Machine learning based prediction of recurrence after curative resection for rectal cancer.

PURPOSE: Patients with rectal cancer without distant metastases are typically treated with radical surgery. Post curative resection, several factors can affect tumor recurrence. This study aimed to analyze factors related to rectal cancer recurrence after curative resection using different machine learning techniques. METHODS: Consecutive patients who underwent curative surgery for rectal cancer between 2004 and 2018 at Gil Medical Center were included. Patients with stage IV disease, colon cancer, anal cancer, other recurrent cancer, emergency surgery, or hereditary malignancies were excluded from the study. The Synthetic Minority Oversampling Technique with Tomek link (SMOTETomek) technique was used to compensate for data imbalance between recurrent and no-recurrent groups. Four machine learning methods, logistic regression (LR), support vector machine (SVM), random forest (RF), and Extreme gradient boosting (XGBoost), were used to identify significant factors. To overfit and improve the model performance, feature importance was calculated using the permutation importance technique. RESULTS: A total of 3320 patients were included in the study. After exclusion, the total sample size of the study was 961 patients. The median follow-up period was 60.8 months (range:1.2-192.4). The recurrence rate during follow-up was 13.2% (n = 127). After applying the SMOTETomek method, the number of patients in both groups, recurrent and non-recurrent group were equalized to 667 patients. After analyzing for 16 variables, the top eight ranked variables {pathologic Tumor stage (pT), sex, concurrent chemoradiotherapy, pathologic Node stage (pN), age, postoperative chemotherapy, pathologic Tumor-Node-Metastasis stage (pTNM), and perineural invasion} were selected based on the order of permutational importance. The highest area under the curve (AUC) was for the SVM method (0.831). The sensitivity, specificity, and accuracy were found to be 0.692, 0.814, and 0.798, respectively. The lowest AUC was obtained for the XGBoost method (0.804), with a sensitivity, specificity, and accuracy of 0.308, 0.928, and 0.845, respectively. The variable with highest importance was pT as assessed through SVM, RF, and XGBoost (0.06, 0.12, and 0.13, respectively), whereas pTNM had the highest importance when assessed by LR (0.05). CONCLUSIONS: In the current study, SVM showed the best AUC, and the most influential factor across all machine learning methods except LR was found to be pT. The rectal cancer patients who have a high pT stage during postoperative follow-up are need to be more close surveillance.

Comparison of Long-Term Oncologic Outcomes Between Surgical T4 and T3 in Patients Diagnosed With Pathologic Stage IIA Right Colon Cancer.

Purpose: T stage plays an important role in the classification of subgroups in stage II colon cancer. Patients with pathologic T4 are at high risk of recurrence and it is recommended to include adjuvant chemotherapy in the treatment plan, while this is not necessary in pathologic T3. There is a discrepancy between the surgical T stage (sT), as determined by the surgeon in the operative field, and pathologic T stage (pT). The pathologic stage is considered a standard prognostic factor, but it has not been established whether the surgical stage has an oncologic impact. The aim of this study was to compare oncologic outcomes between sT4 and sT3 in pathologic stage IIA right colon cancer. Methods: Between January 2005 and December 2018, there were 354 patients who underwent right hemicolectomy performed by a single surgeon (JHB) at a tertiary hospital. The data from these patients were retrospectively collected and analyzed. Only those patients with pathologic stage IIA (pT3N0M0) right colon adenocarcinomas were included in this study. Patients with mucinous carcinoma, signet ring cell carcinoma, squamous cell carcinoma, or hereditary colon cancer, and who had emergent surgery were excluded. Finally, 86 patients were included in this study. The patients were categorized, according to their surgical records, into either the sT4 group (n=28) or the sT3 group (n=58). Results: There were no statistical differences between the two groups in terms of age, sex, body mass index, comorbidities, cancer location, histologic grade, lymphovascular invasion, perineural invasion, number of harvested lymph nodes, and adjuvant chemotherapy. The 5-year overall survival rate was significantly different between the sT4 and sT3 groups (92.6% vs. 97.7%, p=0.024). In addition, the 5-year disease-free survival rate was significantly different between the sT4 and sT3 groups (88.6% vs. 97.7%, p=0.017). In the multivariate Cox regression analysis, a classification of sT4 was a significant independent predictive factor for recurrence (p = 0.023). Conclusions: Long-term oncologic outcomes have shown significant differences between surgical T4 and T3 in pathologic stage IIA right colon cancer patients. Further large-scale, multicenter studies are required to verify the clinical impact of the surgical staging.

Long-term Survival, Tolerability, and Safety of First-Line Bevacizumab and FOLFIRI in Combination With Ginsenoside-Modified Nanostructured Lipid Carrier Containing Curcumin in Patients With Unresectable Metastatic Colorectal Cancer.

BACKGROUND: Colorectal cancer is the third most common malignant disease and the second leading cause of death worldwide. Previous studies showed improved bioavailability and cytotoxicity of ginsenoside-modified nanostructured lipid carrier containing curcumin (G-NLC) in human colon cancer cell lines. This study aimed to evaluate the safety and tolerability with long-term survival rates in patients with colorectal cancer with unresectable metastases after treatment with first-line bevacizumab/FOLFIRI (folinic acid, bolus/continuous fluorouracil, and irinotecan) in combination with a dietary supplement of G-NLC. METHODS: This study was a prospective, observational, single-group analysis. The enrolled patients had colorectal cancer with unresectable metastases and were administered bevacizumab and FOLFIRI in combination with daily oral G-NLC as first-line treatment. Overall survival, progression-free survival, tumor response, and adverse events were evaluated. RESULTS: A total of 44 patients were enrolled between 2015 and 2019. The median age was 65 (range 45-81) years and the sex ratio was 31:13 (male:female). The primary tumor locations were the colon (31 patients) and rectum (13 patients). The metastatic sites included, liver only (n = 20), lung only (n = 6), both liver and lung (n = 12), and others (n = 6). The median duration of curcumin supply was 7.9 (range 0.9-16.6) months. The most common grade 3 or higher adverse events were neutropenia (n = 15, 34.1%), followed by nausea (n = 4, 9.1%) and vomiting (n = 4, 9.1%). Within the median follow-up period of 22.8 months, the median overall survival was 30.7 months, and the median progression-free survival was 12.8 months. None of the patients achieved complete response (CR); however, 9 patients showed partial response (PR), and 3 patients underwent conversion surgery. CONCLUSIONS: Bevacizumab/FOLFIRI with G-NLC as first-line chemotherapy in patients with colorectal cancer with unresectable metastases presented comparable long-term survival outcomes with acceptable toxicity outcomes. Additional randomized controlled studies are needed to establish definitive conclusions regarding this new regimen for metastatic colorectal cancer.

Outcomes of Surgical and Nonsurgical Treatment for Colorectal Cancer in Nonagenarian Patients.

PURPOSE: This study is aimed to evaluate the clinical outcomes of surgical treatment for nonagenarian patients with colorectal cancer. METHODS: This retrospective single-center study included patients diagnosed with colorectal cancer at the age of ≥90 years between 2004 and 2018. Patient demographics were compared between the operation and nonoperation groups (NOG). Perioperative outcomes, histopathological outcomes, and postoperative complications were evaluated. Overall survival was analyzed using Kaplan-Meier methods and log-rank test. RESULTS: A total of 31 patients were included (16 men and 15 women), and the median age was 91 (range: 90-96) years. The number of patients who underwent surgery and who received nonoperative management was 20 and 11, respectively. No statistical differences in baseline demographics were observed between both groups. None of these patients were treated with perioperative chemotherapy or radiotherapy. Surgery comprised 18 (90.0%) colectomies and 2 (10.0%) transanal excisions. Short-term (≤30 days) and long-term (31-90 days) postoperative complications occurred in 7 (35.0%) and 4 (20.0%) patients, respectively. No complications needed reoperation, such as anastomosis leakage or bleeding. No postoperative mortality occurred within 30 days: 90-day postoperative mortality occurred in two patients (10.0%), respectively. The median overall survival of the operation group was 31.6 (95% confidence interval: 26.7-36.5) and that of NOG was 12.5 months (95% CI: 2.4-22.6) (P = 0.012). CONCLUSION: Surgical treatment can be considered in carefully selected nonagenarian patients with colorectal cancer in terms of acceptable postoperative morbidity, with better overall survival than the nonsurgical treatment.

Impact of Mitomycin-C-Induced Neutropenia after Hyperthermic Intraperitoneal Chemotherapy with Cytoreductive Surgery in Colorectal Cancer Patients with Peritoneal Carcinomatosis.

BACKGROUND: Mitomycin-C (MMC) is the most commonly used chemotherapeutic agent for hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS). However, MMC has a side effect of myelosuppression. This study aimed to evaluate the clinical manifestations and impact of MMC-induced neutropenia after CRS and HIPEC in colorectal cancer patients. METHODS: A total of 124 colorectal cancer patients who underwent CRS with HIPEC between March 2015 and January 2019 were evaluated. Patients with malignancies of non-colorectal origin, hospital stay longer than 60 days, peritoneal cancer index > 30, and complete cytoreduction score > 2 were excluded. MMC 35 mg/m2 was administered for 90 min at 41-43 °C. The patients were divided into three groups: no neutropenia, mild neutropenia (grade 1-2), and severe neutropenia (grade 3-4). RESULTS: In total, mild and severe neutropenia occurred in 30 (24.2%) and 48 (38.7%) patients, respectively. Age and body surface area were significantly different among the neutropenia groups. Severe neutropenia developed significantly earlier than mild neutropenia (6.9 days vs. 10.4 days, p < 0.001) and also lasted significantly longer (4.6 days vs. 2.5 days, p = 0.005). The rate of major postoperative complications was significantly higher in the severe neutropenia group than in the no and mild neutropenia groups (8.3% vs. 6.7% vs. 6.5%, p = 0.015) CONCLUSIONS: Severe neutropenia starts earlier and lasts longer than mild neutropenia after CRS and HIPEC using an MMC triple method. The higher rate of major postoperative complications in patients with severe neutropenia highlights the importance of postoperative management during the neutropenia period.

Effect of mistletoe extract on tumor response in neoadjuvant chemoradiotherapy for rectal cancer: a cohort study.

BACKGROUND: Mistletoe extract, used as a complementary chemotherapeutic agent for cancer patients, has anticancer effects against various malignancies. The aim of the present study was to evaluate the effect of mistletoe extract (Abnoba Viscum Q®) on tumor responses to neoadjuvant chemoradiotherapy (NCRT) for locally advanced rectal cancer. METHODS: This study included patients with rectal cancer who underwent NCRT between January 2018 and July 2020. In the mistletoe group (MG), the patients were administered Abnoba Viscum Q® subcutaneously during chemoradiotherapy-maintained just before surgery. Patient demographics, clinical outcomes, histopathological outcomes, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) assay results were compared between the MG and non-mistletoe group (NMG). Two rectal cancer cell lines (SNU-503 and SNU-503R80Gy) were treated with Abnoba Viscum Q® to assess its mechanistic effects in vivo. RESULTS: Overall, the study included 52 patients (MG: n = 15; NMG: n = 37). Baseline demographics between the two groups were similar, except carbohydrate antigen 19-9 levels and tumor location from the anal verge. There was no difference in the clinical stage between the two groups. A better tumor response in the MG, relative to the NMG, was observed with respect to tumor regression grade (TRG), T stage, and overall tumor-node-metastasis stage. Tumor response was significantly better in the MG than in the NMG in terms of pathologic complete response rate (53.3% vs. 21.6%, P = 0.044), good TRG response (66.7% vs. 32.4%, P = 0.024), T downstaging (86.7% vs. 43.2%, P = 0.004), and overall downstaging (86.7% vs. 56.8%, P = 0.040). The toxicities during NCRT were minimal in both groups. More apoptotic cells were noted in MG samples than in the NMG samples on TUNEL staining. Cleaved caspase-3 level following treatment with Abnoba Viscum Q® was higher in SNU-503R80Gy cells than in SNU-503 cells. CONCLUSION: Patients treated with chemoradiation combined with mistletoe extract showed better outcomes than patients not treated with mistletoe extract in terms of tumor responses. This diversity in treatment may improve the efficacy of NCRT, leading to better oncologic outcomes. Prospective and randomized studies with long-term follow-up are warranted to confirm and extend these results.

An analysis of the outcomes of totally implantable access port implantation performed by surgical residents.

Purpose: This study aimed to investigate the clinical outcomes after totally implantable access port (TIAP) implantation performed by general surgery residents in patients with colorectal cancer. Methods: A total of 291 consecutive patients who underwent TIAP implantations were evaluated. The patients were divided into three groups: second-, third-, and fourth-grade residents. Results: The mean follow-up was 22.1 months (range, 1-87 months). The total times of operation, puncture, and cannulation decreased as the resident grade increased (P<0.001). Early complications significantly decreased with higher resident grades (P=0.039). The non-use of ultrasonography and non-use of C-arm were identified as independent risk factors for complications. Resident grades between second and third (P=0.005) and between second and fourth (P=0.041) were identified as independent risk factors for optimal tip position. Conclusion: TIAP implantation can be safely and effectively performed by residents. Low-grade residents were associated with early complications.

Short-course radiotherapy and chemotherapy for conversion surgery in patients with unresectable metastatic rectal cancer: a preliminary case series study.

Purpose: Curative treatment is challenging in patients with locally advanced rectal cancer and unresectable metastases. The aim of this study was to evaluate the clinical outcomes of short-course radiotherapy (RT) followed by systemic chemotherapy for patients with rectal cancer with mesorectal fascia (MRF) involvement and unresectable distant metastases. Methods: The study included consecutive patients diagnosed as having metastatic mid-to-low rectal cancer treated with short-course RT followed by systemic chemotherapy for conversion radical or palliative surgery between 2014 and 2019 at Gil Medical Center. The patients had primary rectal tumors involving the MRF and unresectable distant metastases. The treatment strategies were determined in a multidisciplinary team discussion. Results: Seven patients (five men and two women) underwent short-course RT (5×5 Gy) and preoperative systemic chemotherapy. The median age was 68 years (range, 46-84 years), and the median distance from the anal verge to the primary tumor was 6.0 cm (range, 2.0-9.0 cm). During the median follow-up period of 29.4 months, three patients underwent conversion radical surgery with R0 resection, two underwent palliative surgery, and two could not undergo surgery. No postoperative major morbidity or mortality occurred. The patients who underwent conversion complete radical surgery showed good long-term survival outcomes, with an overall survival time of 29.4-48.8 months and progression-free survival time of 14.7-41.1 months. Conclusion: Short-course RT followed by systemic chemotherapy could provide patients with unresectable stage IV rectal cancer a chance to undergo to conversion radical surgery with good long-term survival outcomes.

Evaluation of a Novel Trocar-Site Closure Device in Laparoscopic Surgery.

BACKGROUND AND OBJECTIVES: We evaluated the effectiveness and safety of EZ-CloseTM compared to those of hand suture for trocar-site closure according to obesity. METHODS: Fifty-four cases of laparoscopic colorectal surgery were enrolled. For the same patient, the right port site was closed using EZ-CloseTM and left port site was closed by hand suture among cases with port-site diameter ≥10 mm. Cases switched to use of a conventional fascial closure device or with closure time 120 s were considered failures. Closure time was analyzed according to body mass index (BMI) and abdominal wall thickness (AWT). RESULTS: The mean closure time was significantly shorter with EZ-CloseTM than with hand suture (87.9 ± 21.0 vs. 128.0 ± 59.0 s, p < 0.001). The number of failure cases was significantly lower with EZ-CloseTM than with hand suture (7 vs. 27, p < 0.001). The closure time of EZ-CloseTM was significantly shorter than that of hand suture in patients with BMI ≥ 25 and < 27 kg/m2 (n = 15, 85.9 ± 19.8 vs. 135.6 ± 67.9 s, p < 0.014) and ≥ 27 kg/m2 (n = 13, 85.1 ± 18.4 vs. 150.2 ± 70.6 s, p < 0.010). With respect to AWT, the closure time of EZ-CloseTM was significantly shorter than that of hand suture in patients with AWT ≥ 20 and < 26 mm (n = 12, 81.1 ± 11.5 vs. 142.3 ± 83.7 s, p = 0.023) and ≥ 26 mm (n = 17, 85.6 ± 22.6 vs. 160.2 ± 55.5, p < 0.001). No infection and herniation were detected in both trocar sites during the follow-up period (median 20.4 months). CONCLUSION: EZ-CloseTM could provide time efficiency in trocar-site closure, especially in obese patients.

Clinical outcomes of complete cytoreduction with concurrent liver resection followed by hyperthermic intraperitoneal chemotherapy for synchronous peritoneal and liver metastatic colorectal cancer.

BACKGROUND: This study aimed to evaluate the clinical outcomes of concurrent liver resection with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in colorectal cancer patients with synchronous liver and peritoneal metastases. METHODS: Patients with colorectal liver and peritoneal metastasis who underwent complete cytoreduction and hyperthermic intraperitoneal chemotherapy with concurrent liver surgery between September 2014 and July 2018 were included. Perioperative outcomes, overall survival, and progression-free survival were analyzed retrospectively. RESULTS: In total, 22 patients were included. The median peritoneal cancer index was 13 (range, 0-26), and the median number of liver metastases was 3 (range, 1-13). The mean total operative time was 11.4 ± 2.6 h. Minor postoperative complications (Clavien-Dindo grade I-II) were reported in 10 patients (45.5%), and major postoperative complications (grade III-V) were reported in five patients (22.7%), including one mortality patient. The median overall survival since diagnosis with metastasis was 27.4 months. The median overall survival since surgical intervention and the progression-free survival were 16.7 months and 7.1 months, respectively. CONCLUSIONS: This short-term follow-up study showed that, in an experienced center, combined resection with hyperthermic intraperitoneal chemotherapy for colorectal liver and peritoneal metastases was feasible and safe with acceptable oncologic outcomes.

Oxaliplatin-loaded chemically cross-linked hydrogels for prevention of postoperative abdominal adhesion and colorectal cancer therapy.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer among both men and women worldwide. New therapeutic strategies involving cytoreductive surgery and intra-peritoneal chemotherapy could lead to a definitive cure in some cases. However, postoperative intra-abdominal adhesion can cause further complications. In this study, hyaluronic acid (HA)- and carboxymethyl cellulose sodium (CMCNa)-based novel cross-linked hydrogels (HC hydrogels) were synthesized and fully characterized. We demonstrated that varied compositions of HA and CMCNa altered the microstructure, rheology, and degradation behavior of hydrogels. Pre-constructed hydrogels were further loaded with oxaliplatin to prevent intra-abdominal adhesion following chemotherapy. Sustained release of oxaliplatin was observed from hydrogels compared that from solutions, which release drugs through diffusion, following the Higuchi and Korsmeyer-Peppas models. Moreover, low adhesion scores in an in vivo SD rat model demonstrated inhibition of intra-peritoneal adhesion in response to HC hydrogels. Therefore, HC hydrogels offer a novel formulation strategy for providing an intra-abdominal anti-adhesion barrier after cytoreductive surgery and intra-peritoneal chemotherapy for CRC treatment.

Robotic Surgery for Rectal Cancer and Cost-Effectiveness.

Robotic surgery is considered as one of the advanced treatment modality of minimally invasive surgery for rectal cancer. Robotic rectal surgery has been performed for three decades and its application is gradually expanding along with technology development. It has several technical advantages which include magnified three-dimensional vision, better ergonomics, multiple articulated robotic instruments, and the opportunity to perform remote surgery. The technical benefits of robotic system can help to manipulate more meticulously during technical challenging procedures including total mesorectal excision in narrow pelvis, lateral pelvic node dissection, and intersphincteric resection. It is also reported that robotic rectal surgery have been shown more favorable postoperative functional outcomes. Despite its technical benefits, a majority of studies have been reported that there is rarely clinical or oncologic superiority of robotic surgery for rectal cancer compared to conventional laparoscopic surgery. In addition, robotic rectal surgery showed significantly higher costs than the standard method. Hence, the cost-effectiveness of robotic rectal surgery is still questionable. In order for robotic rectal surgery to further develop in the field of minimally invasive surgery, there should be an obvious cost-effective advantages over laparoscopic surgery, and it is crucial that large-scale prospective randomized trials are required. Positive competition of industries in correlation with technological development may gradually reduce the price of the robotic system, and it will be helpful to increase the cost-effectiveness of robotic rectal surgery.