Antitumor effects of Andrographis via ferroptosis-associated genes in gastric cancer.

The overall prognosis of advanced/metastatic gastric cancer (GC) remains poor despite the development of pharmacotherapy. Therefore, other treatment options, such as complementary and alternative medicine, should be considered to overcome this aggressive malignancy. Andrographis, which is a generally unharmful botanical compound, has gained increasing interest for its anticancer effects in multiple malignancies via the regulation of cancer progression-associated signaling pathways. In the present study, a series of in vitro experiments (cell proliferation, colony formation and apoptosis assays) was designed to elucidate the antitumor potential and mechanism of Andrographis in GC cells. The present study demonstrated that Andrographis exerted antitumor effects in GC cell lines (MKN74 and NUGC4) by inhibiting proliferation, reducing colony formation and enhancing apoptotic activity. Furthermore, it was demonstrated that the expression levels of the ferroptosis-associated genes heme oxygenase-1, glutamate-cysteine ligase catalytic and glutamate-cysteine ligase modifier were significantly upregulated after Andrographis treatment in both GC cell lines in reverse transcription-quantitative PCR experiments (P<0.05); this finding was further confirmed by immunoblotting assays (P<0.05). In conclusion, to the best of our knowledge, the present study was the first to demonstrate that Andrographis possessed antitumor properties by altering the expression levels of ferroptosis-associated genes, thereby providing novel insights into the potential of Andrographis as an adjunctive treatment option for patients with metastatic GC.

Laparoscopic removal of an aberrant acupuncture needle in the gluteus that reached the pelvic cavity: a case report.

BACKGROUND: Intrapelvic aberrant needles are rare in clinical practice. Long-term foreign bodies in the abdominal cavity may form granulation tissue or an abscess, and may cause organ injury. Therefore, such foreign bodies need prompt removal. CASE PRESENTATION: A 26-year-old male athlete was referred to our hospital for investigation of an aberrant acupuncture needle in the gluteus. The needle was unable to be removed during acupuncture treatment, and the end broke off and remained in the gluteus. Abdominal X-ray examination showed a thin, 40-mm-long, metallic foreign body resembling an acupuncture needle. Abdominal computed tomography showed an abnormal shadow in the gluteus. However, it was unclear whether the tip of the needle reached the pelvic cavity. Thus, it was decided to surgically extract the needle via laparoscopic surgery under X-ray guidance as a safe and minimally invasive method. Although X-ray fluoroscopy confirmed that the aberrant needle was located in the gluteus, the needle could not be felt with the forceps, as the peritoneum surrounding the needle had granulomatous changes due to inflammation. Therefore, the retroperitoneum was further dissected to search for the needle. Once the needle was identified, its flexibility enabled it to be easily removed by grasping it directly with a needle holder. The length of the aberrant needle was 40 mm. The postoperative course was uneventful, and the patient was discharged from hospital on postoperative day 2. CONCLUSIONS: When a foreign body remains in the gluteus and its tip touches intrapelvic organs, such as the rectum, it is critical to determine the best approach for its safe removal. Given the anatomical location of the foreign body and the patient background, laparoscopic removal was considered the best approach in the present case.

Identification of Predictors of Recurrence in Patients with Lower Rectal Cancer Undergoing Neoadjuvant Chemotherapy: A Direct Comparison of Short-Course and Long-Course Chemoradiotherapy.

OBJECTIVE: This study aimed to investigate clinicopathological responses and oncological outcome in patients receiving short- or long-course chemoradiotherapy (CRT) and to assess the predictive factor for recurrence in each treatment. METHODS: A total of 118 rectal cancer patients receiving preoperative CRT were enrolled. Clinicopathological responses and oncological outcome in patients receiving short- or long-course CRT were investigated. RESULTS: Despite there being no significant differences in the prognosis of disease-free survival (DFS) based on TNM stage classification in patients receiving long-course CRT, patients with advanced stage demonstrated poor DFS after short-course CRT. The presence of lymph node metastasis was a predictor of poor DFS in short-course CRT, whereas poor pathological response was a predictor of recurrence in long-course CRT. CONCLUSIONS: Distinct predictors of recurrence depending on the CRT course might be needed to discriminate candidates from rectal cancer patients receiving preoperative CRT who might benefit from more intensive adjuvant therapy after surgery.

Fish oil-enriched nutrition combined with systemic chemotherapy for gastrointestinal cancer patients with cancer cachexia.

Despite recent advances in chemotherapy for gastrointestinal cancer, a crucial factor related to poor prognosis is reduced tolerance to chemotherapy induced by cancer cachexia. Fish oil (FO)-derived eicosapentaenoic acid (EPA) modulates inflammation in patients with various malignancies; however, the impact of FO-enriched nutrition as a combined modality therapy on clinical outcomes remains controversial. We systemically analysed chronological changes in biochemical and physiological status using bioelectrical impedance analysis in 128 gastrointestinal cancer patients provided with or without FO-enriched nutrition during chemotherapy. Furthermore, we evaluated the clinical significance of FO-enriched nutrition and clarified appropriate patient groups that receive prognostic benefits from FO-enriched nutrition during treatment of gastrointestinal cancer. The control group showed significant up-regulation of serum CRP) levels and no significant difference in both skeletal muscle mass and lean body mass. In contrast, the FO-enriched nutrition group showed no changes in serum CRP concentration and significantly increased skeletal muscle mass and lean body mass over time. Furthermore, high CRP levels significantly correlated with reduced tolerance to chemotherapy, and FO-enriched nutrition improved chemotherapy tolerance and prognosis, particularly in gastrointestinal cancer patients with a modified Glasgow prognostic score (mGPS) of 1 or 2. We conclude that FO-enriched nutrition may improve the prognosis of patients with cancer cachexia and systemic inflammation (i.e., those with a mGPS of 1 or 2).

Puborectal sling interposition combined with seton drainage for pouch-vaginal fistula after rectal cancer surgery with colonic J pouch-anal reconstruction: report of a case.

The management of postoperative rectovaginal fistula (RVF) after rectal cancer surgery is difficult and requires reconstruction of the anastomotic site and fistula. Though various surgical procedures have been reported for the repair of RVFs, the results of surgical repair are often unsatisfactory, and failure of the initial repair leads to difficulty in the later operations. Furthermore, it has been reported that cases associated with local infection result in low success rates. We report a case of an 80-year-old woman with a recurrent colonic J pouch-vaginal fistula after anoabdominal rectal resection with partial internal sphincteric resection, who achieved a good outcome following a repair using a puborectal sling interposition combined with seton drainage. It may be a useful option for RVF management in repair of such pouch-vaginal fistula after coloanal anastomosis with intersphincteric resection.

Podoplanin and SOX2 expression in esophageal squamous cell carcinoma after neoadjuvant chemo-radiotherapy.

Neoadjuvant chemo-radiotherapy (CRT) followed by surgery are the standard approaches for locally advanced esophageal cancer. However, the overall cure rate is very low. The aim of this preliminary study was to evaluate the expression of podoplanin and SOX2 known as stemness markers for esophageal squamous cell carcinoma (ESCC) and their association with clinical outcome. We obtained a total of 20 specimens from patients with ESCC who underwent neoadjuvant CRT (30-40 Gy; 5-fluorouracil plus cisplatin) followed by surgery. Podoplanin and SOX2 expression was evaluated using immunohistochemistry and the association of their expressions with clinicopathological variables was investigated. Podoplanin and SOX2 staining was detected not only in residual cancer cells, but also in the basal layer of adjacent normal mucosa after neoadjuvant CRT. High expression of podoplanin was correlated with lymph node metastasis, advanced postoperative stage and vascular invasion (P<0.05), while, high expression of SOX2 was correlated with lymphatic, vascular invasion, poor differentiated tumor and incomplete resection (P<0.05). High expression of podoplanin was significantly associated with poor overall survival (P<0.05). In conclusion, the expression levels of podoplanin and SOX2 expression may be useful prognostic markers for ESCC treated with neoadjuvant CRT.

Possibility of paclitaxel as an alternative radiosensitizer to 5-fluorouracil for colon cancer.

To evaluate the feasibility of paclitaxel (PTX) radiosensitization for colon cancer, we investigated the cytotoxic and G2/M checkpoint protein (Chk1, Wee1, Bub1, MAD2) effects of 5-fluorouracil (5-FU) or PTX combined with radiation in the human colon cancer cell line LoVo. Cytotoxicity and radiocytotoxicity were evaluated for each drug by the WST-8 colorimetric assay. The IC20 for each drug was determined as a cytotoxic concentration from a survival curve. LoVo cells were exposed to the IC20 of each drug for 24 h and then irradiated. Expressions of the G2/M checkpoint proteins were confirmed by Western blot analysis. Cytotoxicity was induced by 5-FU or PTX alone in a time- and dose-dependent manner. The IC20 of PTX caused higher radiosensitivity than the IC20 of 5-FU (P<0.05). Western blot analysis revealed different expression patterns of the G2/M checkpoint proteins between 5-FU and PTX pre-treatments. 5-FU combined with radiation tended to decrease the expressions of all G2/M checkpoint proteins in a time-dependent manner. PTX combined with radiation maintained high expressions of Chk1 and MAD2 proteins for 24 h post-radiation and, in particular, MAD2 protein was strongly induced by PTX with high-dose radiation. PTX showed higher radio-sensitization than 5-FU for the colon cancer cell line LoVo and may be an alternative radiosensitizer to 5-FU in the clinical setting.

Clinical significance of the gene expression profile in residual tumor cells after neoadjuvant chemo-radiotherapy for esophageal cancer.

Recurrence after neoadjuvant chemo-radiotherapy (CRT) followed by surgery is high in patients with esophageal cancer. No standard second line therapy is currently available for patients with recurrence. This study aimed to evaluate the expression of chemo-radiosensitive genes after neoadjuvant CRT in residual tumor cells. Thirteen patients with esophageal squamous cell carcinoma underwent 5-fluorouracil (5-FU) and cisplatin (CDDP) based CRT followed by surgery. Total RNA was successfully obtained from 6 formalin-fixed paraffin-embedded (FFPE) specimens using proteinase K digestion and phenol chloroform extraction. TS and DPD as the 5-FU pathway gene, ERCC1 as the CDDP pathway gene, and EGFR, VEGF, HIF1a as radioresistant genes were measured using real-time reverse transcription polymerase chain reaction; comparing the mRNA level of each gene in pre-CRT biopsy with that in post-CRT FFPE specimens. Five patients had less than one-third residual tumor cells in resected specimens histopathologically; eight had more than two-thirds residual tumor cells. There were significant increases in TS (p=0.02) and DPD (p=0.01) levels in residual tumor cells after CRT. Significant decreases in ERCC1 (p=0.03), EGFR (p=0.01), VEGF (p=0.003) and HIF1a (p=0.003) levels were observed. 5-FU and CDDP based CRT up-regulated 5-FU pathway genes and down-regulated CDDP pathway and radioresistant genes. The expression of chemo-radiosensitive genes was significantly changed in residual tumor cells after CRT. Gene expression analysis of residual tumor cells in FFPE specimens may be useful when selecting a second line chemotherapy regimen for recurrent esophageal cancer after CRT.

Preoperative C-reactive protein as a prognostic and therapeutic marker for colorectal cancer.

BACKGROUND AND OBJECTIVES: This study aimed to evaluate the significance of preoperative C-reactive protein (CRP) as a prognostic marker for carcinoembryonic antigen (CEA)-independent stage I or II colorectal cancer (CRC) patients. METHODS: Preoperative CRP was measured in 300 CRC patients to assess its relationships with clinicopathological factors and long-term survival. Based on the results of the initial study, the relationship between preoperative CRP and long-term survival was evaluated with reference to adjuvant 5-fluorouracil (5-FU)-based chemotherapy in a further 128 stage II patients. RESULTS: CRP was associated with disease progression and factors reflecting nutritional depletion such as serum albumin, lymphocyte count and body weight loss ratio. In stage I or II patients, CRP could predict early disease recurrence, even when a CEA test could not. Multivariate analyses revealed that CRP was an independent prognostic variable in stage I or II patients. In the additional 128 stage II patients, CRP-positive patients showed a 3-year survival rate of only 55% without adjuvant chemotherapy, but this increased to 90% with adjuvant chemotherapy. CONCLUSIONS: CRP may be a potent prognostic and therapeutic indicator that provides valuable information for determining the need for adjuvant chemotherapy in stage II CRC patients.

Mechanism of resistance to chemoradiation in p53 mutant human colon cancer.

To understand one of the mechanisms of resistance to chemoradiation in colon cancer cells, we investigated whether 5-fluorouracil (5-FU) mediated the expression of epidermal growth factor receptor (EGFR) and modified repair of radiation-induced DNA damage, especially in a p53 independent pathway. Cytotoxicity was determined for 5-FU combined with radiation for three colon cancer cell lines that contain mutant p53 (SW480, HT29 and WiDr), using the WST-8 colorimetric assay. EGFR and the excision repair cross complementation group 1 (ERCC1) proteins during chemoradiation were measured by Western blot analysis. SW480 cells were significantly resistant to chemoradiation compared to the other mutant p53 cell lines. The alteration of EGFR and ERCC1 proteins during chemoradiation in SW480 was apparently inversely related to that of the other radiosensitive cell lines. 5-FU-induced activation of EGFR followed by radiation in SW480 cells resulted in up-regulation of ERCC1. In contrast, 5-FU-induced degradation of EGFR followed by radiation in the other radiosensitive cell lines resulted in down-regulation of ERCC1. This suggested a complementary interaction between EGFR and ERCC1, and that 5-FU-induced EGFR activation conferred protection against radiation, through activation of DNA repair. Interaction of EGFR and ERCC1 might correlate with radiation-induced DNA damage when p53 mutant colon cancer cell lines are exposed to 5-FU followed by radiation.

Preoperative steroid-related complications in Japanese pediatric patients with ulcerative colitis.

PURPOSE: This study was designed to clarify a limit for steroid therapy in patients with ulcerative colitis through analyzing the preoperative major steroid-related complications and to define when alternative therapies, including surgery, should be performed in pediatric ulcerative colitis patients. METHODS: The medical records of 28 pediatric and 57 adult patients with ulcerative colitis who underwent total proctocolectomy and ileal J-pouch-anal anastomosis were reviewed. The relationship between the preoperative dose of glucocorticoids and major steroid-related complications, as well as the surgery variables, was evaluated. RESULTS: Significantly higher incidences of growth retardation, osteoporosis, glaucoma, and cataracts were noted in pediatric patients than in adult patients. In pediatric patients, major steroid-related complications occurred at a significantly lower preoperative total dosage of glucocorticoids/body weight (mg/kg) or preoperative total dosage of glucocorticoids/body surface area (mg/m2) than in adult patients. A similar surgical procedure was performed in both pediatric and adult patients. The presence of major steroid-related complications can lower a patient's long-term quality of life. CONCLUSIONS: Evidence-based guidelines for the recommended dose of glucocorticoids according to body weight or body surface area are needed. To allow patients to feel well and maintain a good quality of life, early introduction of alternative treatments, including surgery, should be considered.