The Combination of Methionine Restriction and Docetaxel Synergistically Arrests Androgen-independent Prostate Cancer But Not Normal Cells.

Background/Aim: Androgen-independent prostate cancer (AIPC) is resistant to androgen-depletion therapy and is a recalcitrant disease. Docetaxel is the first-line treatment for AIPC, but has limited efficacy and severe side-effects. All cancers are methionine-addicted, which is termed the Hoffman effect. Recombinant methioninase (rMETase) targets methionine addiction. The purpose of the present study was to determine if the combination of docetaxel and rMETase is effective for AIPC. Materials and Methods: The half-maximal inhibitory concentrations (IC50) of docetaxel and rMETase alone were determined for the human AIPC cell line PC-3 and Hs27 normal human fibroblasts in vitro. The synergistic efficacy for PC-3 and Hs27 using the combination of docetaxel and rMETase at their IC50s for PC-3 was determined. Results: The IC50 of docetaxel for PC-3 and for Hs27 was 0.72 nM and 0.94 nM, respectively. The IC50 of rMETase for PC-3 and for Hs27 was 0.67 U/ml and 0.76 U/ml, respectively. The combination of docetaxel and rMETase was synergistic for PC-3 but not Hs27 cells. Conclusion: The combination of a relatively low concentration of docetaxel and rMETase was synergistic and effective for AIPC. The present results also suggest that the effective concentration of docetaxel can be reduced by using rMETase, which may reduce toxicity. The present results also suggest the future clinical potential of the combination of docetaxel and rMETase for AIPC.

Head-to-head Comparison of Green Fluorescent Protein (GFP) Imaging With Luciferase-luciferin Imaging In Vivo Using Single-nanometer Laser-excitation Tuning and an Ultra-low-light-detection Camera and Optics Demonstrates the Superiority of GFP.

BACKGROUND/AIM: Genetic reporters encoding fluorescent proteins or luciferase have been used in vivo for the last three decades with claims about their superiority or inferiority over each other. In the present report, a head-to-head in vivo comparison of green fluorescent protein (GFP) fluorescence imaging and luciferase-luciferin imaging, using single-nanometer laser-excitation tuning of fluorescence excitation and an ultra-low-light-detection camera and optics was performed. MATERIALS AND METHODS: Mouse Lewis-lung carcinoma cells labeled with GFP (LLC-GFP) or luciferase (LL/2-Luc2) were injected subcutaneously into the flank of nude mice. One week after injection, GFP-fluorescence imaging and luciferase-luciferin imaging was performed using the UVP Biospectrum Advanced system with excitation at 487 nm and peak emission at 513 nm for GFP, and with emission at 560 nm for luciferase-luciferin. GFP fluorescence images were obtained at 0, 10, and 20 min. Luciferase-luciferin images were obtained 10 and 20 min after the injection of D-luciferin. RESULTS: The intensity of GFP images was 55,909 at 0 min, 56,186 at 10 min, and 57,085 at 20 min, and maintained after 20 min. The intensity of luciferase-luciferin images was 28,065 at 10 min after the injection of D-luciferin and 5,199 at 20 min after the injection. The intensity of luciferase-luciferin images decreased by approximately 80% at 20 min compared to 10 min. An exposure time of 30 s for luciferase-luciferin imaging was needed compared to 100 ms for GFP fluorescence imaging in order to detect signals. CONCLUSION: An imaging system with single-nanometer tuning fluorescence excitation and an ultra-low-light detection camera and optics was able to directly visualize both GFP and luciferase-luciferin images in vivo. The intensity and stability of the signals were both greater for GFP than for luciferase-luciferin, and the exposure time for GFP was 300 times faster, demonstrating the superiority of GFP.

Expression of PD-L1 Is Increased by Methionine Restriction Using Recombinant Methioninase in Human Colorectal Cancer Cells.

BACKGROUND/AIM: It has been recently demonstrated that a methionine-restricted diet increases the response to immune checkpoint inhibitors (ICIs) via an increase in PD-L1 in a syngeneic mouse colorectal-cancer model. Our laboratory has developed recombinant methioninase (rMETase) to restrict methionine. The aim of the present study was to determine if rMETase can increase PD-L1 expression in a human colorectal cancer cell line in vitro. MATERIALS AND METHODS: We evaluated the half-maximal inhibitory concentration (IC50) value of rMETase on HCT-116 human colorectal cancer cells. HCT-116 cells were treated with rMETase at the IC50 Western immunoblotting was used to compare PD-L1 expression in HCT-116 cells treated with and without rMETase. RESULTS: The IC50 value of rMETase on HCT-116 was 0.79 U/ml. Methionine restriction using rMETase increased PD-L1 expression compared to the untreated control (p<0.05). CONCLUSION: Methionine restriction with rMETase up-regulates PD-L1 expression in human colorectal cancer cells and the combination of rMETase and ICIs may have the potential to improve immunotherapy in human colorectal cancer.

DNA-Binding Agent Trabectedin Combined With Recombinant Methioninase Is Synergistic to Decrease Fibrosarcoma Cell Viability and Induce Nuclear Fragmentation But Not Synergistic on Normal Fibroblasts.

BACKGROUND/AIM: The alkylating agent trabectedin, which binds the minor groove of DNA, is second-line therapy for soft-tissue sarcoma but has only moderate efficacy. The aim of the present study was to determine the synergistic efficacy of recombinant methioninase (rMETase) and trabectedin on fibrosarcoma cells in vitro, compared with normal fibroblasts. MATERIALS AND METHODS: HT1080 human fibrosarcoma cells expressing green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in the cytoplasm and Hs27 normal human fibroblasts, were used. Each cell line was cultured in vitro and divided into four groups: no-treatment control; trabectedin treated; rMETase treated; and trabectedin plus rMETase treated. The dual-color HT1080 cells were used to quantitate nuclear fragmentation in each treatment group. RESULTS: The combination of rMETase and trabectedin was highly synergistic to decrease HT1080 cell viability. In contrast, there was no synergy on Hs27 cells. Moreover, nuclear fragmentation occurred synergistically with the combination of trabectedin and rMETase on dual-color HT1080 cells. CONCLUSION: The combination treatment of trabectedin plus rMETase was highly synergistic on fibrosarcoma cells in vitro suggesting that the combination can improve the outcome of trabectedin alone in future clinical studies. The lack of synergy of rMETase and trabectedin on normal fibroblasts suggests the combination is not toxic to normal cells. Synergy of the two drugs may be due to the high rate of nuclear fragmentation on treated HT1080 cells, and the late-S/G2 cell-cycle block of cancer cells by rMETase, which is a target for trabectedin. The results of the present study suggest the future clinical potential of the combination of rMETase and trabectedin for soft-tissue sarcoma.

Extensive Shrinkage and Long-term Stable Disease in a Teenage Female Patient With High-grade Glioma Treated With Temozolomide and Radiation in Combination With Oral Recombinant Methioninase and a Low-methionine Diet.

BACKGROUND/AIM: Gliomas are the most common and recalcitrant malignant primary brain tumors. All cancer types are addicted to methionine, which is a fundamental and general hallmark of cancer known as the Hoffman effect. Particularly glioma cells exhibit methionine addiction. Because of methionine addiction, [11C]-methionine positron emission tomography (MET-PET) is widely used for glioma imaging in clinical practice, which can monitor the extent of methionine addiction. Methionine restriction including recombinant methioninase (rMETase) and a low-methionine diet, has shown high efficacy in preclinical models of gliomas, especially in combination with chemotherapy. The aim of the present study was to determine the efficacy of methionine restriction with oral rMETase (o-rMETase) and a low-methionine diet, combined with radiation and temozolomide (TMZ), on a teenage female patient with high-grade glioma. CASE REPORT: A 16-year-old girl was diagnosed with high-grade glioma. Magnetic resonance imaging (MRI) showed a left temporal-lobe tumor with compression to the left lateral ventricle and narrowing of sulci in the left temporal lobe. After the start of methionine restriction with o-rMETase and a low-methionine diet, along with TMZ combined with radiotherapy, the tumor size shrunk at least 60%, with improvement in the left lateral ventricle and sulci. The patient's condition remains stable for 19 months without severe adverse effects. CONCLUSION: Methionine restriction consisting of o-rMETase and a low-methionine diet, in combination with radiation and TMZ as first-line chemotherapy, were highly effective in a patient with high-grade glioma.

Targeting Methionine Addiction Combined With Low-dose Irinotecan Arrested Colon Cancer in Contrast to High-dose Irinotecan Alone, Which Was Ineffective, in a Nude-mouse Model.

BACKGROUND/AIM: Colorectal cancer (CRC) is the third-leading cause of death in the world. Although the prognosis has improved due to improvement of chemotherapy, metastatic CRC is still a recalcitrant disease, with a 5-year survival of only 13%. Irinotecan (IRN) is used as first-line chemotherapy for patients with unresectable CRC. However, there are severe side effects, such as neutropenia and diarrhea, which are dose-limiting. We have previously shown that methionine restriction (MR), effected by recombinant methioninase (rMETase), lowered the effective dose of IRN of colon-cancer cells in vitro. The aim of the present study was to evaluate the efficacy of the combination of low-dose IRN and MR on colon-cancer in nude mice. MATERIALS AND METHODS: HCT-116 colon-cancer cells were cultured and subcutaneously injected into the flank of nude mice. After the tumor size reached approximately 100 mm3, 18 mice were randomized into three groups; Group 1: untreated control on a normal diet; Group 2: high-dose IRN on a normal diet (2 mg/kg, i.p.); Group 3: low-dose IRN (1 mg/kg i.p.) on MR effected by a methionine-depleted diet. RESULTS: There was no significant difference between the control mice and the mice treated with high-dose IRN, without MR. However, low-dose IRN combined with MR was significantly more effective than the control and arrested colon-cancer growth (p=0.03). Body weight loss was reversible in the mice treated by low-dose IRN combined with MR. CONCLUSION: The combination of low-dose IRN and MR acted synergistically in arresting HCT-116 colon-cancer grown in nude mice. The present study indicates the MR has the potential to reduce the effective dose of IRN in the clinic.

Plastic Wound Protector vs Surgical Gauze for Surgical Site Infection Reduction in Open GI Surgery: A Randomized Clinical Trial.

Importance: Surgical site infections (SSIs) are prevalent hospital-acquired infections with significant patient impacts and global health care burdens. The World Health Organization recommends using wound protector devices in abdominal surgery as a preventive measure to lower the risk of SSIs despite limited evidence. Objective: To examine the efficacy of a dual-ring, plastic wound protector in lowering the SSI rate in open gastrointestinal (GI) surgery irrespective of intra-abdominal contamination levels. Design, Setting, and Participants: This multicenter, patient-blinded, parallel-arm randomized clinical trial was conducted from August 2017 to October 2022 at 13 hospitals in an academic setting. Patients undergoing open abdominal bowel surgery (eg, for bowel perforation) were eligible for inclusion. Intervention: Patients were randomized 1:1 to a dual-ring, plastic wound protector to protect the incision site of the abdominal wall (experimental group) or a conventional surgical gauze (control group). Main Outcomes and Measures: The primary end point was the rate of SSI within 30 days of open GI surgery. Results: A total of 458 patients were randomized; after 1 was excluded from the control group, 457 were included in the intention-to-treat analysis (mean [SD] age, 58.4 [12.1] years; 256 [56.0%] male; 341 [74.6%] with a clean-contaminated wound): 229 in the wound protector group and 228 in the surgical gauze group. The overall SSI rate in the intention-to-treat analysis was 15.7% (72 of 458 patients). The SSI rate for the wound protector was 10.9% (25 of 229 patients) compared with 20.5% (47 of 229 patients) with surgical gauze. The wound protector significantly reduced the risk of SSI, with a relative risk reduction (RRR) of 46.81% (95% CI, 16.64%-66.06%). The wound protector significantly decreased the SSI rate for clean-contaminated wounds (RRR, 43.75%; 95% CI, 3.75%-67.13%), particularly for superficial SSIs (RRR, 42.50%; 95% CI, 7.16%-64.39%). Length of hospital stay was similar in both groups (mean [SD], 15.2 [10.5] vs 15.3 [10.2] days), as were the overall postoperative complication rates (20.1% vs 18.8%). Conclusions and Relevance: This randomized clinical trial found a significant reduction in SSI rates when a plastic wound protector was used during open GI surgery compared with surgical gaze, supporting the World Health Organization recommendation for use of wound protector devices in abdominal surgery. Trial Registration: ClinicalTrials.gov Identifier: NCT03170843.

Reduction of Tumor Biomarkers from very High to Normal and Extensive Metastatic Lesions to Undetectability in a Patient With Stage IV HER2-positive Breast Cancer Treated With Low-dose Trastuzumab Deruxtecan in Combination With Oral Recombinant Methioninase and a Low-methionine Diet.

BACKGROUND/AIM: Breast cancer is the most common and the deadliest cancer among women in the world. Treatment options for HER2-positive metastatic breast cancer patients are limited. Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC), has recently been introduced as second-line chemotherapy for HER2-positive metastatic breast cancer. The aim of the present study was to evaluate the efficacy of methionine restriction with oral recombinant methioninase (o-rMETase) and a low-methionine diet combined with T-DXd, on a patient with HER2-positive recurrent stage IV breast cancer. CASE REPORT: A 66-year-old female was diagnosed with HER2-positive metastatic breast cancer. Computed tomography (CT) indicated peritoneal dissemination, thickening of the sigmoid colon and splenic flexure and widespread bone metastases. The patient was previously treated with fulvestrant, trastuzumab, pertuzumab, paclitaxel and capecitabine which were ineffective. T-DXd was administered as a second-line chemotherapy. Since the patient experienced strong side effects, the dose of T-Dxd was decreased. The patient began methionine restriction using o-rMETase and a low-methionine diet along with T-DXd. After the start of the combined treatment, CA15-3 and CA27.29, tumor markers for breast cancer, decreased rapidly from a very high level. The levels of both tumor markers are currently normal. Additionally, peritoneal-dissemination nodules, ascites and the thickness of the sigmoid colon and splenic flexure are no longer detected on CT. The patient maintains a high performance status, without severe side effects of the combination treatment. CONCLUSION: Methionine restriction consisting of o-rMETase and a low-methionine diet, in combination with T-DXd as second-line chemotherapy, was highly effective in a patient with HER2-positive stage IV breast cancer.

Extensive Synergy Between Recombinant Methioninase and Eribulin Against Fibrosarcoma Cells But Not Normal Fibroblasts.

BACKGROUND/AIM: The aim of the present study was to determine the synergy of recombinant methioninase (rMETase) and the anti-tubulin agent eribulin on fibrosarcoma cells, in comparison to normal fibroblasts, in vitro. MATERIALS AND METHODS: HT1080 human fibrosarcoma cells and HS27 human fibroblasts were used for in vitro experiments. Four groups were analyzed in vitro: No-treatment control; eribulin; rMETase; eribulin plus rMETase. Dual-color HT1080 cells which express red fluorescent protein (RFP) in the cytoplasm and green fluorescent protein (GFP) in the nuclei were used to visualize cytoplasmic and nuclear dynamics during treatment. RESULTS: Eribulin combined with rMETase greatly decreased the viability of HT 1080 cells. In contrast, eribulin combined with rMETase did not show synergy on Hs27 normal fibroblasts. Eribulin combined with rMETase also caused more fragmentation of the nucleus than all other treatments. CONCLUSION: The combination treatment of eribulin plus rMETase demonstrated efficacy on fibrosarcoma cells in vitro. In contrast, normal fibroblasts were resistant to this combination, indicating the potential clinical applicability of the treatment.

Recombinant Methioninase Decreased the Effective Dose of Irinotecan by 15-fold Against Colon Cancer Cells: A Strategy for Effective Low-toxicity Treatment of Colon Cancer.

BACKGROUND/AIM: Irinotecan (IRN), a topoisomerase I inhibitor and pro-drug of SN-38, is first-line treatment of colon cancer as part of FOLFIRI and FOLFOXIRI combination chemotherapy. However, IRN causes dose-limiting adverse events such as neutropenia and diarrhea. Dose reductions are sometimes required, which reduce efficacy. Recombinant methioninase (rMETase) targets the fundamental basis of cancer, methionine addiction, known as the Hoffman effect, and enhances the efficacy of numerous chemotherapy drugs. The present study determined the efficacy of rMETase when administered in combination with IRN. MATERIALS AND METHODS: Cell viability was assessed by cultivating the HCT-116 human colorectal cancer cell line in 96-well plates at 1×103 cells per well in Dulbecco's modified Eagle's medium (DMEM). Subsequently, HCT-116 cells were treated with increasing concentrations of SN-38, the active form of IRN, ranging from 0.5 nM to 32 nM, and/or rMETase ranging from 0.125 to 8 U/ml. After treatment for 72 h, the half-maximal inhibitory concentration (IC50) of SN-38 alone and rMETase alone for HCT-116 cells were determined. Using the IC50 concentration of rMETase, we determined the IC50 of SN-38 in combination with rMETase. Cell viability was determined with the cell-counting Kit-8 with the WST-8 reagent.. RESULTS: The IC50 of rMETase alone for the HCT-116 cells was 0.55 U/ml, and the IC50 of IRN (SN-38) alone was 3.50 nM. rMETase at 0.55 U/ml lowered the IC50 of SN-38 to 0.232 nM (p<0.0001), a 15-fold reduction. CONCLUSION: rMETase and IRN are strongly synergistic, giving rise to the possibility of lowering the effective dose of IRN for the treatment of patients with colon cancer, thereby reducing its severe toxicity. This new strategy will allow more patients with cancer to be effectively treated with IRN.

A Retrospective Multicenter Study of Risk Factors, Stratification, and Prognosis of Lymph Node Metastasis in T1 and T2 Colorectal Cancer.

BACKGROUND: The objective of this study was to compare the long-term prognosis of patients with T1 and T2 colorectal cancer (CRC) according to lymph node metastasis (LNM) and to identify risk factors for LNM. METHODS: We retrospectively reviewed patients who underwent curative resection for T1 or T2 CRC at five University-affiliated hospitals between January 2012 and December 2021. The patients were divided into several groups depending on the presence of LNM or the number of risk factors. RESULTS: Of the total 765 patients, 87 (11.3%) patients had LNM. These patients had poorer recurrence-free survival (RFS) than patients without LNM (72.6% vs. 88.6%). The multivariable analysis showed that high-grade tumors (p = 0.003), lymphovascular invasion (p < 0.001), and rectal location (p = 0.049) were independent predictors of LNM. When divided into groups according to the number of the three risk factors, the risk of LNM increased from 5.4% (ultralow-risk group; no risk factor) to 60.0% (high-risk group; all three risk factors) and the 5-year RFS rate decreased from 96.3% in the ultralow-risk group to 60% in the high-risk group (p < 0.001). CONCLUSION: Radical surgery should be considered for T1 and T2 CRC patients with these risk factors.

Impact of the COVID-19 pandemic on the outcomes of laparoscopic appendectomy for acute appendicitis.

Purpose: This retrospective study aimed to evaluate the impact of the coronavirus disease 2019 (COVID-19) pandemic on the time interval from symptom onset to surgery and on the operative outcomes of laparoscopic appendectomy for patients with acute appendicitis. Methods: Between October 2018 and July 2021, laparoscopic appendectomy was performed in 502 patients with acute appendicitis admitted to Hallym University Chuncheon Sacred Heart Hospital in Chuncheon, Korea. We compared demographic data, serum levels of inflammatory markers, time to event of appendicitis, and operative outcomes between the pre-COVID-19 and post-COVID-19 pandemic groups. Results: Laparoscopic appendectomy was performed in 271 patients in the pre-COVID-19 group and in 231 patients in the post-COVID-19 group. There were no differences in baseline characteristics, serum inflammatory marker levels, or the proportions of complicated appendicitis between the groups (25.1%, pre-COVID-19 vs. 31.6%, post-COVID-19; P = 0.106). The time intervals between symptom onset and hospital arrival (24.42 hours vs. 23.59 hours, P = 0.743) and between hospital arrival and the start of surgery (10.12 hours vs. 9.04 hours, P = 0.246) did not increase post-COVID-19. The overall 30-day postoperative complication rate did not differ significantly between the groups (9.6% vs. 10.8%, P = 0.650), and the severity of 30-day postoperative complications was also similar in both groups (P = 0.447). Conclusion: This study demonstrates that hospitalization and surgeries were not delayed in patients with acute appendicitis and that the operative outcomes of laparoscopic appendectomy did not worsen despite the COVID-19 pandemic.

Laparoscopic repair of perforated peptic ulcer: a multicenter, propensity score matching analysis.

BACKGROUND: Perforated peptic ulcer (PPU) is a common emergency condition requiring surgery using laparoscopy or open repair of the perforated site. The aim of this study was to assess the role of laparoscopic surgery (LS) based on the safety and efficacy for PPU. METHODS: Medical records of the consecutive patients who underwent LS or open surgery (OS) for PPU at five hospitals between January 2009 and December 2019 were retrospectively reviewed. After propensity score matching, short-term perioperative outcomes were compared between LS and OS in selected patients. RESULTS: Among the 598 patients included in the analysis, OS was more frequently performed in patients with worse factors, including older age, a higher American Society of Anesthesiologists score, more alcohol use, longer symptom duration, a higher Boey score, a higher serum C-reactive protein level, a lower serum albumin level, and a larger-diameter perforated site. After propensity score matching, 183 patients were included in each group; variables were well-balanced between-groups. Postoperative complications were not different between groups (24.6% LS group vs. 31.7% OS group, p = 0.131). However, postoperative length of hospital stay (10.03 vs. 12.53 days, respectively, p = 0.003) and postoperative time to liquid intake (3.75 vs. 5.26 days, p < 0.001) were shorter in the LS group. CONCLUSIONS: LS resulted in better functional recovery than OS and can be safely performed for treatment of PPU. When performed by experienced surgeons, LS is an alternative option, even for hemodynamically unstable patients.

Risk of incisional hernia after laparoscopic colorectal surgery: surgeon's worries and challenges.

The incidence and risk factors of incisional hernia after laparoscopic surgery for colorectal disease have not yet been fully investigated. The surgeon should always consider several potential risk factors of incisional hernia when closing the abdominal wall in laparoscopic colorectal surgery.

Sarcopenia with systemic inflammation can predict survival in patients with hepatocellular carcinoma undergoing curative resection.

Background: This study aimed to examine the prognostic significance of sarcopenia combined with systemic inflammation in patients who underwent curative hepatectomy for hepatocellular carcinoma (HCC). Methods: Between January 2010 and July 2019, we identified 159 patients with HCC who underwent curative hepatectomy at three institutional centers. We retrospectively analyzed clinicopathological outcomes, surgical outcomes, platelet lymphocyte ratio (PLR) as a systemic inflammatory marker, and computed tomography (CT)-assessed sarcopenia at the third lumbar vertebra level (L3). Results: Sarcopenia was noted in 74 (46.5%) of 159 patients and was significantly associated with male sex, low body mass index (BMI), and high PLR. In the multivariate analysis, sarcopenia [hazard ratio (HR): 2.127, P=0.026] and high PLR (HR: 1.971, P=0.038) were associated with a decrease in overall survival (OS) but not in recurrence-free survival (RFS). The combination of sarcopenia and PLR status stratified the 5-year OS into 82.0% (non-sarcopenia and a low PLR), 68.3% (sarcopenia or a high PLR), and 44.4% (sarcopenia and a high PLR) (P=0.001). In the multivariate analysis, "sarcopenia and a high PLR" and "sarcopenia or a high PLR" were revealed to be significant predictors of OS (HR: 4.300, P=0.001 and HR: 2.723, P=0.010, respectively). Conclusions: Sarcopenia and high PLR were significantly associated with poor OS. The combination of these two factors may be useful for predicting survival of patients with HCC undergoing curative hepatectomy.

Prognostic Value of Mesorectal Lymph Node Micrometastases in ypN0 Rectal Cancer After Chemoradiation.

INTRODUCTION: More than 25% of patients with node-negative colorectal cancer experience a recurrent disease even after curative surgery. This suggests the existence and oncologic influence of micrometastasis in regional lymph nodes or in distant organs. The objective of this study was to identify mesorectal lymph node micrometastases using an immunohistochemical analysis and to determine its prognostic value in node-negative rectal cancer after neoadjuvant chemoradiation. MATERIALS AND METHODS: A total of 91 patients who received preoperative chemoradiation and radical resection for rectal cancer were included. Based on conventional hematoxylin and eosin staining, all patients had a node-negative disease. Mesorectal lymph nodes from resected specimens were re-evaluated to detect micrometastases by immunohistochemistry using anticytokeratin antibody AE1/AE3. The clinicopathologic data were collected from a prospectively maintained database of colorectal cancer patients and analyzed retrospectively. RESULTS: Micrometastases of mesorectal lymph nodes were detected in nine patients (9.9%). The three-year overall survival was similar regardless of micrometastasis (88.9% in the positive group versus 90.7% in the negative group, P = 0.681); however, the three-year disease-free survival was significantly poorer in the patients with micrometastases (40.0% versus 84.2%, P = 0.001). In the multivariate analysis, the advanced pT category (ypT3/T4 versus ypT0: hazard ratio [HR] 10.477, 95% confidence interval [CI] 1.102-99.594, P = 0.041) and micrometastases in mesorectal lymph nodes (HR 5.655, 95% CI 1.837-17.409, P = 0.003) were independent prognostic factors for disease-free survival. CONCLUSIONS: In node-negative rectal cancer after preoperative chemoradiation, immunohistochemically detected micrometastases of mesorectal lymph nodes were significantly correlated with poor disease-free survival.

Hybrid Appendectomy in Pediatric Appendicitis: A Comparative Analysis of Single-Port and Multiport Laparoscopic Appendectomy.

Background: Hybrid appendectomy (HA) has the technical advantages of the excellent visual field provided by laparoscopic surgery and is fast and easy similar to open surgery. We aimed to compare the safety and effectiveness of HA with single- and multiport laparoscopic appendectomy (SPLA and MPLA) in pediatric patients with acute appendicitis. Materials and Methods: This retrospective study compared the short-term operative outcomes between HA, SPLA, and MPLA groups. From January, 2010 to December, 2019, 239 patients aged <12 years who underwent laparoscopic appendectomy for acute appendicitis were included. The primary outcome was the 30-day postoperative complication rate, stratified according to the modified Clavien-Dindo classification. Results: In 239 patients, HA was more frequently performed in patients with a low body mass index (17.42 versus 18.97 kg/m2 in the SPLA group versus 18.44 kg/m2 in the MPLA group, P = .029) and tended to be more frequently adopted in uncomplicated appendicitis. In uncomplicated appendicitis, the HA group had a significantly shorter operation time than the MPLA group (31.77 versus 40.09 min, P < .001), but had a comparable operation duration with the SPLA group. The rate of 30-day postoperative complications was not significantly different between the groups (HA 7.6% versus SPLA 7.8% versus MPLA 5.4%, P = .841). The postoperative time to resume water intake was significantly longer in the SPLA group than in the HA and MPLA groups (P = .008). Conclusions: HA showed a short operation time, fast functional recovery, and acceptable postoperative complication rate in patients with uncomplicated appendicitis and can be safely and effectively performed in these patients.

Learning Curve in Laparoscopic Pancreaticoduodenectomy: Using Risk-Adjusted Cumulative Summation Methods.

Background: Laparoscopic pancreaticoduodenectomy (LPD) is one of the most technically challenging operations of minimally invasive surgery. We aimed to analyze the learning curve of a single surgeon who conducted 115 LPDs at a single center. Materials and Methods: From August 2015 to August 2020, 115 patients underwent LPD. Patient characteristics and perioperative variables were retrospectively collected and analyzed. Cumulative summation (CUSUM) and risk-adjusted cumulative summation (RA-CUSUM) analyses were used to evaluate the LPD learning curve. All variables were compared after dividing the learning curve phases. Results: After 74 cases, operative time improved based on the CUSUM analysis of the operation time. From the RA-CUSUM analysis, three distinct phases of the learning curve were identified (phase I: 1-42 cases, phase II: 43-73 cases, and phase III: 74-115 cases). The mean operative time was significantly lower in phase III compared with that in phases I and II (348.5 minutes versus 444.6 minutes and 439.9 minutes, P < .001 and P < .001, respectively). The rate of estimated blood loss >500 mL was significantly decreased among the three phases (P = .017). The conversion rate significantly decreased from 11.9% in phase I to 6.5% in phase II to 0% in phase III (P = .023). The rates of overall complication (Clavien-Dindo >IIIA), postoperative pancreatic fistula, and postpancreatectomy hemorrhage were significantly decreased as phases progressed. Postoperative hospital stay, 30-day mortality, and 30-day readmission did not significantly differ among phases. Conclusions: According to learning curve analyses, the LPD failure rate plateaued after 42 cases and stabilized after 73 cases.

Clinical and oncologic outcomes of laparoscopic versus open surgery in elderly patients with colorectal cancer: a retrospective multicenter study.

BACKGROUND: Laparoscopic surgery is commonly used in elderly patients over 80 years old. The purpose of this study was to compare the perioperative and oncologic outcomes between laparoscopic surgery and open surgery in elderly patients with colorectal cancer. METHODS: We retrospectively analyzed the medical records of patients aged ≥ 80 years who underwent curative resection of colorectal cancer at six Hallym University-affiliated hospitals. The perioperative outcomes and oncologic outcomes were compared between laparoscopic and open surgery RESULTS: Of 294 elderly patients, 104 (35.3%) underwent open surgery and 190 (64.7%) underwent laparoscopic surgery. The postoperative hospital stay (P = 0.019) and time to soft diet (P = 0.009) were shorter in the laparoscopic group than in the open group. Postoperative complications were less frequent in the laparoscopic group than in the open group (P < 0.001), including wound infection (P = 0.005), ileus (P = 0.005), and pneumonia (P = 0.001). The 3-year overall survival (OS) (P = 0.982) and recurrence-free survival rates (RFS) (P = 0.532) were similar in both groups. In multivariable analyses, positive lymph node status was the only independent factor associated with OS (P = 0.019) and RFS (P = 0.012). Laparoscopic surgery was not associated with OS (P = 0.874) and RFS (P = 0.772). CONCLUSION: Laparoscopic surgery offers several perioperative advantages over open surgery and similar long-term oncological outcomes for elderly patients with colorectal cancer. Therefore, we suggest that laparoscopic surgery can be safely performed for the treatment of elderly patients (≥ 80 years old) with colorectal cancer.

Laparoscopic Hartmann's Reversal: Application of a Single-Port Approach Through the Colostomy Site.

PURPOSE: Recently, laparoscopic reversal of Hartmann's colostomy was performed with favorable outcomes by many surgeons. We partially applied the concepts of single-port laparoscopic procedure through the colostomy site to remove intraperitoneal adhesion during initial step of the laparoscopic Hartmann's reversal. This study aimed to evaluate the feasibility and safety of the laparoscopic reversal of Hartmann's colostomy with the application of single-port laparoscopic techniques through the colostomy site. METHODS: From October 2008 to November 2018, the laparoscopic Hartmann's reversal was attempted in 20 patients. After colostomy take-downs, the single-port device was installed at the colostomy site and the single-port laparoscopic procedure was performed to remove intraperitoneal adhesions to provide space for additional trocars. After additional trocars were inserted, the descending colon and rectal stump were mobilized, and the colorectal anastomosis was completed. We retrospectively reviewed the medical records and analyzed the data to identify the perioperative complication rates as the primary outcome. RESULTS: Of the 20 patients, 3 patients (15.0%) had open conversions due to severe adhesions. Intraoperative small bowel injuries occurred in 2 patients (10.0%) and these were repaired through the colostomy site. Postoperative complications developed in 4 patients (20.0%) and were managed with medical treatments or wound closures under local anesthesia. CONCLUSION: The single-port laparoscopic procedure through the colostomy site is sufficiently safe in order to complete the Hartmann's reversal. We recommend that the colostomy site should be used as the access route into the abdominal cavity for the Hartmann's reversal.