Enhancement of target toxin neutralization effect in vivo by PEGylation of multifunctionalized lipid nanoparticles.

Protein-protein (e.g., antibody-antigen) interactions comprise multiple weak interactions. We have previously reported that lipid nanoparticles (LNPs) bind to and neutralize target toxic peptides after multifunctionalization of the LNP surface (MF-LNPs) with amino acid derivatives that induce weak interactions; however, the MF-LNPs aggregated after target capture and showed short blood circulation times. Here we optimized polyethylene glycol (PEG)-modified MF-LNPs (PEG-MF-LNPs) to inhibit the aggregation and increase the blood circulation time. Melittin was used as a target toxin, and MF-LNPs were prepared with negatively charged, hydrophobic, and neutral amino-acid-derivative-conjugated functional lipids. In this study, MF-LNPs modified with only PEG5k (PEG5k-MF-LNPs) and with both PEG5k and PEG2k (PEGmix-MF-LNPs) were prepared, where PEG5k and PEG2k represent PEG with a molecular weight of 5000 and 2000, respectively. PEGylation of the MF-LNPs did not decrease the melittin neutralization ability of nonPEGylated MF-LNPs, as tested by hemolysis assay. The PEGmix-MF-LNPs showed better blood circulation characteristics than the PEG5k-MF-LNPs. Although the nonPEGylated MF-LNPs immediately aggregated when mixed with melittin, the PEGmix-MF-LNPs did not aggregate. The PEGmix-MF-LNPs dramatically increased the survival rate of melittin-treated mice, whereas the nonPEGylated MF-LNPs increased slightly. These results provide a fundamental strategy to improve the in vivo toxin neutralization ability of MF-LNPs.

Dual Programmed Death Receptor-1 and Vascular Endothelial Growth Factor Receptor-2 Blockade Promotes Vascular Normalization and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Activation of the antitumor immune response using programmed death receptor-1 (PD-1) blockade showed benefit only in a fraction of patients with hepatocellular carcinoma (HCC). Combining PD-1 blockade with antiangiogenesis has shown promise in substantially increasing the fraction of patients with HCC who respond to treatment, but the mechanism of this interaction is unknown. APPROACH AND RESULTS: We recapitulated these clinical outcomes using orthotopic-grafted or induced-murine models of HCC. Specific blockade of vascular endothelial receptor 2 (VEGFR-2) using a murine antibody significantly delayed primary tumor growth but failed to prolong survival, while anti-PD-1 antibody treatment alone conferred a minor survival advantage in one model. However, dual anti-PD-1/VEGFR-2 therapy significantly inhibited primary tumor growth and doubled survival in both models. Combination therapy reprogrammed the immune microenvironment by increasing cluster of differentiation 8-positive (CD8+ ) cytotoxic T cell infiltration and activation, shifting the M1/M2 ratio of tumor-associated macrophages and reducing T regulatory cell (Treg) and chemokine (C-C motif) receptor 2-positive monocyte infiltration in HCC tissue. In these models, VEGFR-2 was selectively expressed in tumor endothelial cells. Using spheroid cultures of HCC tissue, we found that PD-ligand 1 expression in HCC cells was induced in a paracrine manner upon anti-VEGFR-2 blockade in endothelial cells in part through interferon-gamma expression. Moreover, we found that VEGFR-2 blockade increased PD-1 expression in tumor-infiltrating CD4+ cells. We also found that under anti-PD-1 therapy, CD4+ cells promote normalized vessel formation in the face of antiangiogenic therapy with anti-VEGFR-2 antibody. CONCLUSIONS: We show that dual anti-PD-1/VEGFR-2 therapy has a durable vessel fortification effect in HCC and can overcome treatment resistance to either treatment alone and increase overall survival in both anti-PD-1 therapy-resistant and anti-PD-1 therapy-responsive HCC models.

Usefulness of laparoscopic surgery and preoperative examinations for chronic recurrent small bowel obstruction.

PURPOSE: The aim of this study was to investigate the usefulness of laparoscopic surgery for patients with postoperative abdominal symptoms, including chronic recurrent small-bowel obstruction (SBO), and preoperative examinations of barium follow-through and computed tomography (CT) to predict the postoperative outcomes of laparoscopic surgery. METHODS: Between 2016 and 2018, 49 patients with postoperative symptoms were treated by laparoscopic surgery at our institute. The data from two preoperative examinations were available for 42 patients. The patients were divided into 4 groups: CT-positive (CP, n = 18), barium follow-through-positive (BP, n = 1), both positive (AP [all positive] n = 13), and both negative (AN [all negative], n = 10). RESULTS: Among the 49 patients, 41 received pure laparoscopic surgery, 7 received laparoscopic-assisted surgery with mini-laparotomy, and 1 required conversion. Intra- and postoperative complications occurred in two and seven patients, respectively. Improvement of abdominal symptoms was observed in 40 patients. In terms of the medium-term outcomes, the rate of improvement of symptoms was poorer in the AN group than in the other three groups, but not to a significant degree. CONCLUSION: Laparoscopic surgery was safe and feasible for patients with chronic recurrent abdominal symptoms, including SBO. Furthermore, in patients with negative results on both preoperative examinations, laparoscopic surgery may yield only poor improvement of symptoms.

Improving Selection for Resection of Synchronous Para-Aortic Lymph Node Metastases in Colorectal Cancer.

INTRODUCTION: The clinical benefit of extended lymphadenectomy for synchronous extraregional lymph node metastasis, such as para-aortic lymph node (PALN) metastasis in colorectal cancer, remains highly controversial. AIM: To evaluate the clinical benefit of PALN dissection in colorectal cancer patients with synchronous PALN metastasis with or without multiorgan metastases. METHODS: Thirty-six patients with pathologically positive PALN metastasis below the renal veins who underwent concurrent PALN dissection and primary colorectal cancer resection from January 1984 through September 2011 at the National Cancer Center Hospital in Tokyo, Japan, were included in this retrospective cohort study. We examined 5-year recurrence-free survival (RFS) rates in patient groups depending on the number of nodes involved (≤2 and ≥3 nodes) and on the presence or absence of other organ involvement (M1a and M1b,c categories in TNM staging). RESULTS: The 5-year RFS rate was significantly different depending on the number of metastatic PALNs (42.1 and 0.6% for PALN ≤2 and ≥3, respectively, p = 0.01). The 5-year RFS rate was significantly better in patients in the M1a category than in patients in the M1b and M1c categories (27.6 and 0.0%, respectively, p < 0.01). Twenty-nine patients (80.6%) experienced recurrence after PALN dissection. Postoperative complications were seen in 14 (38.9%) patients. CONCLUSION: PALN dissection below the renal veins for patients with isolated PALN metastasis with 2 or fewer involved PALNs may be effective in improving prognosis in colorectal cancer.

Long-Term Outcomes After R0 Resection of Synchronous Peritoneal Metastasis from Colorectal Cancer Without Cytoreductive Surgery or Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: The National Comprehensive Cancer Network (NCCN) guidelines for colon cancer recently added the following footnote regarding the therapeutic strategy for peritoneal metastases: "If R0 resection can be achieved, surgical resection of isolated peritoneal disease may be considered at experienced centers." This study investigated the efficacy of R0 resection of peritoneal metastasis from colorectal cancer without cytoreductive surgery or hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: This retrospective cohort study was conducted at a single-institution tertiary care cancer center. Among 496 consecutive M1c colorectal cancer patients, R0 resection was achieved for 94 patients (19%). The subjects were 78 consecutive patients with colorectal cancer and simultaneous peritoneal metastasis but no other distant metastases who underwent R0 resection at the National Cancer Center Hospital from 1971 to 2016 (16% of all M1c patients). Overall survival (OS) was investigated, and clinicopathologic variables were analyzed for prognostic significance. RESULTS: No perioperative mortality was noted. The 3-year OS rate was 45%, and the 5-year OS rate was 28.7%. The median survival time was 33.4 months. Notably, 17 patients survived for more than 5 years, and 9 of these patients did not receive any chemotherapy. Multivariate analysis showed cancer location in the colon and harvesting of 12 or more lymph nodes to be independent factors associated with a better prognosis. CONCLUSIONS: From the perspective of long-term outcomes and no perioperative mortality, R0 resection of peritoneal metastasis from colorectal cancer, without complete peritonectomy or HIPEC, appeared to be an acceptable therapeutic option for some patients with peritoneal metastasis.

Prognostic Impact of R0 Resection and Targeted Therapy for Colorectal Cancer with Synchronous Peritoneal Metastasis.

BACKGROUND: The National Comprehensive Cancer Network guidelines recommend R0 resection and targeted therapy, a combination of cytotoxic and molecular targeted agents, such as bevacizumab, cetuximab, and panitumumab, for colorectal cancer with synchronous peritoneal metastasis (M1c). While these therapeutic strategies are drawing attention, their efficacy has not been fully examined. METHODS: The study population comprised 248 consecutive M1c patients who were treated at the National Cancer Center Hospital from 1997 to 2013. Multivariate analyses were performed to evaluate relationships between overall survival and R0 resection and targeted therapy using Cox proportional hazards regression models. RESULTS: The 3-year overall survival (3 yOS) was 19.5%, and median survival time (MST) was 16.2 months in 248 M1c patients. R0 resection was performed in 34 patients (14%), yielding a 3-year overall survival (OS) of 48.3% and median survival time (MST) of 29.9 months. Targeted therapy was performed in 54 patients (22%) at least once during the course of treatment, yielding a 3-yr OS of 38.2% and MST of 23.9 months. After adjusting for other key clinical factors, such as the number of organs involved with metastases, performance status, primary tumor site, and extent of peritoneal metastasis, both R0 resection and targeted therapy were independent factors associated with longer OS. Targeted therapy was associated with a significantly longer OS compared with multiple cytotoxic agent therapy [hazard ratio 0.65; 95% confidence interval (0.44-0.94); p = 0.02]. CONCLUSIONS: If achievable, R0 resection is a desirable therapeutic strategy for patients with M1c colorectal cancer. Moreover, targeted therapy might be the optimal chemotherapy in this patient population.

ROK study-C (Rainbow of KIBOU study-colorectum): a colorectal cancer survivor cohort study on food, nutrition, physical activity, psychosocial factors and its influences on colorectal cancer recurrence, survival and quality of life in Japan.

BACKGROUND: Many studies have shown that lifestyle factors such as diet, physical activity are related to the incidence of cancer. However, there are few studies on the association between lifestyle factors and cancer prognosis. To investigate the influence of lifestyle factors and psychosocial factors on prognosis, we started a prospective study of women with breast cancer, the Rainbow of KIBOU study-Breast (ROK Study-B) in 2007. As of February 2018, more than 6300 women have been enrolled, thus making this one of the world's largest cancer patient cohort studies. Based on the know-how obtained from this study, we started another new cohort study for colorectal cancer patient (ROK Study-C). METHODS: The ROK Study-C is a prospective observational study for colorectal cancer survivors at the National Cancer Center Hospital. Participants fill in several self-administrated questionnaires about lifestyle, psychosocial factors (including posttraumatic growth and benefit finding, support), and quality of life (QOL) 5 times in total: at diagnosis, 3 and 6 months, 1 and 5 years after surgery. CT-scans will be collected to assess body composition and obesity. We also use blood and cancer tissue from the Biobank. The primary endpoint is disease-free survival. The secondary endpoints are overall survival and health-related QOL. The planned sample size is 2000 and the follow-up period is 5 years after the last enrollment. DISCUSSION: Recruitment began in December 2015 and the study is still ongoing. The ROK Study-C will contribute to improvements in patient prognosis and yield important evidence for colorectal cancer survivorship.

Shorter survival in adolescent and young adult patients, compared to adult patients, with stage IV colorectal cancer in Japan.

BACKGROUND: The incidence of colorectal cancer in adolescent and young adult patients is increasing. However, survival and clinical features of young patients, especially those with stage IV disease, relative to adult patients remain unclear. METHODS: This retrospective single-institution cohort study was conducted at a tertiary care cancer center. Subjects were 861 consecutive patients who were diagnosed with stage IV colorectal cancer at the age of 15 to 74 years and who were referred to the division of surgery or gastrointestinal oncology at the National Cancer Center Hospital from 1999 to 2013. Overall survival (OS) was investigated and clinicopathological variables were analyzed for prognostic significance. RESULTS: Of these, 66 (8%) were adolescent and young adult patients and 795 (92%) were adult patients. Median survival time was 13.6 months in adolescent and young adult patients and 22.4 months in adult patients, and 5-year OS rates were 17.3% and 20.3%, respectively, indicating significant worse prognosis of adolescent and young adult patients (p = 0.042). However, age itself was not an independent factor associated with prognosis by multivariate analysis. When compared with adult patients, adolescent and young adult patients consisted of higher proportion of the patients who did not undergo resection of primary tumor, which was an independent factor associated with poor prognosis in multivariate analysis. In patients who did not undergo resection (n = 349), OS of adolescent and young adult patients were significantly worse (p = 0.033). CONCLUSIONS: Prognoses were worse in adolescent and young adult patients with stage IV colorectal cancer compared to adult patients in Japan, due to a higher proportion of patients who did not undergo resection with more advanced and severe disease, but not due to age itself.

Intersphincteric Resection Has Similar Long-term Oncologic Outcomes Compared With Abdominoperineal Resection for Low Rectal Cancer Without Preoperative Therapy: Results of Propensity Score Analyses.

BACKGROUND: Intersphincteric resection has been performed for very low rectal cancer in place of abdominoperineal resection to avoid permanent colostomy. OBJECTIVE: This study aimed to evaluate long-term oncologic outcomes of intersphincteric resection compared with abdominoperineal resection. DESIGN: In this retrospective study, propensity score matching and stratification analyses were performed to reduce the effects of confounding factors between groups, including age, sex, BMI, CEA value, tumor height, tumor depth, lymph node enlargement, and circumferential resection margin measured by MRI. SETTING: A database maintained at our institute was used to identify patients during the period between 2000 and 2014. PATIENTS: A total of 285 patients who underwent curative intersphincteric resection (n = 112) or abdominoperineal resection (n = 173) for stage I to III low rectal cancer without preoperative chemoradiotherapy were enrolled in this study. MAIN OUTCOME MEASURE: The main outcome was recurrence-free survival. RESULTS: Patients in the abdominoperineal resection group were more likely to have a preoperative diagnosis of advanced cancer before case matching. After case matching, clinical outcomes were similar between intersphincteric resection and abdominoperineal resection groups. Five-year relapse-free survival rates were 69.9% for the intersphincteric resection group and 67.9% for abdominoperineal resection group (p = 0.64), and were similar in the propensity score-matched cohorts (89 matched pairs). Three-year cumulative local recurrence rates were 7.3% for intersphincteric resection and 3.9% for abdominoperineal resection (p = 0.13). In the propensity score-matched model, the hazard ratio for recurrence after intersphincteric resection in comparison with abdominoperineal resection was 0.90. Stratification analysis revealed similar recurrence rates (HR, 0.75-1.68) for intersphincteric resection in comparison with abdominoperineal resection. LIMITATION: Eight covariates were incorporated into the model, but other covariates were not included. CONCLUSIONS: Our findings suggest similar oncologic outcomes for intersphincteric resection and abdominoperineal resection without preoperative chemoradiotherapy in patients with low rectal cancer adjusted for background variables. See Video Abstract at http://links.lww.com/DCR/A661.

Preoperative T staging using CT colonography with multiplanar reconstruction for very low rectal cancer.

BACKGROUND: Preoperative T staging of lower rectal cancer is an important criterion for selecting intersphincteric resection (ISR) or abdominoperineal resection (APR) as well as selecting neoadjuvant therapy. The aim of this study was to evaluate the accuracy of preoperative T staging using CT colonography (CTC) with multiplanar reconstruction (MPR), in which with the newest workstation the images can be analyzed with a slice thickness of 0.5 mm. METHODS: Between 2011 and 2013, 45 consecutive patients with very low rectal adenocarcinoma underwent CTC with MPR. The accuracy of preoperative T staging using CTC with MPR was evaluated. The accuracy of preoperative T staging using MRI in the same patient population (34 of 45 patients) was also examined. RESULTS: Overall accuracy of T staging was 89% (41/45) for CTC with MPR and 71% (24/34) for MRI. CTC with MPR was particularly sensitive for pT2 tumors (82%; 14/17), whereas MRI tended to overstage pT2 tumors and its sensitivity for pT2 was 53% (8/15). CONCLUSIONS: CTC with MPR, with an arbitrary selection, could be aligned to the tumor axis and better demonstrated tumor margins consecutively including the deepest section of the tumor. The accuracy of T2 and T3 staging using CTC with MPR seemed to surpass that of MRI, suggesting a potential role of CTC with MPR in preoperative T staging for very low rectal cancer.

Prognostic Impact of Intra-abdominal/Pelvic Inflammation After Radical Surgery for Locally Recurrent Rectal Cancer.

BACKGROUND: The influence of postoperative infectious complications, such as anastomotic leakage, on survival has been reported for various cancers, including colorectal cancer. However, it remains unclear whether intra-abdominal/pelvic inflammation after radical surgery for locally recurrent rectal cancer is relevant to its prognosis. OBJECTIVE: The purpose of this study was to evaluate factors associated with survival after radical surgery for locally recurrent rectal cancer. DESIGN: The prospectively collected data of patients were retrospectively evaluated. SETTINGS: This study was conducted at a single-institution tertiary care cancer center. PATIENTS: Between 1983 and 2012, patients who underwent radical surgery for locally recurrent rectal cancer with curative intent at the National Cancer Center Hospital were reviewed. MAIN OUTCOME MEASURES: Factors associated with overall and relapse-free survival were evaluated. RESULTS: During the study period, a total of 180 patients were eligible for analyses. Median blood loss and operation time for locally recurrent rectal cancer were 2022 mL and 634 minutes. Five-year overall and 3-year relapse-free survival rates were 38.6% and 26.7%. Age (p = 0.002), initial tumor stage (p = 0.03), pain associated with locally recurrent rectal cancer (p = 0.03), CEA level (p = 0.004), resection margin (p < 0.001), intra-abdominal/pelvic inflammation (p < 0.001), and surgery period (p = 0.045) were independent prognostic factors associated with overall survival, whereas CEA level (p = 0.01), resection margin (p = 0.002), and intra-abdominal/pelvic inflammation (p = 0.001) were associated with relapse-free survival. Intra-abdominal/pelvic inflammation was observed in 45 patients (25.0%). A large amount of perioperative blood loss was the only factor associated with the occurrence of intra-abdominal/pelvic inflammation (p = 0.007). LIMITATIONS: This study was limited by its retrospective nature and heterogeneous population. CONCLUSIONS: Intra-abdominal/pelvic inflammation after radical surgery for locally recurrent rectal cancer is associated with poor prognosis. See Video Abstract at http://journals.lww.com/dcrjournal/Pages/videogallery.aspx.

Comparison of the clinical results of abdominoperanal intersphincteric resection and abdominoperineal resection for lower rectal cancer.

BACKGROUND: The aim of this study was to compare the oncologic results of abdominoperanal intersphincteric resection (ISR) and abdominoperineal resection (APR). METHODS: Between 2003 and 2014, 277 consecutive patients with stage I-III low rectal cancer located within 5 cm from the anal verge underwent curative ISR and APR. A retrospective comparison of these two procedures was performed. RESULTS: Overall, 128 patients underwent ISR and 149 underwent APR. The ISR group had earlier clinical stages and shorter distal margins (p < 0.01). The 5-year relapse-free survival rates in patients who underwent ISR/APR were 84.7/74.7% with T1-2 tumors and 51.3/67.6% with T3-4 tumors. In T3-4 tumors, the rate of local recurrence was higher in the ISR group (13.2%) than in the APR group (3.8%). The 5-year relapse-free survival rates in patients who underwent ISR/APR were 89.7/92.3% for stage I cases, 84.4/87.5% for stage II cases, and 39.8/51.8% for stage III cases. Patients with stage III tumors had high rates of distant recurrence in both groups (24.3 vs. 26.3%). CONCLUSION: ISR is a feasible surgical procedure for T1-2 tumors. Patients with stage III tumors should be considered for adjuvant therapy to control distant recurrence regardless of the surgical procedure.

Surgical outcomes of robot-assisted rectal cancer surgery using the da Vinci Surgical System: a multi-center pilot Phase II study.

INTRODUCTION: We conducted a multi-center pilot Phase II study to examine the safety of robotic rectal cancer surgery performed using the da Vinci Surgical System during the introduction period of robotic rectal surgery at two institutes based on surgical outcomes. METHODS: This study was conducted with a prospective, multi-center, single-arm, open-label design to assess the safety and feasibility of robotic surgery for rectal cancer (da Vinci Surgical System). The primary endpoint was the rate of adverse events during and after robotic surgery. The secondary endpoint was the completion rate of robotic surgery. RESULTS: Between April 2014 and July 2016, 50 patients were enrolled in this study. Of these, 10 (20%) had rectosigmoid cancer, 17 (34%) had upper rectal cancer, and 23 (46%) had lower rectal cancer; six underwent high anterior resection, 32 underwent low anterior resection, 11 underwent intersphincteric resection, and one underwent abdominoperineal resection. Pathological stages were Stage 0 in 1 patient, Stage I in 28 patients, Stage II in 7 patients and Stage III in 14 patients. Pathologically complete resection was achieved in all patients. There was no intraoperative organ damage or postoperative mortality. Eight (16%) patients developed complications of all grades, of which 2 (4%) were Grade 3 or higher, including anastomotic leakage (2%) and conversion to open surgery (2%). CONCLUSION: The present study demonstrates the feasibility and safety of robotic rectal cancer surgery, as reflected by low morbidity and low conversion rates, during the introduction period.

Yokukansan for the treatment of preoperative anxiety and postoperative delirium in colorectal cancer patients: a retrospective study.

BACKGROUND: Yokukansan (YKS), a Japanese traditional herbal medicine for neurosis and insomnia, is speculated to be useful for perioperative psychiatric symptoms in cancer patients, but there exists little empirical evidence. This study provides preliminary data about the efficacy, feasibility, and side effects of YKS for the treatment of preoperative anxiety and postoperative delirium in cancer patients. METHODS: We retrospectively reviewed the medical records of colorectal cancer patients who took YKS for preoperative anxiety, evaluating the following: (1) patient characteristics, (2) feasibility of taking YKS, (3) changes in preoperative anxiety based on the Clinical Global Impression (CGI) scale and Edmonton Symptom Assessment System-revised (ESAS-r-anxiety), (4) incidence of postoperative delirium and (5) YKS-related side effects. RESULTS: We reviewed 19 medical records. There was a significant difference between ESAS-r-anxiety scores (P = 0.028) before and after taking YKS, but no difference between CGI scores (P = 0.056). The incidence of postoperative delirium was 5.2% (95% CI = 0.0-14.5). One patient could not complete the course of YKS during the perioperative administration period, but there were no side effects of Grade 2 or worse according to the Common Terminology Criteria for Adverse Events v4. CONCLUSIONS: Cancer patients could safely take YKS before surgery. There was a significant improvement in preoperative anxiety after taking YKS, and the incident rate of postoperative delirium was lower than in previous studies. These results suggest that YKS may be useful for perioperative psychiatric symptoms in cancer patients. Further well-designed studies are needed to substantiate our results.

Multiple rapidly growing desmoid tumors that were difficult to distinguish from recurrence of rectal cancer.

BACKGROUND: Intra-abdominal desmoid tumors are usually slow growing and solitary, but multifocal desmoid tumors develop on rare occasions. Diagnosing desmoid tumors before histological examination of a surgical biopsy is often difficult. In particular, if a patient has a prior history of malignancy, it may be difficult to differentiate between these lesions and disease recurrence or metastasis. CASE PRESENTATION: We present a rare case of multiple rapidly growing intra-abdominal desmoid tumors after surgical trauma, without familial adenomatous polyposis. A 51-year-old male underwent abdominal perineal resection with lateral lymph node dissection after neoadjuvant chemotherapy for lower rectal cancer. Follow-up computed tomography (CT), performed 6 months after primary surgery, showed a 20-mm solitary mass in the pelvic mesentery. Another CT scan, performed 3 months later, revealed that the mass had grown to 35 mm in size and that two new masses had formed. Based on imaging studies and his medical history, it was difficult to distinguish the desmoid tumors from recurrence of rectal cancer. Curative resection was chosen for therapeutic diagnosis. The pathological diagnosis was multiple mesenteric desmoid tumors. CONCLUSIONS: Desmoid tumors should not be excluded as a differential diagnosis for intra-abdominal masses after intra-abdominal surgery, even in cases of rapidly growing multiple masses.

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.

CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice.

UNLABELLED: Sorafenib, a broad tyrosine kinase inhibitor, is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC) but provides limited survival benefits. Recently, immunotherapy has emerged as a promising treatment strategy, but its role remains unclear in HCCs, which are associated with decreased cytotoxic CD8(+) T-lymphocyte infiltration in both murine and human tumors. Moreover, in mouse models after sorafenib treatment intratumoral hypoxia is increased and may fuel evasive resistance. Using orthotopic HCC models, we now show that increased hypoxia after sorafenib treatment promotes immunosuppression, characterized by increased intratumoral expression of the immune checkpoint inhibitor programmed death ligand-1 and accumulation of T-regulatory cells and M2-type macrophages. We also show that the recruitment of immunosuppressive cells is mediated in part by hypoxia-induced up-regulation of stromal cell-derived 1 alpha. Inhibition of the stromal cell-derived 1 alpha receptor (C-X-C receptor type 4 or CXCR4) using AMD3100 prevented the polarization toward an immunosuppressive microenvironment after sorafenib treatment, inhibited tumor growth, reduced lung metastasis, and improved survival. However, the combination of AMD3100 and sorafenib did not significantly change cytotoxic CD8(+) T-lymphocyte infiltration into HCC tumors and did not modify their activation status. In separate experiments, antibody blockade of the programmed death ligand-1 receptor programmed death receptor-1 (PD-1) showed antitumor effects in treatment-naive tumors in orthotopic (grafted and genetically engineered) models of HCC. However, anti-PD-1 antibody treatment had additional antitumor activity only when combined with sorafenib and AMD3100 and not when combined with sorafenib alone. CONCLUSION: Anti-PD-1 treatment can boost antitumor immune responses in HCC models; when used in combination with sorafenib, anti-PD-1 immunotherapy shows efficacy only with concomitant targeting of the hypoxic and immunosuppressive microenvironment with agents such as CXCR4 inhibitors.

Prognostic Impact of Palliative Primary Tumor Resection for Unresectable Stage 4 Colorectal Cancer: Using a Propensity Score Analysis.

BACKGROUND: The benefits that palliative resection of the primary tumor offers patients with unresectable stage 4 colorectal cancer, specifically with regard to overall survival, are controversial, and the issue is complicated by marked differences in patient backgrounds and characteristics. METHODS: The study enrolled 770 consecutive patients with unresectable stage 4 colorectal cancer referred to the divisions of surgery or gastrointestinal oncology at the National Cancer Center Hospital from 1997 to 2013. Of these patients, 429 (56 %) underwent palliative resection of the primary tumor, whereas 341 (44 %) did not. To lessen the effects of confounding factors between the groups, including age, year, severe symptoms, number of organs involved by metastases, primary tumor site, and carcinoembryonic antigen (CEA) value, propensity score analyses were used for regression adjustment, stratification, and matching, with overall survival as the primary end point. RESULTS: The regression adjustment including the propensity score as a linear predictor in the model showed that palliative resection was associated with a significantly improved overall survival (hazard ratio [HR] 0.60; 95 % confidence interval [CI] 0.50-0.71; p < 0.01)]. Stratification analysis showed that in all five strata, palliative resection was associated with better overall survival (HR 0.43-0.73). Similarly, the propensity score-matched cohort (267 matched pairs) yielded an HR of 0.58 (95 % CI 0.48-0.70; p < 0.01). CONCLUSIONS: The findings suggest that palliative resection of the primary tumor may be associated with improved overall survival. Further investigations such as prospective randomized trials are needed to confirm this result.

Peri-operative chemotherapy for resectable colorectal cancer liver metastases.

Approximately one-third of patients survive for 5 years following curative resection of hepatic metastases from colorectal cancer, and the proportion of hepatectomy-related death is as low as 1-2 %. These observations strongly support the view that hepatectomy seems to be the most effective therapy for treating hepatic metastases from colorectal cancer, due to the potential for long-term survival that is not possible with other treatment modalities. However, a hepatectomy alone does not always provide a complete cure. Adjuvant chemo- therapy may reduce the risk of recurrence and improve long-term survival, but administering systemic agents to the patients with resectable hepatic metastases in the clinical practice is not universal. Until recently, there has been little support for requiring peri-operative chemotherapy in patients with resectable hepatic metastases from colorectal cancer. We, there- fore, conducted a phase II/II randomized controlled trial (JCOG0603) to evaluate modified FOLFOX(mFOLFOX) as adjuvant chemotherapy for patients with curatively resected liver metastases from colorectal cancer. We eagerly await the results of this trial.

Recurrent Laryngeal Nerve Paralysis after Esophagectomy: Respiratory Complications and Role of Nerve Reconstruction.

Recurrent laryngeal nerve paralysis (RLNP) after esophagectomy is a common complication and associated with aspiration pneumonia. In this study, we assessed the risk of RLNP and the usefulness of immediate reconstruction of recurrent laryngeal nerve (RLN) to prevent respiratory complications after esophagectomy. Seven hundred and eighty-two consecutive patients underwent an esophagectomy with three-field lymph node dissection, simultaneous gastric conduit reconstruction, and cervical anastomosis. Vocal cord function was observed using a flexible laryngoscope. Reconstruction between RLN and ipsilateral vagus nerve was performed during esophagectomy. RLNP was observed in 229 (29.3%) of the patients after esophagectomy: 198 unilateral and 31 bilateral cases. Of the 198 unilateral RLNP, vocal cord paralysis was observed predominantly on the left side (82.7%). RLNP was significantly associated with postoperative respiratory complications (P < 0.001) requiring a tracheotomy (P < 0.001) and mechanical ventilation (P < 0.001) and was also associated with esophagogastric anastomotic leakage (P = 0.015); consequently, the postoperative hospital stay was longer for patients with RLNP (P < 0.001). A longer operation time (P < 0.001) and advanced age (P = 0.038) were identified as significant independent predictors of RLNP. Resection of the RLN together with metastatic nodes was performed in 29 cases. The patients underwent RLN reconstruction (n = 11) had a significantly shorter postoperative hospital stay than those without RLN reconstruction (n = 18) (P = 0.019). In conclusion, RLNP was related to a poorer postoperative course among patients undergoing an esophagectomy. New surgical technologies are recommended for prevention of RLNP.