Feasibility and Efficacy of Neoadjuvant Chemotherapy without Radiotherapy for Locally Advanced Rectal Cancer.

OBJECTIVES: This retrospective study explored the feasibility of neoadjuvant chemotherapy (NAC) without radiotherapy in patients with locally advanced rectal cancer (LARC). METHODS: Patients with clinical stage of T3-T4 and/or N-positive LARC patients were included. We retrospectively analyzed patients' NAC-related and perioperative outcomes. RESULTS: The study enrolled 30 patients. mFOLFOX6 or SOX plus cetuximab was administered to 12 patients with the wild-type RAS gene and FOLFOXIRI or SOXIRI to 18 patients with mutant-type RAS. The NAC completion rate was 90.0%. All patients underwent total mesorectal excision, and 29 patients underwent combined bilateral lateral lymph node dissection. The R0 operation rate was 90.0%. Although the postoperative complication rate was 40%, no complications were associated with NAC. The response rate of NAC and the proportion of histological anti-tumor effect grade ≥ 2 were 56.7% and 46.7%, respectively. CONCLUSIONS: NAC was considered to be a safe, feasible treatment option for LARC.

[Two Cases of Locally Advanced Lower Rectal Cancer with Pathological Complete Response after Cetuximab plus SOX as Neoadjuvant Chemotherapy].

We have introduced neoadjuvant chemotherapy(NAC)for locally advanced lower rectal cancer(LARC)since 2014. We report 2 LARC cases in which a pathological complete response(pCR)was obtained by using cetuximab(Cmab)plus oxaliplatin plus S-1(SOX)for NAC. Case 1: A 68-year-old woman underwent 4 courses of Cmab plus SOX for Rb rectal cancer (well-differentiated adenocarcinoma, cStage Ⅲc: cT4b[vagina]N3M0). Lap posterior pelvic exenteration was performed. The pathological findings of the resected specimen revealed no carcinoma and we diagnosed it as pCR. As of 31 months after the operation, she is alive without recurrence. Case 2: A 72-year-old man underwent 4 courses of Cmab plus SOX for middle and lower rectal cancer(Rab, moderately differentiated tubular adenocarcinoma, cStage Ⅲc: cT3N3M0). After NAC, with the diagnosis of ycT3N0M0, laparoscopic-assisted(Lap)super-low anterior resection with bilateral lateral pelvic node dissection was performed. The pathological findings of the resected specimen revealed no carcinoma and we diagnosed it as pCR. As of 37 months after the operation, he is alive without recurrence. NAC with Cmab plus SOX may be an effective treatment for LARC.

[Laparoscopic Total Pelvic Exenteration of Locally Advanced Rectal Cancer Invading Urogenital Organs].

Application of laparoscopic surgery(Lap)for colorectal cancer has expanded, and laparoscopic total pelvic exenteration (TPE)of locally advanced rectal cancer(LARC)invading the urogenital organs has been introduced in some institutions. In our institute, we have performed Lap TPE and posterior-TPE(PPE)in a total of 6 LARC patients so far. Here, we report the surgical technique of Lap TPE, and the associated surgical and short-term outcomes. We performed Lap TPE and Lap PPE in 3 patients each. Operation time was approximately 562 min, and the blood loss was 310 mL on an average. No patient developed postoperative complications above Clavien-Dindo Grade Ⅲ. One patient exhibited recurrence in the liver and another in peritoneum in the Lap PPE group. No recurrence was observed in the Lap TPE group(median follow-up period: 24.5 months). Although Lap TPE and PPE are difficult to perform and time consuming, it is suggested that these procedures may help reduce the intraoperative bleeding volume and shorten the length of postoperative hospital stay compared to open TPE and PPE.

Short-term outcomes of laparoscopic lateral pelvic node dissection for advanced lower rectal cancer.

BACKGROUND: The laparoscopic magnified visual effects and evolution of the laparoscopic camera system have recently enabled us to observe details in the deep pelvic floor. Indications of laparoscopic surgery for colorectal cancer have been expanded, and laparoscopic (Lap) lateral pelvic node dissection (LLND) has been introduced in some institutions. We investigated the feasibility of Lap LLND in patients with locally advanced rectal cancer (LARC). METHODS: Lap LLND was performed in 38 patients diagnosed with cT3-4 or cN1-2 cancer during 2014-2018. We retrospectively analyzed their surgical and short-term outcomes. RESULTS: Laparoscopic surgery was performed in all patients. cStages II/III/IV were found in 6/31/1 patients, respectively. Among them, 25 patients underwent neoadjuvant chemotherapy without radiotherapy. Lap unilateral LLND was performed in 6 patients and Lap bilateral LLND was performed 32 patients. The number of harvested lymph nodes (LNs) were 4 in the unilateral group and 15 in the bilateral group. Operation time was 531 min, and blood loss was 105 ml. Oral intake has started on postoperative day (POD) 3, and pelvic drain was removed on POD 7. Hospital stay was 18.5 days. Seven patients developed a neurogenic bladder (all Clavien-Dindo grade (CD) II and all occured in the bilateral LLND group), one patient developed abdominal bleeding (CD IIIb) and one patient developed anastomotic leakage (CD IIIb). Pathological results revealed 2/5/16/14/1 patients with pStages 0/I/II/III/IV, respectively. Four patients had histopathologically verified lateral pelvic lymph node metastases. There were no local recurrences after curative surgery (median follow-up 24.2 months). CONCLUSION: Although the median follow-up period is relatively short and further follow-up is necessary, oncologically, especially in the point of local control rate, Lap LLND appears to have acceptable in the treatment of LARC without radiotherapy in experienced centers. Further investigations focusing on indications and the Lap LLND procedural technique are required.

Active Hexose Correlated Compound Has Protective Effects in Ischemia-Reperfusion Injury of the Rat Small Intestine.

BACKGROUND: Ischemia-reperfusion (IR) injury of the small intestine is a serious problem in abdominal aortic aneurysm surgery or small intestine transplantation. Active hexose correlated compound (AHCC) is a popular anti-inflammatory drug in complementary and alternative medicine. The aim of this study was to examine whether pretreatment with AHCC reduces intestinal IR injury. METHODS: Rats were given a normal diet (IR group) or normal diet supplemented with 2% AHCC (IR + AHCC group) ad libitum for 10 d. After 1 d of fasting, the superior mesenteric artery was occluded by clipping for 45 min. Intestinal and blood samples were collected for 1-6 h after reperfusion. The messenger RNA (mRNA) and protein levels of inflammatory factors were analyzed. RESULTS: The IR + AHCC group had reduced mucosal abrasion and significantly increased mucosal thickness of the intestinal tissues 6 h after reperfusion, compared with the IR group. AHCC decreased mRNA expression of inducible nitric oxide synthase (iNOS), cytokine-induced neutrophil chemoattractant 1 and interleukin 6 in the mucosa of the small intestine. AHCC also decreased expression of iNOS protein. Serum levels of cytokine-induced neutrophil chemoattractant 1 and tumor necrosis factor α were decreased in the IR + AHCC group compared with the IR group. Electrophoretic mobility shift assay of mucosal nuclear extracts revealed that AHCC inhibited the activation of nuclear factor kappa B. AHCC also inhibited the expression of iNOS antisense transcript, which stabilizes iNOS mRNA. CONCLUSIONS: Our findings suggest that AHCC reduces expression of inflammatory mediators, in part, by inhibiting nuclear factor kappa B activation. AHCC may have anti-inflammatory effect in patients with intestinal IR injury.

Elental® amino acid component has protective effects on primary cultured hepatocytes and a rat model of acute liver injury.

Amino acids can exert protective effects on the liver either when administered as a medication or following an operation. In this study, we examined the protective effects of amino acids on the liver using in vitro and in vivo models by studying their influence on the induction of inducible nitric oxide synthase (iNOS) and nitric oxide production as a liver injury marker in cultured hepatocytes and liver-protective effects in d-galactosamine and lipopolysaccharide (GalN/LPS)-treated rats, respectively. Primary cultured rat hepatocytes were treated with interleukin (IL)-1ß in the presence or absence of Elental® amino acid component (EleAA; 17 amino acids). Rats were pretreated with either EleAA or a diet containing selected amino acids followed by GalN/LPS injection. Survival rate and mRNA expression were analyzed. EleAA inhibited iNOS induction through reduction of mRNA synthesis and stability in cultured hepatocytes, indicating prevention of liver injury, but did not show a liver-protective effect in GalN/LPS rats. Among EleAA, Lys, Trp, His, and Arg (4AA) markedly decreased nitric oxide production and inhibited nuclear factor-κB (NF-κB) activation. In GalN/LPS rats, 4AA (3% of each amino acid in diet) increased survival rate by 50% and decreased mRNA expression of iNOS, tumor necrosis factor-α, and cytokine-induced neutrophil chemoattractant-1 in the liver. 4AA reduced NF-κB activation induced by GalN/LPS. 4AA inhibited the expression of inflammatory mediators, in part through inhibition of NF-κB activation in cultured hepatocytes and GalN/LPS-treated rats. The results suggest that EleAA has therapeutic potential for organ injuries including liver.

Efficacy and safety of thromboembolism prophylaxis with fondaparinux in Japanese colorectal cancer patients undergoing laparoscopic surgery: A phase II study.

PURPOSE: We aimed to assess the safety and efficacy of fondaparinux (FPNX) for patients undergoing laparoscopic colorectal surgery (LAC). METHODS: Patients scheduled for LAC received once-daily subcutaneous injections of FPNX 1.5-2.5 mg for 4-8 days. The primary endpoint was the incidence of bleeding events. The secondary endpoint was the incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE). RESULTS: Among 128 patients evaluable for efficacy, 119 patients were administered FPNX. Nine patients were excluded owing to intraoperative events, including conversion to open surgery among others. Thirteen patients discontinued treatment owing to anastomotic bleeding (n = 5), anastomotic leakage (n = 3), bleeding at drain insertion site (n = 2), subcutaneous bleeding (n = 1), drug-induced rash (n = 1), and sepsis (n = 1). Among the FPNX discontinuations, there were eight cases of bleeding (6.7%), and two cases of major bleeding (1.7%). In multivariate analysis, operative time >300 min was identified as a risk factor for bleeding events (p = 0.001) secondary to FPNX. The incidence rate of DVT was 2.5% (3/119 cases); these patients were asymptomatic. CONCLUSION: There were no cases of PE. It is necessary to establish strict criteria for VTE prophylaxis with FPNX after LAC for Japanese patients considering the incidence of bleeding events.

Outcomes of neoadjuvant chemoradiotherapy in Japanese locally advanced rectal carcinoma patients.

BACKGROUND: We investigated the efficacy and prognosis of neoadjuvant chemoradiotherapy (NACRT) for Japanese locally advanced rectal carcinoma patients. METHODS: Fifty-seven patients diagnosed with cT3-4 or any cT/cN+ disease using enhanced computed tomography or magnetic resonance imaging from 2002 to 2014 were enrolled. The male/female ratio was 42/15, and the median age was 67 years. Ra/Rb/Rb-P/P was expressed by 6/35/14/2 patients. Histological tumor types were tub1/tub2/por/muc in 22/30/4/1 patients. For NACRT, radiotherapy doses were 40-50.4 Gy chemotherapy consisted of 5'-DFUR, capecitabine, or S1. RESULTS: All 57 patients received curative surgical treatment. The anal preservation rate was 65.0%. The ypStage of 0/I/II/IIIa/IIIb was 7/10/25/11/4 cases. The histological antitumor effect (HATE) was ≥grade (G) 2 and G3 in 31 (54.4%) and 7 (12.3%) cases, respectively. Postoperative complications occurred in 17 patients and exceeded GIII (Clavien-Dindo classification) in four patients. Recurrence was observed in 19 patients; the primary local recurrence rate was 5.3%. The 3-year relapse-free survival (RFS) and overall survival (OS) rates were 64.8 and 95.5%, respectively; the 5-year RFS and OS rates were 60.2 and 61.0%, respectively. In multivariate analysis, ypN+ was a high-risk factor for distant organ recurrence. As predictive factors regarding the efficacy of NACRT, a neutrophil concentration <70% and a neutrophil/lymphocyte ratio <3.0 in peripheral blood prior to treatment indicated that NACRT would be significantly more effective. CONCLUSIONS: NACRT was effective in reducing local recurrence but did not suppress distant organ recurrence in Japanese locally advanced rectal carcinoma patients. A further investigation of an extension of the NACRT regimen is required.

Short- and long-term outcomes of laparoscopic surgery for colorectal cancer in the elderly: A prospective cohort study.

BACKGROUND: The aim of this study was to evaluate the safety and validity of laparoscopic colorectal surgery for elderly patients. We compared the short and long-term postoperative outcomes of laparoscopic colorectal surgery in patients aged ≥75 years (elderly patients; EP) and <75 years (relatively younger patients; RP). METHODS: Clinicopathological data and short- and long-term outcomes after laparoscopic surgery for colorectal cancer were compared between the EP (n = 53) and RP groups (n = 155). RESULTS: In the EP group, patients with American Society of Anesthesiologists score II (p = 0.047) and medical comorbidity rate (EP vs RP: 83.0% vs 56.8%, p < 0.001), especially for cardiovascular disease (64.2% vs 37.5%, p < 0.001) and diabetes mellitus (20.8% vs 9.7%, p = 0.044), were significantly higher than those in the RP group. Regarding the clinical characteristics, the ratio of right colectomy (50.9% vs 25.3%, p < 0.001) and pathological tumor grade T4 (18.9% vs 7.7%, p = 0.044) were significantly higher in the EP group. There was no significant difference in the variation of pathological stage between the two groups. In the postoperative course, there were no significant differences regarding short-term postoperative outcomes between the EP and RP groups, including that for timing of oral diet tolerance (3.9 days vs 3.5 days, p = 0.073), first flatus (2.3 days vs 2.0 days, p = 0.636), first bowel movement (3.3 days vs 3.7 days, p = 0.153), ambulation after surgery (1.7 days vs 1.5 days, p = 0.081), postoperative hospital stay (10.5 days vs 10.8 days, p = 0.469), and incidence of postoperative complications (20.8% vs 15.5%, p = 0.385), respectively. Regarding the long-term outcomes, there were no significant differences in recurrence-free survival (RFS) (5-year RFS, 74.0% vs 85.2%, p = 0.091) and overall survival (OS) (5-year OS, 81.8% vs 90.1%, p = 0.112) between the two groups. CONCLUSION: Laparoscopic colorectal surgery in elderly patients was safe and well-tolerated in comparison with the relatively younger patients.

Ultrasonic scalpel for gastric cancer surgery: a prospective randomized study.

BACKGROUND: The aim of the study was to evaluate the potential advantages of the ultrasonic scalpel compared with the conventional technique in gastric cancer surgery. METHODS: Patients with resectable adenocarcinoma of the stomach were randomly assigned to ultrasonic scalpel or conventional technique. We used the HARMONIC FOCUS (Ethicon Endo-Surgery, Inc.) as ultrasonic scalpel. RESULTS: Between February 2010 and December 2010, 60 patients with resectable gastric cancer were enrolled into the study. Operative time was significantly shorter with the ultrasonic arm than with the conventional arm (median 238.5 vs. 300.5 min; P = 0.0004). Blood loss was also significantly lower in the ultrasonic arm than in the conventional arm (median 351.0 vs. 569.5 ml; P = 0.016). Clavien-Dindo grades of postoperative complications were similar in the two groups. From a questionnaire survey of operators, the ultrasonic scalpel significantly reduced the stress of lymph node dissection (3.67 vs. 2.87; P = 0.0006). However, in assisting surgeons, the contributions to surgery, study, and technical improvement of the ultrasonic group were lower than in the conventional group. CONCLUSIONS: This study shows that the ultrasonic scalpel is a reliable and safe tool for open gastric cancer surgery.

[A case study of advanced gastric cancer patient treated with S-1+paclitaxel/lentinan].

A 47 -year-old male presented with gastric cancer, with right cervical and para-aortic lymph node metastases. The patient had not undergone a curative operation, but was treated with immunochemotherapy in combination with S-1 60 mg/m2(2 weeks administration and 2 weeks rest), paclitaxel 60 mg/m²(day 1, 8, 15), and Lentinan 2mg/body(day 1, 8, 15). After 3 courses of this treatment, no hot-spots were identified on cervical and para-aorta lymph nodes by PET-CT examination. We decided to perform total gastrectomy with D3 lymphadenectomy and Roux-en Y reconstruction. On histopathological examination, no malignancy was seen in the lymph nodes and the main tumor was judged to be grade 2. With this combined immunochemotherapy, the patient had a favorable outcome without side effects, which proved effective for far advanced gastric cancer.

[A case of interstitial pneumonitis induced by S-1].

S-1, an oral fluoropyrimidine derivative, has been identified as an effective agent for the treatment of breast cancer. We present here a case of interstitial pneumonitis that occurred after S-1 treatment. A n 80-year-old woman was diagnosed with stage III infiltrating ductal carcinoma of the left breast and underwent a modified radical mastectomy in November 2001, followed by six courses of paclitaxel. In October 2008, metastatic disease was detected in her skeletal system. Therefore, S-1 chemotherapy was initiated (100 mg/body). Five days after starting S-1, she developed severe eruptions along with dyspnea. X-rays and CT scan showed diffuse ground glass shadow. Both her symptoms and the radiographic findings resolved dramatically after the start of high-dose corticosteroid therapy. Clinicians should be aware that S-1 has the potential to cause lung injury when it is included in chemotherapy.