Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer.

Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS, PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62-0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83-1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795 .

Exploratory Biomarker Analysis Using Plasma Angiogenesis-Related Factors and Cell-Free DNA in the TRUSTY Study: A Randomized, Phase II/III Study of Trifluridine/Tipiracil Plus Bevacizumab as Second-Line Treatment for Metastatic Colorectal Cancer.

BACKGROUND: The TRUSTY study evaluated the efficacy of second-line trifluridine/tipiracil (FTD/TPI) plus bevacizumab in metastatic colorectal cancer (mCRC). OBJECTIVE: This exploratory biomarker analysis of TRUSTY investigated the relationship between baseline plasma concentrations of angiogenesis-related factors and cell-free DNA (cfDNA), and the efficacy of FTD/TPI plus bevacizumab in patients with mCRC. PATIENTS AND METHODS: The disease control rate (DCR) and progression-free survival (PFS) were compared between baseline plasma samples of patients with high and low plasma concentrations (based on the median value) of angiogenesis-related factors. Correlations between cfDNA concentrations and PFS were assessed. RESULTS: Baseline characteristics (n = 65) were as follows: male/female, 35/30; median age, 64 (range 25-84) years; and RAS status wild-type/mutant, 29/36. Patients in the hepatocyte growth factor (HGF)-low and interleukin (IL)-8-low groups had a significantly higher DCR (risk ratio [95% confidence intervals {CIs}]) than patients in the HGF-high (1.83 [1.12-2.98]) and IL-8-high (1.70 [1.02-2.82]) groups. PFS (hazard ratio {HR} [95% CI]) was significantly longer in patients in the HGF-low (0.33 [0.14-0.79]), IL-8-low (0.31 [0.14-0.70]), IL-6-low (0.19 [0.07-0.50]), osteopontin-low (0.39 [0.17-0.88]), thrombospondin-2-low (0.42 [0.18-0.98]), and tissue inhibitor of metalloproteinase-1-low (0.26 [0.10-0.67]) groups versus those having corresponding high plasma concentrations of these angiogenesis-related factors. No correlation was observed between cfDNA concentration and PFS. CONCLUSION: Low baseline plasma concentrations of HGF and IL-8 may predict better DCR and PFS in patients with mCRC receiving FTD/TPI plus bevacizumab, however further studies are warranted. CLINICAL TRIAL REGISTRATION NUMBER: jRCTs031180122.

Streamlining robotic-assisted abdominoperineal resection.

BACKGROUND: Robot-assisted surgery has proven to be a safe and feasible approach for the management of rectal cancer, including abdominoperineal resection (APR). However, it often incurs longer operative times and higher costs. This study aimed to overcome these limitations by adopting a synchronous approach utilizing an optimized team composition. METHODS: Data on patients who underwent robot-assisted APR at our facility between June 2022 and June 2023 were analyzed. The key points of the optimized approach included the following: At the start of the surgery, the surgeon performed an anococcygeal ligament resection from the perineal side while the bedside assistants set up the ports. Then, through console manipulation, the presacral fascia, elevated by previously placed gauze, was easily and safely incised, providing access to the perineal region. RESULTS: A total of nine patients were included in this study. The median operation time was 231 min, and the intraoperative blood loss was 170 ml. The operation time was reduced to 167.5 min, and the blood loss was 80.5 ml in cases without a trainee. Surgical site infections, classified as Clavien-Dindo grade II complications, were observed in two cases, but no obvious urinary or erectile dysfunction was observed. CONCLUSION: The study results indicate that the challenges associated with APR can be efficiently addressed without requiring additional personnel by streamlining team composition and the synchronous approach. This optimization strategy minimizes the need for a larger surgical team, while maximizing the utilization of surgical time and resources.

The Feasibility and Reliability of Upper Arm-Worn Apple Watch Heart Rate Monitoring for Surgeons During Surgery: Observational Study.

BACKGROUND: Health care professionals, particularly those in surgical settings, face high stress levels, impacting their well-being. Traditional monitoring methods, like using Holter electrocardiogram monitors, are impractical in the operating room, limiting the assessment of physicians' health. Wrist-worn heart rate monitors, like the Apple Watch, offer promise but are restricted in surgeries due to sterility issues. OBJECTIVE: This study aims to assess the feasibility and accuracy of using an upper arm-worn Apple Watch for heart rate monitoring during robotic-assisted surgeries, comparing its performance with that of a wrist-worn device to establish a reliable alternative monitoring site. METHODS: This study used 2 identical Apple Watch Series 8 devices to monitor the heart rate of surgeons during robotic-assisted surgery. Heart rate data were collected from the wrist-worn and the upper arm-worn devices. Statistical analyses included calculating the mean difference and SD of difference between the 2 devices, constructing Bland-Altman plots, assessing accuracy based on mean absolute error and mean absolute percentage error, and calculating the intraclass correlation coefficient. RESULTS: The mean absolute errors for the whole group and for participants A, B, C, and D were 3.63, 3.58, 2.70, 3.93, and 4.28, respectively, and the mean absolute percentage errors were 3.58%, 3.34%, 2.42%, 4.58%, and 4.00%, respectively. Bland-Altman plots and scatter plots showed no systematic error when comparing the heart rate measurements obtained from the upper arm-worn and the wrist-worn Apple Watches. The intraclass correlation coefficients for participants A, B, C, and D were 0.559, 0.651, 0.508, and 0.563, respectively, with a significance level of P<.001, indicating moderate reliability. CONCLUSIONS: The findings of this study suggest that the upper arm is a viable alternative site for monitoring heart rate during surgery using an Apple Watch. The agreement and reliability between the measurements obtained from the upper arm-worn and the wrist-worn devices were good, with no systematic error and a high level of accuracy. These findings have important implications for improving data collection and management of the physical and mental demands of operating room staff during surgery, where wearing a watch on the wrist may not be feasible.

Genomic landscape and its prognostic significance in stage III colorectal cancer: JCOG1506A1, an ancillary of JCOG0910.

Large-scale genomic sequencing of colorectal cancers has been reported mainly for Western populations. Differences by stage and ethnicity in the genomic landscape and their prognostic impact remain poorly understood. We investigated 534 Japanese stage III colorectal cancer samples from the Phase III trial, JCOG0910. Targeted-capture sequencing of 171 potentially colorectal cancer-associated genes was performed, and somatic single-nucleotide variants and insertion-deletions were determined. Hypermutated tumors were defined as tumors with MSIsensor score >7 and ultra-mutated tumors with POLE mutations. Genes with alterations associated with relapse-free survival were analyzed using multivariable Cox regression models. In all patients (184 right-sided, 350 left-sided), mutation frequencies were TP53, 75.3%; APC, 75.1%; KRAS, 43.6%; PIK3CA, 19.7%; FBXW7, 18.5%; SOX9, 11.8%; COL6A3, 8.2%; NOTCH3, 4.5%; NRAS, 4.1%; and RNF43, 3.7%. Thirty-one tumors were hypermutated (5.8%; 14.1% right-sided, 1.4% left-sided). Modest associations were observed: poorer relapse-free survival was seen with mutant KRAS (hazard ratio 1.66; p = 0.011) and mutant RNF43 (2.17; p = 0.055), whereas better relapse-free survival was seen with mutant COL6A3 (0.35; p = 0.040) and mutant NOTCH3 (0.18; p = 0.093). Relapse-free survival tended to be better for hypermutated tumors (0.53; p = 0.229). In conclusion, the overall spectrum of mutations in our Japanese stage III colorectal cancer cohort was similar to that in Western populations, but the frequencies of mutation for TP53, SOX9, and FBXW7 were higher, and the proportion of hypermutated tumors was lower. Multiple gene mutations appeared to impact relapse-free survival, suggesting that tumor genomic profiling can support precision medicine for colorectal cancer.

Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial.

Importance: For patients with RAS wild-type metastatic colorectal cancer, adding anti-epidermal growth factor receptor (anti-EGFR) or anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibodies to first-line doublet chemotherapy is routine, but the optimal targeted therapy has not been defined. Objective: To evaluate the effect of adding panitumumab (an anti-EGFR monoclonal antibody) vs bevacizumab (an anti-VEGF monoclonal antibody) to standard first-line chemotherapy for treatment of RAS wild-type, left-sided, metastatic colorectal cancer. Design, Setting, and Participants: Randomized, open-label, phase 3 clinical trial at 197 sites in Japan in May 2015-January 2022 among 823 patients with chemotherapy-naive RAS wild-type, unresectable metastatic colorectal cancer (final follow-up, January 14, 2022). Interventions: Panitumumab (n = 411) or bevacizumab (n = 412) plus modified fluorouracil, l-leucovorin, and oxaliplatin (mFOLFOX6) every 14 days. Main Outcomes and Measures: The primary end point, overall survival, was tested first in participants with left-sided tumors, then in the overall population. Secondary end points were progression-free survival, response rate, duration of response, and curative (defined as R0 status) resection rate. Results: In the as-treated population (n = 802; median age, 66 years; 282 [35.2%] women), 604 (75.3%) had left-sided tumors. Median follow-up was 61 months. Median overall survival was 37.9 months with panitumumab vs 34.3 months with bevacizumab in participants with left-sided tumors (hazard ratio [HR] for death, 0.82; 95.798% CI, 0.68-0.99; P = .03) and 36.2 vs 31.3 months, respectively, in the overall population (HR, 0.84; 95% CI, 0.72-0.98; P = .03). Median progression-free survival for panitumumab vs bevacizumab was 13.1 vs 11.9 months, respectively, for those with left-sided tumors (HR, 1.00; 95% CI, 0.83-1.20) and 12.2 vs 11.4 months overall (HR, 1.05; 95% CI, 0.90-1.24). Response rates with panitumumab vs bevacizumab were 80.2% vs 68.6%, respectively, for left-sided tumors (difference, 11.2%; 95% CI, 4.4%-17.9%) and 74.9% vs 67.3% overall (difference, 7.7%; 95% CI, 1.5%-13.8%). Median duration of response with panitumumab vs bevacizumab was 13.1 vs 11.2 months for left-sided tumors (HR, 0.86; 95% CI, 0.70-1.10) and 11.9 vs 10.7 months overall (HR, 0.89; 95% CI, 0.74-1.06). Curative resection rates with panitumumab vs bevacizumab were 18.3% vs 11.6% for left-sided tumors; (difference, 6.6%; 95% CI, 1.0%-12.3%) and 16.5% vs 10.9% overall (difference, 5.6%; 95% CI, 1.0%-10.3%). Common treatment-emergent adverse events were acneiform rash (panitumumab: 74.8%; bevacizumab: 3.2%), peripheral sensory neuropathy (panitumumab: 70.8%; bevacizumab: 73.7%), and stomatitis (panitumumab: 61.6%; bevacizumab: 40.5%). Conclusions and Relevance: Among patients with RAS wild-type metastatic colorectal cancer, adding panitumumab, compared with bevacizumab, to standard first-line chemotherapy significantly improved overall survival in those with left-sided tumors and in the overall population. Trial Registration: ClinicalTrials.gov Identifier: NCT02394795.

Trifluridine/tipiracil+bevacizumab (BEV) vs. fluoropyrimidine-irinotecan+BEV as second-line therapy for metastatic colorectal cancer: a randomised noninferiority trial.

BACKGROUND: This open-label, multicentre, phase II/III trial assessed the noninferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab vs. fluoropyrimidine and irinotecan plus bevacizumab (control) as second-line treatment for metastatic colorectal cancer (mCRC). METHODS: Patients were randomised (1:1) to receive FTD/TPI (35 mg/m2 twice daily, days 1-5 and days 8-12, 28-day cycle) plus bevacizumab (5 mg/kg, days 1 and 15) or control. The primary endpoint was overall survival (OS). The noninferiority margin of the hazard ratio (HR) was set to 1.33. RESULTS: Overall, 397 patients were enrolled. Baseline characteristics were similar between the groups. Median OS was 14.8 vs. 18.1 months (FTD/TPI plus bevacizumab vs. control; HR 1.38; 95% confidence interval [CI] 0.99-1.93; Pnoninferiority = 0.5920). In patients with a baseline sum of the diameter of target lesions of <60 mm (n = 216, post hoc analyses), the adjusted median OS was similar between groups (FTD/TPI plus bevacizumab vs. control, 21.4 vs. 20.7 months; HR 0.92; 95% CI 0.55-1.55). Grade ≥3 adverse events (FTD/TPI plus bevacizumab vs. control) included neutropenia (65.8% vs. 41.6%) and diarrhoea (1.5% vs. 7.1%). CONCLUSIONS: FTD/TPI plus bevacizumab did not demonstrate noninferiority to fluoropyrimidine and irinotecan plus bevacizumab as second-line treatment for mCRC. CLINICAL TRIAL REGISTRATION: JapicCTI-173618, jRCTs031180122.

Robotic surgery for simultaneous gastric and rectal cancers.

The number of patients with multiple primary malignancies is increasing due to the improvements in diagnostic techniques, which increases the necessity of simultaneous resection. Meanwhile, minimally invasive robotic surgery is becoming popular in Japan, and its use in multiple cancer resection will increase. We present our experience with the settings and ports placement when using the da Vinci Xi system for simultaneous resection of rectal and gastric cancer.

Local skin flap procedure for repair of rectovaginal fistula: A case report.

INTRODUCTION: Rectovaginal fistula (RVF) is an increasingly common rectal surgery complication. Although various RVF closure operations have been reported, no one approach is considered ideal. Consequently, some patients must undergo more complex and technically challenging surgical procedures. We describe the successful use of simple local skin flap plasty for RVF repair. PRESENTATION OF CASE: A 74-year-old Japanese female developed RVF after robot-assisted laparoscopic proctectomy with intersphincteric resection, hand-sewn coloanal anastomosis, and a temporary ileostomy. Three months later, reconstructive surgery was performed using a local flap. The fistula was successfully closed and healed well without complications. DISCUSSION: A local flap consists of the skin and subcutaneous tissue harvested from a nearby site that maintains its intrinsic blood supply. CONCLUSION: This novel approach to RVF repair appears simple, effective, and safe.

Primary tumor location as a predictor of survival in patients with RAS wild-type colorectal cancer who receive molecularly targeted drugs as first-line therapy: a multicenter real-world observational study by the Japanese Society for Cancer of the Colon and Rectum.

BACKGROUND: Primary tumor location is considered a predictor of overall survival (OS) in RAS wild-type (WT) metastatic colorectal cancer (mCRC) treated with bevacizumab (BEV) or an anti-epidermal growth factor antibody (cetuximab or panitumumab [CET/PAN]) as first-line molecularly targeted therapy. BEV is recommended for right-sided mCRC and CET/PAN for left-sided mCRC based on post-hoc analyses of clinical trial data, but real-world evidence is lacking. METHODS: We retrospectively collected data of patients who started BEV or CET/PAN plus 5-fluorouracil-based doublet chemotherapy between January 2013 and December 2016 as first-line treatment for RAS WT mCRC at any of 24 Japanese institutions. OS was compared between the BEV and CET/PAN groups according to primary tumor location by Cox multivariate regression analysis in the full cohort and in a propensity score-matched cohort. RESULTS: In total, 935 patients were enrolled. Median OS was 24.6 months with BEV and 20.9 months with CET/PAN in right-sided mCRC (n = 213; adjusted hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.50-1.06) and 35.7 months and 30.0 months, respectively, in left-sided mCRC (n = 722; adjusted HR 0.92, 95% CI 0.74-1.13). In the propensity score-matched cohort, OS was significantly better in the BEV group than in the CET/PAN group in right-sided mCRC (HR 0.52, 95% CI 0.28-0.96) but was not significantly different in left-sided mCRC (HR 0.78, 95% CI 0.53-1.07). CONCLUSION: Real-world data showed that OS was better with BEV than with CET/PAN in right-sided mCRC. However, there was no significant difference in OS in left-sided mCRC.

Phase 3 trial of sequential versus combination treatment in colorectal cancer: The C-cubed study.

BACKGROUND: An optimal treatment strategy using oxaliplatin and bevacizumab for metastatic colorectal cancer has not been defined. We investigated whether the sequential treatment using fluoropyrimidines with bevacizumab followed by the addition of oxaliplatin at first progression was better than a combination treatment using fluoropyrimidines and oxaliplatin with bevacizumab. METHODS: In the sequential treatment, the escalation from fluoropyrimidines plus bevacizumab to fluoropyrimidines plus oxaliplatin with bevacizumab was recommended in case of progressive disease. Time to failure of strategy was the primary end-point, whereas the secondary end-points were overall survival, progression-free survival, overall response rate and safety. RESULTS: Three hundred patients with previously untreated metastatic colorectal cancer were randomised to receive either the sequential treatment (n = 151) or the combination treatment (n = 149). The sequential treatment was superior to the combination treatment about time to failure of strategy (15.2 months; 95% CI, 12.5-17.2 months vs. 7.8 months: 95% CI, 6.3-9.5 months; P < 0.001). However, the median overall survival was 27.5 (95% CI, 24.4 to 32.7) months in the sequential treatment and 27.0 (95% CI, 22.8 to 36.0) months in the combination treatment (hazard ratio, 0.92; 95% CI, 0.66 to 1.28; P = 0.61). The overall response rate was 33.1% in the sequential treatment arm and 51.7% in the combination treatment. CONCLUSIONS: The findings support the extension of the sequential treatment starting from fluoropyrimidine plus bevacizumab to selected patients who do not need an objective response to the threatening disease.

Decreased numbers of gastric, colorectal, lung, and breast cancer surgeries performed in 17 cancer-designated hospitals in Gunma Prefecture of Japan during the COVID-19 pandemic.

PURPOSE: This study aims to clarify the influence of the COVID-19 pandemic on cancer surgery in Gunma Prefecture. METHODS: A total of 9839 cases (1406 gastric cancer, 3569 colorectal cancer, 1614 lung cancer, and 3250 breast cancer) from 17 hospitals in Gunma Prefecture were investigated. We compared the number of surgical cases, proportion of cases found by screening, and cStage at the time of the first visit by month in 2020 and 2021 with those in 2019. RESULTS: The rate of decline in cancer surgery was 8.9% in 2020 compared with 2019 (p = 0.0052). Compared with the same month of 2019, in some months of 2020 and 2021, significant decreases were observed in the number of surgeries for gastric and colorectal cancer, the percentage of surgical cases detected by screening in all four cancers, and the proportion of cancers with a relatively early cStage in gastric and breast cancer. CONCLUSIONS: The number of surgical cases of the four cancer types detected by cancer screening decreased in Gunma Prefecture owing to the influence of the COVID-19 pandemic. Furthermore, for some cancer types, the number of operations performed in patients with early-stage cancer is also decreased.

Learning curve for robotic bedside assistance for rectal cancer: application of the cumulative sum method.

BACKGROUND: This investigation assesses the learning curve for dedicated bedside assistance at a facility that recently adopted robot-assisted rectal resection. METHODS: Data from patients with rectal cancer who underwent robotic rectal resections from September 2019 through April 2020 were retrospectively analyzed. Before starting robotic surgery, we set the rule that a console surgeon would not enter the sterile field and all of those maneuvers would be left to a dedicated physician. Docking time was analyzed using the cumulative sum (CUSUM) method to evaluate the learning curve. Different phases in the learning curve were identified according to CUSUM plot configuration. A comparison was made of phases 1 and 2 combined, and phase 3. RESULT: The procedures were performed in 30 patients. Median docking time, console time was 13 min. A total of nine patients had histories of abdominal surgery. CUSUM analysis of docking time demonstrated 3 phases. Each docking time was longer in Phase 1 (the first 3 cases) than the average docking time over the all cases. The docking time in Phase 2 (the 9 middle cases) approximated the average time over the all cases. Phase 3 (the remaining 18 cases) showed further improvement of the docking procedure and time was reduced. A comparison of Phases 1 and 2 combined, and Phase 3, revealed that Phase 3 had a significantly higher rate of history of abdominal surgery. CONCLUSION: Docking manipulation proficiency was achieved in approximately 10 cases without the influence of surgical difficulty.

Three-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 plus docetaxel versus S-1 alone in stage III gastric cancer: JACCRO GC-07.

PURPOSE: The second planned interim analysis (median follow-up 12.5 months) in a phase III trial of postoperative adjuvant chemotherapy for stage III gastric cancer revealed significant improvement in relapse-free survival (RFS) for S-1 plus docetaxel over S-1 alone. Although enrollment was terminated on the recommendation of the independent data and safety monitoring committee, we continued follow-up and herein report on 3-year RFS, the primary endpoint. PATIENTS AND METHODS: Patients with histologically confirmed stage III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were randomly assigned to receive adjuvant chemotherapy with either S-1 plus docetaxel or S-1 alone. In the S-1 plus docetaxel group, S-1 was given orally for 2 weeks followed by 1 week of rest for seven courses, and docetaxel was given intravenously on day 1 of the second to seventh courses. The combination therapy was followed by S-1 monotherapy for up to 1 year. RESULTS: The 3-year RFS rate of the S-1 plus docetaxel group was 67.7%. This was significantly superior to that of 57.4% in the S-1 group (hazard ratio [HR] 0.715, 95% CI 0.587-0.871, P = 0.0008). This translated into a significant benefit in the 3-year overall survival (OS) rate in the S-1 plus docetaxel group (77.7% versus 71.2%, HR 0.742, 95% CI 0.596-0.925, P = 0.0076). CONCLUSION: On 3-year follow-up data, postoperative adjuvant therapy with S-1 plus docetaxel was confirmed to improve both RFS and OS and can be recommended as a standard of care for patients with stage III gastric cancer treated by D2 dissection.

Effects of Sex and Seasonal Climatic Changes on the Risk of Incidence of Anti-EGFR Therapy-Induced Rash in Cancer Patients: A Retrospective Study.

Background and Objectives: Seasonal climatic changes may affect the development of the rash that is characteristic of treatment with anti-epidermal growth factor receptor (EGFR) antibodies. We evaluated the association between seasons and rash incidence among patients with cancer. Materials and Methods: Data from patients with colorectal or head and neck cancer treated with cetuximab or panitumumab during summer (S group; n = 34) or winter (W group; n = 37) between June 2014 and February 2019 were collected to retrospectively examine patient characteristics and rash incidence ≤ 8 weeks after treatment initiation. Results: Rashes were observed in 73.5% (n = 25) and 78.4% (n = 29) and grade 3 rashes were observed in 17.6% (n = 6) and 2.7% (n = 1) of the patients in the S and W groups, respectively. The incidence of grade ≥ 2 rashes in males in the S group was higher than that in the rest of the patient groups (p < 0.01). Conclusions: The higher incidence of skin rashes in males during summer might be attributed to the effects of ultraviolet light, lack of skincare, male hormones, and secretion of anti-EGFR antibodies in sweat. These findings highlight the need for research on preventive measures for such rashes.

PD-L1 upregulation is associated with activation of the DNA double-strand break repair pathway in patients with colitic cancer.

Ulcerative colitis (UC) is a DNA damage-associated chronic inflammatory disease; the DNA double-strand break (DSB) repair pathway participates in UC-associated dysplasia/colitic cancer carcinogenesis. The DSB/interferon regulatory factor-1 (IRF-1) pathway can induce PD-L1 expression transcriptionally. However, the association of PD-L1/DSB/IRF-1 with sporadic colorectal cancer (SCRC), and UC-associated dysplasia/colitic cancer, remains elusive. Therefore, we investigated the significance of the PD-L1/DSB repair pathway using samples from 17 SCRC and 12 UC patients with rare UC-associated dysplasia/colitic cancer cases by immunohistochemical analysis. We compared PD-L1 expression between patients with SCRC and UC-associated dysplasia/colitic cancer and determined the association between PD-L1 and the CD8+ T-cell/DSB/IRF-1 axis in UC-associated dysplasia/colitic cancer. PD-L1 expression in UC and UC-associated dysplasia/colitic cancer was higher than in normal mucosa or SCRC, and in CD8-positive T lymphocytes in UC-associated dysplasia/colitic cancer than in SCRC. Moreover, PD-L1 upregulation was associated with γH2AX (DSB marker) and IRF-1 upregulation in UC-associated dysplasia/colitic cancer. IRF-1 upregulation was associated with γH2AX upregulation in UC-associated dysplasia/colitic cancer but not in SCRC. Multicolour immunofluorescence staining validated γH2AX/IRF-1/PD-L1 co-expression in colitic cancer tissue sections. Thus, immune cell-induced inflammation might activate the DSB/IRF-1 axis, potentially serving as the primary regulatory mechanism of PD-L1 expression in UC-associated carcinogenesis.

Conversion surgery for metastatic gastric cancer at 2 years after initial diagnosis of cancer of unknown primary with metastasis of cervical lymph nodes and ovary: a case report.

BACKGROUND: Patients with stage IV gastric cancer have a poor prognosis despite improvements in intensive treatment regimens, including chemotherapy. Recently, conversion surgery has received much attention as it can provide long-term survival in stage IV gastric cancer patients who are responsive to chemotherapy. Herein, we describe the case of a patient who underwent conversion surgery for metastatic gastric cancer that was performed over 2 years after an initial diagnosis of cancer of unknown primary (CUP) with metastasis of the cervical lymph nodes and the ovary. CASE PRESENTATION: A 67-year-old woman with cervical lymphadenopathy was referred to our hospital. Computed tomography showed left cervical lymphadenopathy and bilateral ovarian enlargement. Endoscopic survey revealed no signs of malignancy in the upper or the lower gastrointestinal tract. Pathological findings after cervical lymphadenectomy revealed a signet-ring cell carcinoma and were suggestive of gastric cancer metastases. However, multiple evaluations yielded no evidence of gastric cancer and the patient was diagnosed with CUP. She was prescribed chemotherapy for gastric cancer and underwent bilateral oophorectomy after undergoing chemotherapy for 18 months. Pathologic analysis of oophorectomy tissue revealed findings identical to those seen in the cervical lymph nodes. At about 2 years after the initial diagnosis, an esophagogastroduodenoscopy revealed evidence of gastric cancer. We performed a distal gastrectomy with D2 lymphadenectomy. Her postoperative course was uneventful and she remains alive with no signs of disease recurrence at 3 months post-surgery. CONCLUSIONS: To the best of our knowledge, this is the first report describing successful conversion surgery for stage IV gastric cancer in a patient whose cancer was definitively diagnosed 2 years after an initial diagnosis of CUP.

Primary Tumor Resection Plus Chemotherapy Versus Chemotherapy Alone for Colorectal Cancer Patients With Asymptomatic, Synchronous Unresectable Metastases (JCOG1007; iPACS): A Randomized Clinical Trial.

PURPOSE: It remains controversial whether primary tumor resection (PTR) before chemotherapy improves survival in patients with colorectal cancer (CRC) with asymptomatic primary tumor and synchronous unresectable metastases. PATIENTS AND METHODS: This randomized phase III study investigated the superiority of PTR followed by chemotherapy versus chemotherapy alone in relation to overall survival (OS) in patients with unresectable stage IV asymptomatic CRC and three or fewer unresectable metastatic diseases confined to the liver, lungs, distant lymph nodes, or peritoneum. Chemotherapy regimens of either mFOLFOX6 plus bevacizumab or CapeOX plus bevacizumab were decided before study entry. The primary end point was OS, which was analyzed by intention-to-treat. RESULTS: Between June 2012 and September 2019, a total of 165 patients were randomly assigned to either chemotherapy alone (84 patients) or PTR plus chemotherapy (81 patients). When the first interim analysis was performed in September 2019 with 50% (114/227) of the expected events observed among 160 patients at the data cutoff date of June 5, 2019, the Data and Safety Monitoring Committee recommended early termination of the trial because of futility. With a median follow-up of 22.0 months, median OS was 25.9 months (95% CI, 19.9 to 31.5) in the PTR plus chemotherapy arm and 26.7 (95% CI, 21.9 to 32.5) in the chemotherapy-alone arm (hazard ratio, 1.10; 95% CI, 0.76 to 1.59; one-sided P = .69). Three postoperative deaths occurred in the PTR plus chemotherapy arm. CONCLUSION: Given that PTR followed by chemotherapy showed no survival benefit over chemotherapy alone, PTR should no longer be considered a standard of care for patients with CRC with asymptomatic primary tumors and synchronous unresectable metastases.

Optimal timing for the resection of pulmonary metastases in patients with colorectal cancer.

This study aims to clarify the surgical treatment time of pulmonary metastasis in patients with colorectal cancer.Early relapse after resection of pulmonary metastasis is often encountered when the interval from the detection of pulmonary metastasis to pulmonary metastasectomy was short.In this retrospective analysis, data of patients with colorectal cancer who underwent surgical treatment of pulmonary metastasis at the Gunma Prefectural Cancer Center, Gunma, from April 2001 through September 2018 were evaluated. The patients were divided into 2 groups. We examined the interval period from the diagnosis of pulmonary metastasis to pulmonary metastasectomy. This period was divided into every 3 months, and the prognosis of each group was compared with clarify the appropriate timing of pulmonary metastasectomy.The primary endpoints were 5-year overall survival and recurrence-free survival rates.The most significant difference was observed when the cutoff value was 9 months (5-year recurrence-free survival 45.8% vs 85.6%, P < .01). No significant difference was found in any background factors between the 2 groups. Twenty-five patients (34.7%) experienced recurrence after pulmonary metastasectomy. The most common site of recurrence was the lung (48%). Among the 12 cases of recurrence of pulmonary metastasis, 11 cases belonged to the <9 months group. A multivariable survival analysis found that the interval period of <9 months was a significant predictor of recurrence.Our study suggests that clinical follow-up for 9 months prior pulmonary metastasectomy in colorectal patients would improve the prognosis.

Four stay-sutures method: a simplified hand-sewn purse-string suture in laparoscopic circular-stapled esophagojejunostomy.

Laparoscopic esophagojejunostomy is a challenging procedure because of its technical difficulty. We herein report a new method involving circular-stapled anastomosis using a hand-sewn suture with four stay-sutures and evaluate its outcomes. Esophagojejunostomy using this method was performed in 36 consecutive patients with clinical stage I gastric cancer at the authors' institutions. The key feature of our procedure was the placement of four full-thickness stay-sutures to anchor the esophageal stump prior to the hand-sewn purse-string suture. The median operation time and mean anvil fixation time were 315.5 and 21.9 min, respectively. The mortality rate was 0%, although anastomotic leakage following esophagojejunostomy was observed in 1 patient (2.8%), and anastomotic stenosis was observed in another patient (2.8%). Intracorporeal esophagojejunostomy using the four stay-sutures method appears to be safe and feasible. We believe that this method enables hand-sewn purse-string suturing to be performed more easily.