Kohei Shigeta

Expression of Epidermal Growth Factor Receptor Detected by Cetuximab Indicates Its Efficacy to Inhibit In Vitro and In Vivo Proliferation of Colorectal Cancer Cells.

Cetuximab is a chimeric mouse–human monoclonal antibody that targets the human epidermal growth factor receptor (EGFR). However, EGFR expression determined by immunohistochemistry does not predict clinical outcomes of colorectal cancer (CRC) patients treated with cetuximab. Therefore, we evaluated the correlation between EGFR levels detected by cetuximab and drug sensitivities of CRC cell lines (Caco-2, WiDR, SW480, and HCT116) and the A431 epidermoid carcinoma cell line. We used flow cytometry (FCM) to detect EGFR-binding of biotinylated cetuximab on the cell surface. Subcloned cell lines showing the highest and lowest EGFR expression levels were chosen for further study. Cytotoxic assays were used to determine differential responses to cetuximab. Xenograft models treated with cetuximab intraperitoneally to assess sensitivity to cetuximab. Strong responses to cetuximab were specifically exhibited by subcloned cells with high EGFR expression levels. Furthermore, cetuximab inhibited the growth of tumors in xenograft models with high or low EGFR expression levels by 35% and 10%–20%, respectively. We conclude that detection of EGFR expression by cetuximab promises to provide a novel, sensitive, and specific method for predicting the sensitivity of CRC to cetuximab.

Randomized phase II trial of TEGAFIRI (tegafur/uracil, oral leucovorin, irinotecan) compared with FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) in patients with unresectable/recurrent colorectal cancer

Irinotecan‐based chemotherapy with bevacizumab is one of the first‐line standard therapies for metastatic colorectal cancer (mCRC). TEGAFIRI (UFT/LV + irinotecan) is an irinotecan‐based chemotherapy regimen. Currently, few clinical data regarding TEGAFIRI are available. This study evaluated the efficacy and safety of TEGAFIRI in Japanese patients with mCRC. This is a multicenter, randomized, phase II study. The major inclusion criteria were previously untreated patients with mCRC (age: 20–75 years, Eastern Cooperative Oncology Group performance status: 0–1). Eligible patients were randomly assigned (1:1) to receive either FOLFIRI ± bevacizumab or TEGAFIRI ± bevacizumab. The primary endpoint was progression‐free survival (PFS). The secondary endpoints were response rate, overall survival, dose intensity and toxicity. From November 2007 to October 2011, 36 and 35 patients assigned to the FOLFIRI and TEGAFIRI groups were included in the primary analysis. No significant difference in PFS was observed between the groups {median PFS: TEGAFIRI 9.9 months [95% confidence interval (CI), 6.5–14.7], FOLFIRI 10.6 months [95% CI, 7.7–16.5]; Hazard ratio, 0.98, 95% CI, 0.57–1.66, p = 0.930}. The response rates in the FOLFIRI and TEGAFIRI groups were 56% and 66%, respectively. Relative dose intensity was similar between the groups. The most common Grade 3/4 adverse event was diarrhea (26%) in TEGAFIRI group and neutropenia (39%) in the FOLFIRI group. The results of the present study indicate that TEGAFIRI ± bevacizumab is an effective and tolerable first‐line treatment regimen for mCRC.

Use of Angiotensin System Inhibitors is Associated with Immune Activation and Longer Survival in Non-Metastatic Pancreatic Ductal Adenocarcinoma

Purpose: Angiotensin system inhibitors (ASI) can improve prognosis in multiple cancer types, including pancreatic ductal adenocarcinoma (PDAC). However, no study has examined the effect of ASIs alone or combined with adjuvant chemotherapy in resected PDAC patients. Experimental Design: We performed an analysis of the records of ASI users and nonuser patients with PDAC seen at Massachusetts General Hospital (Boston, MA) between January 2006 and December 2010. To identify mechanisms of ASIs in PDAC, we performed RNA sequencing (RNA-Seq) of resected primary lesions. Results: A total of 794 consecutive patients were included. In 299 resected patients, ASI users experienced longer overall survival (OS) in both univariate (median OS, 36.3 vs. 19.3 months, P = 0.011) and adjusted multivariate [HR, 0.505; 95% confidence interval (CI), 0.339–0.750; P = 0.001] analyses. Propensity score–adjusted analysis also showed a longer median OS for chronic ASI users. In unresected patients, the beneficial effect of ASIs was significant in patients with locally advanced disease, but not in metastatic patients. RNA-Seq analysis revealed in tumors of ASI users (lisinopril) a normalized extracellular matrix, a reduced expression of genes involved in PDAC progression (e.g., WNT and Notch signaling), and an increased expression of genes linked with the activity of T cells and antigen-presenting cells. Finally, chronic use of ASI was associated with a gene expression signature that is predictive of survival in independent validation cohorts. Conclusions: In patients with nonmetastatic PDAC, chronic ASI use is associated with longer OS independently of chemotherapy. Our RNA-Seq analysis suggests that ASIs reduce the malignant potential of cancer cells and stimulate the immune microenvironment in primary PDAC. Clin Cancer Res; 23(19); 5959–69. ©2017 AACR.

Comparison of Preoperative Inflammation-based Prognostic Scores in Patients with Colorectal Cancer

Objective: To evaluate the prognostic impact of the systemic inflammation score (SIS) in colorectal cancer (CRC) patients in comparison with a conventional inflammation-based score, the modified Glasgow Prognostic Score (mGPS). Summary Background Data: The SIS, which is calculated based on the preoperative serum albumin level and lymphocyte-to-monocyte ratio, is a reported prognostic marker in clear-cell renal cell carcinoma. However, the utility of the SIS in CRC remains unclear. Methods: The study involved 727 CRC patients who underwent curative resection between September 2005 and December 2011. The prognostic impact of SIS and mGPS was evaluated using survival analyses. The prognostic impact of each score was compared visually by means of time-dependent receiver operating characteristics analysis. Results: The median age of the patients was 67 (interquartile range: 58–75) years. The TNM stage distribution was stage I, 29.8%; stage II, 33.6%; stage III, 30.3%; and stage IV, 6.3%. The median follow-up period was 5.61 years (interquartile range: 4.24–7.06). Multivariate analysis revealed that an increased SIS and mGPS were independent prognostic factors (SIS: P = 0.018; mGPS: P = 0.005, respectively). The time-dependent receiver operating characteristics curve of the SIS was superior to that of the mGPS throughout the observation period. The estimated area under the curve (AUC) of the SIS was significantly higher than that of the mGPS (7-yr survival: SIS 0.673, mGPS 0.605, P = 0.030). Conclusions: The SIS is a novel prognostic factor in CRC patients. Additionally, the SIS is an alternative inflammation-based biomarker, which may improve the prediction of clinical outcomes.

The impact of hepatic fibrosis on the incidence of liver metastasis from colorectal cancer

Background:The aim of this study was to clarify the influence of hepatic fibrosis on metachronous liver-specific recurrence in colorectal cancer (CRC) patients who underwent colorectal surgery with curative intent. Non-alcoholic steatohepatitis (NASH) is closely associated with hepatic fibrosis (HF). The number of patients who suffer from NASH is increasing because of the consumption of high-calorie diets. It remains unclear how much of an impact NASH and HF have on the development of liver metastasis in CRC.Methods:Patients who underwent curative surgical resection for CRC between 2000 and 2011 were included in this study. We evaluated the progression of HF by the non-alcoholic fatty liver disease fibrosis score (NFS) based on preoperative blood test results, age, body mass index, and diabetes mellitus. Patients were grouped according to high (fibrotic liver; FL) or low (normal liver; NL) NFS. The influence of HF on hepatic recurrence was assessed by survival analyses.Results:A total of 953 CRC patients were enrolled, comprising 293 in stage I, 327 in stage II, and 333 in stage III. The patients included were categorised as FL (77) or NL (876). The hepatic recurrence rates were 5.3% in the NL group and 10.4% in the FL group (P=0.02), whereas the overall recurrence rates were 16.0% in the NL group and 20.7% in the FL group (P=0.03). The 5-year liver-specific recurrence-free survival rate in the FL group was significantly poorer than that in the NL group (FL 89.1%, 95% confidence interval (CI) 78.4–94.7 vs NL 96.0%, 95% CI 94.3–97.2, log-rank test P<0.01). Multivariate analysis demonstrated that HF significantly promoted liver-specific recurrence compared with NL (HR=2.98, 95% CI 1.23–7.21; P=0.02).Conclusion:HF is a valuable prognostic factor for hepatic recurrence after curative surgical resection of CRC.

Metabolic Tumor Volume and Total Lesion Glycolysis in PET/CT Correlate With the Pathological Findings of Colorectal Cancer and Allow Its Accurate Staging.

Introduction PET/CT plays an important role in cancer diagnosis. Recently, novel metabolic parameters in PET/CT such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG) have been reported to be diagnostic and prognostic biomarkers of various cancers. We evaluated the diagnostic value of these metabolic parameters in colorectal cancer (CRC). Methods The study included 138 patients who underwent surgical resection of CRCs between August 2012 and March 2014. The MTVs and TLGs of tumors were measured using various SUV thresholds. The diagnostic abilities of the metabolic parameters were analyzed using ROC curves and classification and regression trees. Results The AUCs of the MTVs and TLGs for predicting T stage (0.881–0.892) were significantly higher than the AUC of the SUVmax (0.824). In the M stage, the AUCs of MTVs and TLGs (0.688–0.723) were significantly higher than that of the SUVmax (0.606). Recursive partitioning applying classification and regression trees demonstrated that the optimal cutoff values of the most important variables for discriminating T, N, and M stages are MTV2.5 = 9.35 and 63.33 mL, TLG50% = 328.1, and TLG50% = 94.81, respectively. Conclusion Metabolic tumor volumes and TLGs in PET/CT are reliable diagnostic biomarkers. Using these parameters, more accurate preoperative diagnoses for CRC can be made.

Reduced-port surgery for rectal cancer

Laparoscopic surgery for rectal cancer has short-term and long-term oncological outcomes similar to those of open surgery. Conventional multiport laparoscopic surgery (CMLS) for rectal cancer requires four or five abdominal incisions for trocars, each of which could lead to complications and/or pain. Single-incision laparoscopic surgery (SILS) would reduce the incidence of such wound-related complications and achieve better cosmetic outcomes relative to CMLS. The potential advantages of SILS are less pain and more rapid recovery than achieved with CMLS. However, SILS is rarely used for rectal cancer because of the high-level technical expertise required. Reduced-port laparoscopic surgery (RPS), which involves one additional port, may bridge the technical gap between CMLS and SILS and has a less steep learning curve. RPS for rectal cancer has a short history, and its usefulness has not yet been fully established. Here, we review the present situation, challenges, and future prospects for RPS for rectal cancer.

Anti-VEGFR Therapy as a Partner for Immune-Based Therapy Approaches in HCC

In hepatocellular carcinoma (HCC), chronic inflammation and vascular abnormalities often promote an environment characterized by hypoxia, immunosuppressive cell infiltration (M2-activated macrophages, T regulatory cells and myeloid-derived suppressor cells) and upregulation of immune checkpoints. These immunosuppressive cues lead to impaired effector CD8+ T lymphocyte infiltration and function, and ultimately to immune evasion. Reactivation of the immune response is critical to overcoming treatment resistance in HCC. Large clinical trials of anti-PD-1 blockade therapy are ongoing, and interim analyses showed promising responses in a subset of patients. The current challenge is to rationally combine anti-PD-1 antibodies with the existing drugs to substantially increase survival more broadly in HCC patients. Antiangiogenic multikinase inhibitors (sorafenib, regorafenib, lenvatinib) have shown efficacy in HCC. These drugs work in part by VEGF pathway inhibition in tumor endothelial cells, which can delay tumor growth. If the antivascular effects are too pronounced, treatment leads to increased hypoxia, inflammation, and fibrosis in the tumor tissues. These effects may affect anti-tumor immune response, which are critical for achieving durable treatment responses. Thus, successful implementation of combination therapies will require synergy between these interventions to reduce angiogenesis, modify vascular function, reverse the immunosuppressive environment and activate anti-tumor immunity in HCC.

Is preoperative spirometry a predictive marker for postoperative complications after colorectal cancer surgery

Background Spirometry is a basic test that provides much information about pulmonary function; it is performed preoperatively in almost all patients undergoing colorectal cancer (CRC) surgery in our hospital. However, the value of spirometry as a preoperative test for CRC surgery remains unknown. The aim of this study was to determine whether spirometry is useful to predict postoperative complications (PCs) after CRC surgery. Methods The medical records of 1236 patients who had preoperative spirometry tests and underwent CRC surgery between 2005 and 2014 were reviewed. Preoperative spirometry results, such as forced vital capacity (FVC), one-second forced expiratory volume (FEV1), %VC (FVC/predicted VC) and FEV1/FVC (%FEV1), were analyzed with regard to PCs, including pneumonia. Results PCs were found in 383 (30.9%) patients, including 218 (56%) with surgical site infections, 67 (17%) with bowel obstruction, 62 (16%) with leakage and 20 (5.2%) with pneumonia. Of the spirometry results, %VC was correlated with PC according to logistic regression analysis (odds ratio, OR = 0.99, 95% confidence interval, CI = 0.98-0.99; P = 0.034). Multivariate analysis after adjusting for male sex, age, laparoscopic surgery, tumor location, operation time and blood loss showed that a lower %VC tends to be a risk factor for PC (OR = 0.99, 95% CI = 0.98-1.002; P = 0.159) and %VC was an independent risk factor for postoperative pneumonia in PCs (OR = 0.97, 95% CI = 0.94-0.99; P = 0.049). Conclusions In CRC surgery, %VC may be a predictor of postoperative complications, especially pneumonia.

The use of laparoscopic rectopexy to manage rectal prolapse with Pseudo‐Meigs’ syndrome in a 64‐year‐old female: a case report

We report a rare case of rectal prolapse with Pseudo‐Meigs’ syndrome in which laparoscopic bilateral oophorectomy and rectopexy were performed simultaneously and resulted in improved quality of life due to the loss of ascites and the repair of rectal prolapse. Laparoscopic surgery is feasible for rectal prolapse with Pseudo‐Meigs’ syndrome.