important and needs further research.

Artificial Intelligence Imaging Diagnosis Using Super-Resolution and 3D Shape for Lymph Node Metastasis of Low Rectal Cancer: A Pilot Study From a Single Center.

BACKGROUND: Although accurate preoperative diagnosis of lymph node metastasis is essential for optimizing treatment strategies for low rectal cancer, the accuracy of present diagnostic modalities has room for improvement. OBJECTIVE: To establish a high-precision diagnostic method for lymph node metastasis of low rectal cancer using artificial intelligence. DESIGN: A retrospective observational study. SETTINGS: A single cancer center and a college of engineering in Japan. PATIENTS: Patients with low rectal adenocarcinoma who underwent proctectomy, bilateral lateral pelvic lymph node dissection, and contrast-enhanced multi-detector row computed tomography (slice ≤1 mm) between July 2015 and August 2021 were included in the present study. All pelvic lymph nodes from the aortic bifurcation to the upper edge of the anal canal were extracted, regardless of whether within or beyond the total mesenteric excision area, and pathological diagnoses were annotated for training and validation. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. RESULTS: A total of 596 pathologically negative and 43 positive nodes from 52 patients were extracted and annotated. Four diagnostic methods, with and without using super-resolution images and without using 3D shape data, were performed and compared. The super-resolution + 3D shape data method had the best diagnostic ability for the combination of sensitivity, negative predictive value, and accuracy (0.964, 0.966, and 0.968, respectively), while the super-resolution only method had the best diagnostic ability for the combination of specificity and positive predictive value (0.994 and 0.993, respectively). LIMITATIONS: Small number of patients at a single center and the lack of external validation. CONCLUSIONS: Our results enlightened the potential of artificial intelligence for the method to become another game changer in the diagnosis and treatment of low rectal cancer. See Video Abstract.

Short- and long-term outcomes of surgical treatment for inguinal lymph node metastasis in rectal and anal canal adenocarcinoma.

AIM: The significance of lymphadenectomy and its indications in patients with inguinal lymph node metastasis (ILNM) of anorectal adenocarcinoma is unclear. This study aimed to clarify the surgical outcomes and prognostic factors of inguinal lymphadenectomy for ILNM. METHOD: This study included patients who underwent surgical resection for ILNM of rectal or anal canal adenocarcinoma with pathologically positive metastases between 1997 and 2011 at 20 participating centres in the Study Group for Inguinal Lymph Node Metastasis from Colorectal Cancer organized by the Japanese Society for Cancer of the Colon and Rectum. Clinicopathological characteristics and short- and long-term postoperative outcomes were retrospectively analysed. RESULTS: In total, 107 patients were included. The primary tumour was in the rectum in 57 patients (53.3%) and in the anal canal in 50 (46.7%). The median number of ILNMs was 2.34. Postoperative complications of Clavien-Dindo Grade III or higher were observed in five patients. The 5-year overall survival rate was 38.8%. Multivariate analysis identified undifferentiated histological type (P < 0.001), pathological venous invasion (P = 0.01) and pathological primary tumour depth T0-2 (P = 0.01) as independent prognostic factors for poor overall survival. CONCLUSION: The 5-year overall survival after inguinal lymph node dissection was acceptable, and it warrants consideration in more patients. Further larger-scale studies are needed in order to clarify the surgical indications.

Thoracoscopic salvage esophagectomy with prophylactic mediastinal lymph node dissection after definitive chemoradiotherapy for patients with esophageal cancer.

BACKGROUND: Salvage esophagectomy for residual tumor and localized relapses after definitive chemoradiotherapy (dCRT) for patients with esophageal cancer is associated with a high rate of postoperative complications and in-hospital mortality. In addition, there are many controversial issues associated with salvage esophagectomy, such as the acceptability of minimally invasive surgery and the need for prophylactic dissection of mediastinal lymph nodes. The aim of this study was to evaluate the safety and usefulness of thoracoscopic salvage esophagectomy with prophylactic mediastinal lymph node dissection. METHODS: The study included 31 patients who underwent thoracoscopic salvage esophagectomy with prophylactic mediastinal lymph node dissection after dCRT between 2013 and 2022 (salvage patients) and 610 nonsalvage patients who underwent conventional thoracoscopic esophagectomy during the same time period. RESULTS: Differences between the median ages and sexes of the 2 patient groups were not significant. The dominant location of tumors in the salvage patients was the upper thoracic esophagus. More salvage patients had clinical T4 disease. The salvage patients had a lower median number of retrieved mediastinal lymph nodes than the nonsalvage patients. The differences between the rates of R0, postoperative complications, and in-hospital deaths in the 2 patient groups were not significant. The 3-year overall survival (OS) rates for the salvage patients were 73%, with 3-year OS rates for R0 vs non-R0 of 81% vs 0%, p < 0.01 and pN0 vs pN1-3 of 89% vs 49%, p < 0.01. CONCLUSION: Regarding short-term outcomes, prophylactic mediastinal lymph node dissection for patients undergoing thoracoscopic salvage esophagectomy was as safe as prophylactic dissection for patients undergoing conventional thoracoscopic esophagectomy. R0 surgery and pN0 are important factors for long-term survival in patients undergoing thoracoscopic salvage esophagectomy.

Significance of lateral lymph node dissection in squamous cell carcinoma of the anal canal: a retrospective cohort study.

PURPOSE: The JCOG (Japan Clinical Oncology Group) 0212 study did not confirm the noninferiority of mesorectal excision (ME) alone to ME with LLND for rectal or anal adenocarcinomas. Furthermore, the significance of LLND for SCCs remains unknown. We evaluated the significance of lateral lymph node dissection (LLND) of squamous cell carcinoma (SCC) of the anal canal. METHODS: This retrospective cohort study was conducted in 435 patients with SCCs among 1,781 patients with anal canal tumors. In 40 patients who underwent LLND, the 5-year relapse-free survival (5y-RFS) and 5-year overall survival (5y-OS) were compared between groups with positive and negative histopathological findings. In 71 patients with negative lateral lymph node metastasis in the preoperative diagnosis, the 5y-RFS, 5y-OS, and 5-year local recurrence-free survival were compared between patients who did and did not undergo LLND. RESULTS: The clinical and pathological T stages predicted pathological lateral pelvic lymph node metastasis. There was no statistically significant difference in 5y-RFS and 5y-OS between patients who did and did not undergo LLND. Among patients who underwent LLND, 5y-RFS in those with positive histopathological findings (15.0%) was worse than that in those without (59.2%) (p = 0.002). CONCLUSIONS: In patients who underwent LLND, 5y-RFS in those with positive histopathological findings than in those without LLND did not contribute to prognosis.

Risk factors affecting delay of initiating adjuvant chemotherapy for stage III colorectal cancer.

PURPOSE: Delay in initiating adjuvant chemotherapy (AC) after curative resection of colorectal cancer (CRC) has been reported to lead to poor prognosis, but few studies have looked at associated factors. This study aimed to identify risk factors for delay in initiating AC. METHODS: Data from 200 consecutive patients who underwent curative resection and AC for stage III CRC between 2013 and 2018 were retrospectively collected and analyzed. RESULTS: AC was initiated more than 8 weeks after surgery in 12.5% of patients (the delay group). Compared to those with no delay (the non-delay group), patients in the delay group had significantly higher rates of synchronous double cancers (2.3% vs. 16.0%, p = 0.001), preoperative bowel obstruction (10.3% vs. 32.0%, p = 0.003), laparotomy (56.0% vs. 80.0%, p = 0.02), concomitant resection (2.9% vs. 24.0%, p < 0.001), and postoperative complications (32.0% vs. 56.0%, p = 0.02), and a significantly longer length of hospital stay (median 12 vs. 30 days, p < 0.001). In multivariate analysis, synchronous double cancers (odds ratio 10.2, p = 0.008), preoperative bowel obstruction (odds ratio 4.6, p = 0.01), concomitant resection (odds ratio 5.2, p = 0.03), and postoperative complications of Clavien-Dindo grade ≥ IIIa (odds ratio 4.0, p = 0.03) were identified as independent risk factors for delay in initiating AC. CONCLUSION: Careful preoperative treatment planning for CRC patients with synchronous double cancers, preoperative bowel obstruction, and concomitant resection, and management for postoperative complication are necessary to avoid delay in initiating AC.

Risk of metachronous colorectal cancer after surgical resection of index rectal cancer in Lynch syndrome: a multicenter retrospective study in Japan.

PURPOSE: This study evaluated the risk of metachronous colorectal cancer (CRC) after resection of index (first) rectal cancer in patients with Lynch syndrome (LS). METHODS: Clinicopathological data of patients with genetically proven LS were retrospectively analyzed in this multicenter Japanese study. The cumulative incidence of metachronous CRC and the overall survival were compared between patients with index rectal cancer (rectal group) and those with index colon cancer (colon group). RESULTS: The median age at index CRC surgery was lower in the rectal group than in the colon group (37 vs. 46 years old, P = 0.01). The cumulative 5-, 10-, and 20-year incidences of metachronous CRC were 3.5%, 13.9%, and 21.1%, respectively, in the rectal cancer group and 14.9%, 22.0%, and 57.9%, respectively, in the colon cancer group (P = 0.02). The overall survival curves were not significantly different between two groups (P = 0.23). CONCLUSION: This is the first report from an East Asian country to report the risk of metachronous CRC after resection of index rectal cancer in patients with LS. Despite this study having several limitations, we cannot recommend extended resection, such as total proctocolectomy, for index rectal cancer as a standard surgical treatment in patients with LS.

[Tips and Outcomes of Safe Laparoscopic Rectal Resection with Adequate Lymph Node Dissection in Patients with Obesity].

BACKGROUND: This study aimed to describe the surgical procedures involved in laparoscopic rectal resection in patients with obesity and report the short-term outcomes. MATERIALS AND METHODS: A total of 194 consecutive patients who underwent laparoscopic rectal resection in our department from 2013 to 2018 were divided into non-obese(body mass index[BMI] <25 kg/m2; n=161)and obese groups(BMI≥25 kg/m2; n=33)and subsequently analyzed. RESULTS: The operative time was significantly longer in the obese group(225 vs 266 min; p=0.003)than in the non-obese group. No conversions to laparotomy occurred in either group, and no discernible differences in blood loss(1 vs 5 mL; p=0.582), number of harvested lymph nodes(20 vs 17; p=0.356), and postoperative complication rates(9.3 vs 6.1%; p=0.547)were observed. CONCLUSION: Establishing an appropriate operative field, clarifying landmarks, and standardizing the procedure are important to assure safe laparoscopic rectal resection with adequate lymph node dissection in patients with obesity.

Effect of Biologics on the Risk of Advanced-Stage Inflammatory Bowel Disease-Associated Intestinal Cancer: A Nationwide Study.

INTRODUCTION: The aim of this study was to evaluate the effect of biologics on the risk of advanced-stage inflammatory bowel disease (IBD)-associated intestinal cancer from a nationwide multicenter data set. METHODS: The medical records of patients with Crohn's disease (CD) and ulcerative colitis (UC) diagnosed with IBD-associated intestinal neoplasia (dysplasia or cancer) from 1983 to 2020 were included in this study. Therapeutic agents were classified into 3 types: biologics, 5-aminosalicylic acid, and immunomodulators. The pathological cancer stage was compared based on the drug used in both patients with CD and UC. RESULTS: In total, 1,042 patients (214 CD and 828 UC patients) were included. None of the drugs were significantly associated with cancer stage in the patients with CD. In the patients with UC, an advanced cancer stage was significantly associated with less use of biologics (early stage: 7.7% vs advanced stage: 2.0%, P < 0.001), 5-aminosalicylic acid, and immunomodulators. Biologic use was associated with a lower incidence of advanced-stage cancer in patients diagnosed by regular surveillance (biologics [-] 24.5% vs [+] 9.1%, P = 0.043), but this was not the case for the other drugs. Multivariate analysis showed that biologic use was significantly associated with a lower risk of advanced-stage disease (odds ratio = 0.111 [95% confidence interval, 0.034-0.356], P < 0.001). DISCUSSION: Biologic use was associated with a lower risk of advanced IBD-associated cancer in patients with UC but not with CD. The mechanism of cancer progression between UC and CD may be different and needs to be further investigated.

Clinical Impact of Radical Resection of Synchronous and Metachronous Peritoneal Metastases from Colorectal Cancer.

BACKGROUND: According to some case series, patients with colorectal cancer (CRC) who underwent radical resection of synchronous peritoneal metastases (PM) with the primary tumor had better survival than patients who underwent non-surgical treatment. However, little evidence exists regarding the significance of radical resection for metachronous PM. OBJECTIVE: This study aimed to evaluate the clinical significance of surgical intervention for isolated PM from CRC, with a particular focus on time to PM. METHODS: A total of 74 consecutive patients with isolated PM from CRC, including 40 and 34 patients with synchronous and metachronous PM, respectively, treated between 2007 and 2018 were retrospectively analyzed. The primary outcome measure was overall survival (OS) from diagnosis, and the OS was compared between radical resection and palliative chemotherapy. RESULTS: Five-year OS was 39.7% for all patients. Patients with radical resection had significantly better 5-year OS compared with those with palliative chemotherapy (62.8% vs. 11.0%; p < 0.0001). According to time to PM, patients with radical resection had significantly better 5-year OS compared with those with palliative chemotherapy for both synchronous PM (47.6% vs. 0%; p = 0.019) and metachronous PM (77.2% vs. 15.2%; p < 0.0001). Multivariable analysis stratified by time to PM revealed that surgical intervention is a significant favorable prognostic factor only in patients with metachronous PM (hazard ratio 0.117, 95% confidence interval 0.020-0.678; p = 0.017). CONCLUSIONS: Patients with radical resection of PM had good survival compared with those with chemotherapy alone, especially for metachronous PM. Surgical intervention should be considered for isolated metachronous PM when radical resection is feasible.

NEXUS trial: a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant colorectal oligometastases.

BACKGROUND: The optimal treatment strategy for resectable BRAF V600E mutant colorectal oligometastases (CRM) has not been established due to the rarity and rapid progression of the disease. Since the unresectable recurrence rate is high, development of novel perioperative therapies are warranted. On December 2020, the BEACON CRC triplet regimen of encorafenib, binimetinib, and cetuximab was approved for unresectable metastatic colorectal cancer in Japan. METHODS: The NEXUS trial is a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant CRM. The key inclusion criteria are as follows: histologically diagnosed with colorectal adeno/adenosquamous carcinoma; RAS wild-type and BRAF V600E mutation by tissue or blood; and previously untreated resectable distant metastases. The triplet regimen (encorafenib: 300 mg daily; binimetinib: 45 mg twice daily; cetuximab: 400 mg/m2, then 250 mg/m2 weekly, 28 days/cycle) is administered for 3 cycles each before and after curative resection. The primary endpoint of the study is the 1-year progression-free survival (PFS) rate and the secondary end points are the PFS, disease-free survival, overall survival, and objective response rate. The sample size is 32 patients. Endpoints in the NEXUS trial as well as integrated analysis with the nationwide registry data will be considered for seeking regulatory approval for the perioperative use of the triplet regimen. DISCUSSION: The use of the triplet regimen in the perioperative period is expected to be safe and effective in patients with resectable BRAF V600E mutant CRM. TRIAL REGISTRATION: jRCT2031220025, April. 16, 2022.

Nomogram as a novel predictive tool for lymph node metastasis in T1 colorectal cancer treated with endoscopic resection: a nationwide, multicenter study.

BACKGROUND AND AIMS: Since 2009, the Japanese Society for Cancer of the Colon and Rectum guidelines have recommended that tumor budding and submucosal invasion depth, in addition to lymphovascular invasion and tumor grade, be included as risk factors for lymph node metastasis (LNM) in patients with T1 colorectal cancer (CRC). In this study, a novel nomogram was developed and validated by usirge-scale, real-world data, including the Japanese Society for Cancer of the Colon and Rectum risk factors, to accurately evaluate the risk of LNM in T1 CRC. METHODS: Data from 4673 patients with T1 CRC treated at 27 high-volume institutions between 2009 and 2016 were analyzed for LNM risk. To prepare a nonrandom split sample, the total cohort was divided into development and validation cohorts. Pathologic findings were extracted from the medical records of each participating institution. The discrimination ability was measured by using the concordance index, and the variability in each prediction was evaluated by using calibration curves. RESULTS: Six independent risk factors for LNM, including submucosal invasion depth and tumor budding, were identified in the development cohort and entered into a nomogram. The concordance index was .784 for the clinical calculator in the development cohort and .790 in the validation cohort. The calibration curve approached the 45-degree diagonal in the validation cohort. CONCLUSIONS: This is the first nomogram to include submucosal invasion depth and tumor budding for use in routine pathologic diagnosis based on data from a nationwide multi-institutional study. This nomogram, developed with real-world data, should improve decision-making for an appropriate treatment strategy for T1 CRC.

Lateral pelvic lymph node metastasis in T2 low rectal cancer: is TME alone sufficient for cure?

BACKGROUND: Some patients with even T2 low rectal cancer are known to develop lateral pelvic lymph node metastasis. This study aimed to investigate real-world evidence regarding lateral nodal metastasis on T2 low rectal cancer treatment. METHODS: Consecutive patients with pathological T2 low rectal adenocarcinoma who underwent curative-intent surgery between January 2007 and December 2015 at two Japanese cancer centres dedicated to lateral pelvic lymph node dissection were identified and included in the analysis. Lateral pelvic lymph node metastasis was defined as pathologically confirmed metastatic lateral pelvic lymph node or lateral-local recurrence after primary surgery. RESULTS: A total of 215 consecutive patients, including 101 and 114 patients who did and did not undergo bilateral lateral pelvic lymph node dissection, were included in the analysis. Overall, 19 (8.8%) patients had lateral pelvic lymph node metastasis, including 13 with pathologically confirmed metastatic lateral pelvic lymph node and six with lateral-local recurrence. A total of 10 (4.7%) patients had local recurrence, including six with lateral-local recurrence, two with central-local recurrence and two with anastomotic recurrence. Five/7-year cumulative risks of lateral-local recurrence in patients with and without lateral pelvic lymph node dissection were 1.1/1.1% and 3.9/5.2%, respectively. CONCLUSION: The problem of the relatively high rate of lateral local recurrence remains in treating T2 low rectal cancer with only total mesorectal excision. The selection of high-risk patients of lateral pelvic lymph node metastasis and the indication of additional treatment in T2 low rectal cancer should be discussed further.

Definitive S-1/mitomycin-C chemoradiotherapy for stage II/III anal canal squamous cell carcinoma: a phase I/II dose-finding and single-arm confirmatory study (JCOG0903).

BACKGROUND: Definitive chemoradiotherapy (CRT) with 5-fluorouracil plus mitomycin-C is a standard treatment for stage II/III squamous cell carcinoma of the anal canal (SCCA). We performed this dose-finding and single-arm confirmatory trial of CRT with S-1 plus mitomycin-C to determine the recommended dose (RD) of S-1 and evaluate its efficacy and safety for locally advanced SCCA. METHODS: Patients with clinical stage II/III SCCA (UICC 6th) received CRT comprising mitomycin-C (10 mg/m2 on days 1 and 29) and S-1 (60 mg/m2/day at level 0 and 80 mg/m2/day at level 1 on days 1-14 and 29-42) with concurrent radiotherapy (59.4 Gy). Dose-finding used a 3 + 3 cohort design. The primary endpoint of the confirmatory trial was 3-year event-free survival. The sample size was 65, with one-sided alpha of 5%, power of 80%, and expected and threshold values of 75% and 60%, respectively. RESULTS: Sixty-nine patients (dose-finding, n = 10; confirmatory, n = 59) were enrolled. The RD of S-1 was determined as 80 mg/m2/day. Three-year event-free survival in 63 eligible patients who received the RD was 65.0% (90% confidence interval 54.1-73.9). Three-year overall, progression-free, and colostomy-free survival rates were 87.3%, 85.7%, and 76.2%, respectively; the complete response rate was 81% on central review. Common grade 3/4 acute toxicities were leukopenia (63.1%), neutropenia (40.0%), diarrhea (20.0%), radiation dermatitis (15.4%), and febrile neutropenia (3.1%). No treatment-related deaths occurred. CONCLUSIONS: Although the primary endpoint was not met, S-1/mitomycin-C chemoradiotherapy had an acceptable toxicity profile and favorable 3-year survival and could be a treatment option for locally advanced SCCA. CLINICAL TRIAL INFORMATION: jRCTs031180002.

Risk of metachronous colorectal cancer after colectomy for first colon cancer in Lynch syndrome: multicenter retrospective study in Japan.

BACKGROUND: We evaluated the risk of metachronous colorectal cancer (mCRC) and explored the optimal extent of colectomy in patients with Lynch syndrome (LS) and first colon cancer (fCC) in Japan, where the extent of colectomy for colon cancer (CC) is shorter than that in Western countries. METHODS: The clinicopathologic and survival data of patients with LS who developed CC were collected from a nationwide database and analyzed retrospectively. The cumulative incidence of mCRC after actual segmental colectomy was compared with that of mCRC when more extensive colectomy was assumed. RESULTS: There were 142 eligible patients (65 female). The median age at fCC surgery was 46.5 (range: 14-80) years. The cumulative incidence of 5-, 10-, and 20-year mCRC rate was 13.4%, 20.8%, and 53.6%, respectively. The incidence was higher in the left-sided group (splenic flexure to rectosigmoid colon, n = 54) than in the right-sided group (cecum to transvers colon, n = 88) (66.3% vs. 45.3% in 20 years, P < 0.01). Assuming that all patients would have undergone hemicolectomy or total colectomy, the estimated mCRC risk was 41.5% and 9.4% (P < 0.01, vs. actual procedures), respectively. The 20-year overall survival rate of all the patients was 83.3% without difference by fCC sidedness (P = 0.38). CONCLUSIONS: To reduce the incidence of mCRC, patients with genetically diagnosed LS and fCC, preferentially located in the left-sided colon, may need to undergo more extended colectomy than that usually performed in Japan. However, such extended colectomy should be counterbalanced with favorable overall survival and actual risk of mCRC development.

Maximum phonation time: an independent predictor of late-onset pneumonia after esophageal cancer surgery.

Dysphagia after esophagectomy is a major risk factor for aspiration pneumonia, thus preoperative assessment of swallowing function is important. The maximum phonation time (MPT) is a simple indicator of phonatory function and also correlates with muscle strength associated with swallowing. This study aimed to determine whether preoperative MPT can predict postoperative aspiration pneumonia. The study included 409 consecutive patients who underwent esophagectomy for esophageal cancer between 2017 and 2021. Pneumonia detected by routine computed tomography on postoperative days 5-6 was defined as early-onset pneumonia, and pneumonia that developed later (most often aspiration pneumonia) was defined as late-onset pneumonia. The correlation between late-onset pneumonia and preoperative MPT was investigated. Patients were classified into short MPT (<15 seconds for males and <10 seconds for females, n = 156) and normal MPT groups (≥15 seconds for males and ≥10 seconds for females, n = 253). The short MPT group was significantly older, had a lower serum albumin level and vital capacity, and had a significantly higher incidence of late-onset pneumonia (18.6 vs. 6.7%, P < 0.001). Multivariate analysis showed that short MPT was an independent risk factor for late-onset pneumonia (odds ratio: 2.26, P = 0.026). The incidence of late-onset pneumonia was significantly higher in the short MPT group (15.6 vs. 4.7%, P = 0.004), even after propensity score matching adjusted for clinical characteristics. MPT is a useful predictor for late-onset pneumonia after esophagectomy.